- Email: [email protected]
Progesterone for Traumatic Brain Injury: A Meta-Analysis Review of Randomized Controlled Trials
Accepted Manuscript Progesterone for traumatic brain injury: a meta-narrative review of randomized controlled trials Xin-Yu Lu, M.D., Ph.D., Hui Sun, M.B, Qiao-Yu Li, M.D., Ph.D., Pei-Song Lu, M.D., Ph.D PII:
S1878-8750(16)00358-2
DOI:
10.1016/j.wneu.2016.02.110
Reference:
WNEU 3812
To appear in:
World Neurosurgery
Received Date: 31 December 2015 Revised Date:
24 February 2016
Accepted Date: 25 February 2016
Please cite this article as: Lu X-Y, Sun H, Li Q-Y, Lu P-S, Progesterone for traumatic brain injury: a meta-narrative review of randomized controlled trials, World Neurosurgery (2016), doi: 10.1016/ j.wneu.2016.02.110. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Unmarked revised Progesterone for traumatic brain injury: a meta-narrative review of randomized controlled trials
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Xin-Yu Lu1, M.D., Ph.D., Hui Sun2*, M.B., Qiao-Yu Li1, M.D., Ph.D., Pei-Song Lu1, M.D., Ph.D.
Department of Neurosurgery, People’s Hospital Affiliated of Jiangsu University,
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1
Zhenjiang, Jiangsu 212001, China
Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China
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2
*Corresponding author: Hui Sun, Department of Plastic Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China. Tel: +86-511-88915090;
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Email: [email protected]
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RUNNING HEAD: Progesterone in traumatic brain injury
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Abstract Objective: The ability of progesterone treatment to reduce mortality and improve neurological outcome in traumatic brain injury (TBI) is controversial. Thus, the aim
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of this study was to conduct a meta-analysis to determine whether progesterone, compared with placebo or no treatment, influences mortality and neurological outcome in TBI.
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Methods: To identify eligible studies, systematic searches for randomized controlled trials (RCTs) of progesterone treatment in TBI were conducted in PubMed, Web of
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Science, EMBASE, Cochrane library, and clinicaltrials.gov databases. The search yielded 8 studies that were included in the meta-analysis. The data included the study characteristics, patient demographics, baseline characteristics, progesterone treatment protocol, main outcome of mortality, and secondary neurological outcome evaluated using the Glasgow Outcome Scale (GOS).
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Outcome: The eight included studies comprised 2585 patients. The meta-analysis indicated that there was no evidence that progesterone treatment decreased the risk of mortality in TBI patients; the overall risk ratio (RR) was 0.852 (95% confidence
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interval (CI) 0.632-1.144, P=0.284). In the secondary outcome analysis, progesterone had no neuroprotective role in improving neurological outcome; the overall RR was
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1.151 (95% CI 0.0991-1.338, P=0.06). Subgroup analysis according to the injury degree assessed by the Glasgow Coma Scale (GCS) also demonstrated similar results. Conclusion: This study is the largest meta-analysis conducted to date to determine whether progesterone is effective in the treatment of TBI. The findings indicate that progesterone treatment does not decrease mortality or improve neurological outcome in TBI patients. Keywords: traumatic brain injury; progesterone; mortality; outcome; meta-analysis 2
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Introduction Traumatic brain injury (TBI) is a worldwide public health problem and is the major cause of mortality and morbidity in individuals <35 years of age (9). It is estimated
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that 1.7 million individuals suffer TBI each year in the United States, and approximately 25% of these injuries result in long-term disabilities that cause significant familial, social, and economic burdens (1, 17). The clinical treatment of
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TBI has been greatly improved following progress in diagnosis, neuroradiology, and neurosurgical care in recent years. Nevertheless, there are no effective options for the
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treatment of extensive TBI in limiting disability following injury. Consequently, it is of critical importance to develop more effective treatment strategies for these patients. Progesterone, an endogenous steroid hormone, has long been merely regarded as a female reproductive hormone; however, increasing evidence has indicated that progesterone may have a neuroprotective role after TBI. Previous work has indicated
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that progesterone administration after TBI has a neuroprotective role on cerebral edema and secondary neuronal death. Furthermore, progesterone has been demonstrated to attenuate inflammation and apoptosis after TBI (4, 12, 13, 26).
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Several phase II, randomized, double-blind, placebo-controlled clinical trials have also demonstrated that progesterone may improve the neurological outcome of acute
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TBI (6, 11); however, there have been increasing debates regarding the neuroprotective role of progesterone after TBI. Two recently published, multicenter clinical trials demonstrated that there was no benefit of progesterone compared with placebo in the improvement of outcome in patients with acute TBI (7, 8). To comprehensively evaluate the effectiveness of progesterone administration in reducing mortality and morbidity in patients with TBI, we searched global published randomized controlled trials (RCTs) and used the Cochrane systematic review method 3
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(www.cochranelibrary.com) to perform a quantitative analysis of a large sample of patients with TBI, which can ultimately be used to develop an evidence-based
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conclusion regarding the efficacy of progesterone for clinical treatment.
Methods Data sources and search strategy
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To identify eligible studies, systematic searches regarding TBI and progesterone were
performed using the PubMed, Web of Science, EMBASE, Cochrane library, and
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clinicaltrials.gov databases. The following search terms were used: progesterone, progestins, gonadal steroid hormones, estrogens, craniocerebral trauma, Glasgow Outcome Scale (GOS), traumatic brain injury, brain injury, head injury, and head trauma. We also manually searched the reference lists of all relevant studies for any
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additional trials.
Inclusion/exclusion criteria
The inclusion criteria comprised published RCTs of progesterone versus placebo or no
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treatment for the treatment of all severities of TBI, irrespective of dose, by any route of administration and any duration. If an institution or author had published multiple
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studies, only the report with the largest sample size was included in the analysis. If an author had reported outcomes for two or more different follow-up time points, we used the data from the longest follow-up point for each trial. No limits were set regarding the date of publication or the duration of follow-up. We excluded studies that lacked key information or for which the estimated risk ratio (RR) could not be determined either by the available data or after a request was sent to the authors via email and no response was obtained. 4
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Selection of studies and data extraction Two review authors independently examined the titles and abstracts of all references
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and determined whether they were likely eligible for inclusion in the review. The full texts of all relevant studies were obtained, and it was determined whether the studies met the pre-defined inclusion criteria. Data extraction was conducted and
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cross-checked independently by two reviewers. The type of intervention, patient characteristics, follow-up time, and relevant outcome of each study were recorded.
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Disagreements were resolved by discussion or arbitration from Hui Sun. The primary outcome was mortality; the secondary outcome was neurological function, which was evaluated according to the GOS or the expanded Glasgow Outcome Scale (EGOS). The GOS is a scale that classifies TBI patients into groups that provide standardized descriptions of the objective degree of recovery based on different neurological
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outcomes (16). To improve the data analysis, we dichotomized the neurological function into favorable outcomes and unfavorable outcomes. Unfavorable outcomes were defined as death, vegetative state, or severe disability (GOS 1-3 or EGOS 1-4),
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and favorable outcomes were defined as moderate disability and good recovery (GOS
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4-5 or EGOS 5-8).
Risk of bias assessment for the included studies Two independent authors assessed the risk of bias for each trial using the risk of bias assessment tool in Revman Software (2011; Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark), including random sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other sources of bias. We assessed the risk of bias for each domain as 5
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low risk, unclear risk, or high risk. Sensitivity analyses Based on the quality assessment, a sensitivity analysis was carried out, which
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included studies with a low risk of bias to identify the reliability of the meta-analysis results and determine the potential impact of studies with poor qualities on the results.
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Statistical analysis
A meta-analysis was performed for the eight included studies. We calculated the RR
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with its 95% confidence interval (CI) for mortality and favorable outcome (moderate disability, good recovery, GOS 4-5 or EGOS 5-8). A RR <1 indicated that progesterone decreased the risk of mortality or increased the favorable outcome. The overall RR was computed with Comprehensive Meta-Analysis 2.0 Software (Borenstein M, Hedges L, Higgins J, Rothstein H. Comprehensive Meta-analysis
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Version 2, Biostat, Englewood, NJ, USA, 2005). P-values <0.05 were considered statistically significant. The data were synthesized using a fixed effect model, and the heterogeneity was assessed by considering the I2 method with the Chi2 p value. An
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I2>50% and a Chi2 test P<0.1 indicated that there was substantial heterogeneity; a random-effects model was subsequently applied to synthesize the data for each trial. A
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subgroup analysis was also performed that compared the severe TBI subgroup (Glasgow Coma Scale (GCS) ≤8) and moderate TBI subgroup (GCS 9-12).
Results
Study selection Six hundred eighty-three studies were initially identified using the search strategy previously described. After 67 duplicated studies were excluded, 616 studies were 6
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screened. After screening the titles and abstracts, 593 studies were excluded, and 23 studies were retrieved and subjected to detailed evaluation. Based on the inclusion and exclusion criteria, 14 articles were excluded. One publication comprised only a
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conference abstract with insufficient information for inclusion; we attempted to contact the author of the article to obtain the study details but did not receive a
response. The article was therefore excluded (21). Thus, eight studies were included
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in the meta-analysis (Fig. 1).
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Study characteristics
The eight included RCTs comprised 2585 patients (2, 6-8, 11, 14, 18, 19). There were 1324 patients assigned to the progesterone group and 1261 patients assigned to the control group. One of the eight RCTs comprised a conference proceeding for which the full text was not available; however, the abstract supplied the necessary
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information regarding the patients and treatment and was thus included (14). The sample size of the eight RCTs ranged from 59 to 1179 individuals, whereas the follow-up time ranged from 30 days to 6 months. All studies compared the efficacy of
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progesterone to a control, with the exception of one study that divided patients into three groups (placebo, progesterone, and progesterone-vitamin D) to examine the
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effect of vitamin D and progesterone on brain injury treatment after brain trauma. We extracted the data separately regarding the control and progesterone only groups. Seven studies enrolled severe to moderate injury patients (GCS 3-12); one RCT (14) did not present the injury degree, and only indicated that the GCS score of the enrolled patients was >8. The characteristics of the included studies are shown in Table 1. All studies reported mortality at the end of the follow-up with the exception of Abokhabar 2012, which only reported the neurological outcome and duration of 7
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ICU stay. Xiao 2007 reported the mean GOS at three months post-injury for the progesterone and control groups, but the data could not be dichotomized into favorable and unfavorable outcomes; thus, the neurological outcome data were not
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included in the meta-analysis. One study (14) enrolled patients whose GOS scores were >8, two studies (6, 7) enrolled moderate-severe patients with GOS scores 4-12 and reported the outcome according to moderate (9-12) and severe (4-8) TBI groups,
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whereas the remaining five studies accessed the neuroprotective role of progesterone in severe injury patients (GOS 3-8). The characteristics of the included studies are
Risk of bias in included studies
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shown in Table 1.
One study (14) comprised a report of the 25th Annual Congress of the European Society of Intensive Care Medicine, and only the abstract was available. Thus, the
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random sequence generation, allocation concealment, blinding, and incomplete outcome data could not be determined. Four studies (6-8, 11) provided detailed information regarding random sequence generation, allocation concealment, blinding
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method, and no selective reporting. In the remaining studies, various degrees of methodological bias were identified. Two studies (2, 18) reported the random
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sequence generation; however, the allocation concealment and blinding were not described. One study (6) was randomized but not reported as double-blind, and no information was reported regarding withdrawals, drop-outs, attrition between groups, or losses to follow-up. The risk of bias across the eight studies is summarized in Figs. 2 and 3.
Meta-analysis results 8
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Mortality Seven studies reported the mortality rate after progesterone treatment. Heterogeneity clearly existed in these studies and could not be eliminated by subgroup analysis
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according to the injury degree. The heterogeneity among trials was a result of the different injury severities, varying follow-up periods, and difference in the initiation treatment time, as well as the difference in progesterone doses, which resulted in the
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application of a random-effects model during data analysis. The pooled RR of
mortality at the end of the follow-up was 0.852 with a 95% CI of 0.632-1.144. This
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meta-analysis provides no evidence that progesterone decreased the mortality of patients with TBI (Fig. 4). Similarly, a sensitivity analysis also suggested that progesterone decreased the mortality of TBI patients when the low quality studies by Xiao 2007 were deleted (RR=0.855, 95% CI=0.635-1.153). An additional subgroup analysis was performed to assess the efficacy of progesterone in the severe subgroup;
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the pooled RR of mortality at the end of the follow-up was 0.817 with a 95% CI of 0.592-1.127, and the heterogeneity evaluated by I2 was 59.005, P=0.023. For the moderate subgroup, the pooled RR of mortality was 1.301, with a 95% CI of
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0.703-2.410. Thus, there was no substantial evidence of heterogeneity (I2=0, P=0.914) (Figs. 5 and 6). Overall, the findings indicated that there was no significant difference
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in the mortality rates between the progesterone and control groups, and progesterone treatment did not decrease the mortality in the severe or moderate subgroups.
Neurological outcome As previously discussed, Xiao 2007 reported the mean GOS at three months
post-injury, which was significantly different between the progesterone (5.0±1.7) and control (4.0±1.9) groups (P<0.05). The author argued that progesterone can improve 9
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the neurological outcome of TBI. The other seven studies reported the neurological outcome evaluated by the GOS at the end of the 30 days to six months follow-up period. We dichotomized the GOS scores into favorable outcome (moderate disability,
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good recovery; GOS 4-5 or EGOS 5-8) and unfavorable outcome (death, vegetative state, severe disability; GOS 1-3 or EGOS 1-4). The pooled RR of the favorable neurological outcome at the end of the follow-up was 1.151 with a 95% CI of
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0.0991-1.338. The findings indicated that there was no significant difference between the progesterone and control groups (Fig. 7), which was confirmed by the results of
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the sensitivity analysis when the low quality studies by Abokhar 2012 were deleted (RR = 1.101, 95% CI=0.952-1.272). An additional subgroup analysis was also conducted to assess the efficacy of progesterone. In the severe subgroup, the pooled RR of the favorable outcome rate at the end of the follow-up was 1.1084, with a 95% CI of 0.928-1.267, and the heterogeneity evaluated by I2 was 43.427, P=0.116. In the
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moderate subgroup, the pooled RR of the favorable outcome rate was 1.229, with a 95% CI of 0.838-1.802 (Figs. 8 and 9). Overall, the findings indicated that there was no significant difference in the favorable outcome rate between the progesterone and
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control groups, and progesterone treatment could not improve the neurological
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outcome after TBI.
Discussion
To the best of our knowledge, the current study represents the largest meta-analysis to date to determine the efficacy of progesterone in the treatment of TBI. Ma et al. conducted a meta-analysis regarding the efficacy of progesterone in the treatment of TBI (20) and identified a 39% lower mortality rate and 23% more favorable outcome in the patients who received progesterone treatment; however, this previous 10
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meta-analysis only included three small single-center studies. Furthermore, it only focused on moderate-severe TBI patients, whereas the current study included TBI patients with any severity and duration of illness. The current systematic review and
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meta-analysis investigated the association between progesterone treatment and outcome in a large sample of patients with TBI across 8 RCTs. Seven studies reported
the mortality in TBI in progesterone treatment and placebo groups, whereas seven
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studies reported the neurological outcome measured by the GCS after various lengths
of follow up. The results of the meta-analysis demonstrated there was no evidence
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that progesterone has a protective role in TBI patients. Furthermore, the subgroup analysis also indicated that progesterone did not decrease mortality in severe or moderate TBI patients.
Progesterone, an endogenous steroid hormone, is well known for its role in the menstrual cycle. Its neuroprotective effects were identified in an animal TBI model in
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1987 in which pseudo-pregnant animals exhibited less impairment and brain edema after frontal cortex lesions compared with their normal cycling counterparts (3). It was subsequently confirmed that cox-2 and caspase-3 expression in TBI mice treated with
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progesterone was significantly lower than the control group, and TBI rats with progesterone treatment had shorter latencies, more platform crossings, and spent more
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time swimming compared with TBI rats (25). Progesterone has also been demonstrated to reduce cell death, pro-inflammatory cytokines, such as IL-6 and TNF-α, and oxidative stress in rodent models of TBI (5, 22, 28). Furthermore, a phase II proTECT RCT recruited 77 TBI patients to investigate the role of progesterone in TBI and demonstrated that progesterone caused no discernible harm and had a lower 30-day mortality rate compared with the controls (6). A Chinese team reported similar findings that progesterone treatment decreased the mortality rate at a 6-month 11
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follow-up and improved neurological outcome (19). Based on these two studies, two multi-center phase III clinical trials (7, 8) of progesterone for severe TBI were conducted; however, the findings indicated that progesterone had no protective role in
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TBI. Despite the considerable supportive evidence that progesterone exhibited a
protective role in animal TBI models, it is difficult to translate experimental data to
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the clinical context of TBI in human patients. There are several potential reasons for the negative results regarding progesterone treatment. First, there is substantial
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heterogeneity in human TBI in accordance with the nature of the injury (e.g., diffuse, focal), different parenchymal lesion locations, and highly diverse injury mechanisms. However, animal studies elude the complexities linked to heterogeneity in human studies. When one animal TBI model is adopted, the injury mechanism and exposure time are the same. Second, the individual response to human TBI varies substantially
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depending on age and coexisting conditions; thus, it is difficult and impossible to fully replicate the complexities of human TBI in animal trauma models in which the animals used are healthy and young with significant comorbid conditions (10, 23, 27).
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Finally, in a widely cited article in which Ioannidis explained why most published positive research findings are less likely to be true, he argued that the studies
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conducted in the field are smaller; thus, the effect sizes are smaller, and unrecognized bias and low odds of a true relationship exist prior to the start of the research, which may all contribute to these findings (15). Thus, Schwamm (15, 24) suggested that research in this area requires radical changes in the culture of investigation and funding; TBI research should include the creation of collaborative research networks, more rigorous reporting and pooling of preclinical data, coordinated and sequential exploratory phase 2 trials in which standardized outcomes are measured, and phase 3 12
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trials designed to test well-vetted hypotheses. In future TBI trials, more strict inclusion criteria should be adopted to further reduce the impact of comorbid conditions and varying clinical characteristics. Patients should be grouped according
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to age, sex, pupillary reaction, CT findings, comorbidities, biomarkers, or genotypes. In addition, to more properly assess drug efficacy, the pharmacokinetics, optimal dosage, and time suitability of different drugs should be considered together.
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Several factors may explain the significant heterogeneity in our study. With the exception of two multi-center phase III studies, six studies comprised small single
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center studies and one study was a conference article with limited data available. Second, there were different follow up periods that ranged from 30 days to six months. Third, the dosage and treatment routine of progesterone varied across studies. Fourth, the included TBI patient conditions varied across studies; one study enrolled TBI patients with GCS scores >8, five studies included severe TBI patients (GCS <8), and
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two studies included moderate-severe TBI patients (GCS <12). Although subgroup analyses were performed, heterogeneity still existed; thus, a random-effects model was employed, but there are no differences between the random-model and fixed
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model.
A major strength of our study is the systematic and standardized methodology
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employed to perform a systematic review and meta-analysis. Moreover, the thorough and methodical research design included various databases without limitations regarding publication date or language, and a comprehensive analytical method was implemented. Nevertheless, the number of included studies in the systematic review was limited, and the quality of the included studies was variable according to the quality assessment, especially the studies by Xiao 2007 and Abokhar 2012, which represent key limitations of this systematic review. Furthermore, the heterogeneity 13
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among the studies was obvious for all outcomes of interest. Finally, we analyzed the GOS scores to determine neurological function outcome in this meta-analysis; however, the GOS may not completely reflect the patients’ neurological function
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condition. It is critical for future studies to identify sensitive parameters that may be used to assess the outcome of TBI. Moreover, modified functional independence measure scores and cognitive dysfunction assessment may also be helpful to include
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to provide a more comprehensive clinical picture.
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Conclusions
This study comprises the largest systematic review and meta-analysis of progesterone treatment in TBI to date, which included eight studies and 2585 patients. The current clinical evidence indicates that progesterone treatment does not decrease mortality or
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improve neurological function outcome in patients with acute TBI.
Disclosure
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in thispaper.
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Author contributions to the study and manuscript preparation include the following. Acquisition of data: XinYu Lu, Qiaoyu Li. Analysis and interpretation of data: XinYu Lu, Pei-Song Lu. Drafting the article: XinYu Lu, Hui Sun. Critically
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revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Sun. Study supervision: Sun.
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Figure legends Fig. 1. Flow diagram of the search for relevant references. Of the 683 studies initially identified from our electronic search, 8 studies met the inclusion criteria and were
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included in the meta-analysis.
Fig. 2. Risk of bias summary: review of the authors’ judgments regarding each risk of bias item for each included study.
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Fig. 3. Risk of bias graph: review of the authors’ judgments regarding each risk of
bias item presented as percentages across all included studies. Four studies are
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included in this review.
Fig. 4. Progesterone versus placebo for the mortality rates in all TBI patients at the end of the follow-up period.
Fig. 5. Progesterone versus placebo for the mortality rates in severe TBI patients at the end of the follow-up period.
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Fig. 6. Progesterone versus placebo for the mortality rates in moderate TBI patients at the end of the follow-up period.
Fig. 7. Progesterone versus placebo for the favorable neurological outcome rates in all
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TBI patients at the end of the follow-up period. Fig. 8. Progesterone versus placebo for the favorable neurological outcome rates in
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severe TBI patients at the end of the follow-up period. Fig. 9. Progesterone versus placebo for the favorable neurological outcome rates in moderate TBI patients at the end of the follow-up period.
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Follow-up 30 days
Matching placebo
GCS, GOS, mortality
3 months
1 mg/kg progesterone via nasogastric tube every 12 h for five days
No placebo
GOS, mortality
3 months
five days of
Matching
GOS at 3 and 6 months,
6 months
Skolnick 2014
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Shakeri 2013
Outcome Glasgow Outcome Scale (GOS), duration of ICU stay
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N=40, males=28, females=12 GCS<8 for all patients Inclusion criteria: brain trauma and diffuse axonal injury within 8 h of injury and GCS <8 Exclusion criteria: lack of consent by patient’s legal representative N=76 male adults (>18 years old) GCS ≤8 for all patients Inclusion criteria: adult male patients with head trauma and diagnosis of diffuse axonal injury victims within 8 h of injury and GCS <8. Exclusion criteria: hormonal drug use 30 days prior to enrollment, male patients <18 years old N=1179 adults (>18 years old),
Comparison Matching placebo
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Aminmansour 2012
Intervention 1 mg/kg progesterone via intramuscular injection within 8 h of admission and then every 12 h for five consecutive days 1 mg/kg progesterone via intramuscular injection every 12 h for five days
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Patients N=100 Inclusion criteria: Glasgow Coma Scale (GCS) >8 Exclusion criteria: not available
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Study Abokhabar 2012
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mortality at 1 and 6 months, intracranial pressure, cerebral perfusion pressure, and therapeutic intensity levels, CT scan on day 6, and the 36-Item Short-Form Health Survey (SF-36) scale at 3 and 6 months
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intravenous placebo treatment; First h: 0.71 mg/kg/h; Next 119 h: 0.50 mg/kg/h
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three days of intravenous progesterone treatment; First h: 0.71 mg/kg at 14 mL/h; Next 11 h: 10 ml/h to deliver 0.5 mg/kg/h; Next five additional 12 h
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males=927, females=252 GCS ≤8 for all patients Inclusion criteria: adult blunt trauma victims within 8 h of injury and GCS≤8 Exclusion criteria: GCS=3 and bilaterally fixed and dilated pupils, a life expectancy of <24 h, prolonged or uncorrectable hypoxemia, hypotension, spinal cord injury, pregnancy, only an isolated epidural hematoma, or coma that was suspected to be primarily the result of other causes N=100 adults (>18 years old), males=71, females=29, GCS 4-8 n=72, GCS >9 n=28 Inclusion criteria: adult blunt trauma victims within 11 h of injury and GCS=4-12 Exclusion criteria: blood alcohol concentration >250 mg/dl, penetrating brain injury, <18 years of age, GCS <4 or >12, indeterminate time of injury, pregnancy, a family-reported history of active cancer, acute stroke, a
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Mortality, GOS, Disability 30 days Rating Score (DRS), duration of coma, duration of post-traumatic amnesia, intracranial pressure, temperature, blood pressure during the first 3 days of treatment and for 1 day afterwards, adverse events
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GOS, mortality, DRS score, adverse events
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of maintenance infusions: standard rate of 10 ml/h four days of intravenous progesterone treatment; First h: 14.3 ml/h; Next 71 h: 10 ml/h; Last 24 h: 2.5 ml/h every 8 h
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Wright 2014
family-reported history of older stroke with residual motor deficits, or acute or chronic spinal cord injury with neurological deficits N=882 adults (>18 years old), males=650, females=232 GCS 4-8 n=628, GCS >9 n=254 Inclusion criteria: adult blunt trauma victims within 4 h of injury and GCS=4-12 Exclusion criteria: bilateral, dilated, unresponsive pupils; cardio-pulmonary resuscitation, hypoxemia, hypotension, spinal cord injury, epilepticus status, pregnancy, prisoner or ward of the state, severe intoxication (ethanol level, >249 mg/dl), known history of reproductive cancer, allergy to progesterone or a fat-emulsion vehicle, a blood-clotting disorder, active myocardial infarction, ischemic stroke, pulmonary embolism, or deep-vein thrombosis
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6 months
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Table 1. Characteristics of the studies included in the meta-analysis.
Mortality, intracranial pressure, GCS score, complications during treatment, verbal and motor function at 10 days and 3 months after injury
3 months
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Matching placebo
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80 mf progesterone via intramuscular injection when admitted followed by one dose every 12 h for five consecutive days five days of N=159 adults (>18 years old), progesterone via males=115, females=44 intramuscular GCS≤8 for all patients injection; Inclusion criteria: adult blunt trauma First dose at 1.0 victims within 8 h of injury and GCS mg/kg via <8 intramuscular Exclusion criteria: previous use of injection investigational drugs 30 days prior to enrollment, severe anoxic intracerebral followed by one dose every 12 h damage or brain death, clinical for five condition was unstable (partial consecutive days pressure of oxygen <60 mmHg, a systolic blood pressure <90 mmHg, or both), pregnancy, lactation, acute or chronic spinal cord injury
N=56 adults Inclusion criteria: adult blunt trauma victims within 24 h of injury and GCS=5-8 Exclusion criteria: previous use of investigational drugs, pregnancy, lactation, severe chronic disease
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Xiao 2007
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GOS, modified Functional Independence Measure (FIM) score, mortality
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0 additional records identified through other source
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683 articles screened
reduplicated 67 articles excluded
616 articles screened
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non-relevant title/abstract
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23 articles screened
14 of full text articles excluded because violation of inclusion criteria
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8 studies included in the systematic review and meta-analysis
1 article excluded because of no data availeble
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Highlight 1) Progesterone treatment did not decrease the mortality after TBI.
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2) Progesterone treatment could not improve the neurological outcome after TBI.
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Conflict of interest statement: declare
with
other people
work,
there
that
is
we
have
no
financial
or organizations that
no professional
can
and
personal
inappropriately
relationships influence
our
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or other personal interest of any nature or
kind in any product, service and/or company that could be construed as influencing
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the position presented in, or the review of, the manuscript entitled.
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Abbreviations: traumatic brain injury
RCTs
randomized controlled trials
GOS
Glasgow Outcome Scale
RR
risk ratio
GCS
Glasgow Coma Scale
EGOS
expanded Glasgow Outcome Scale
CI
confidence interval
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TBI
S1878-8750(16)00358-2
DOI:
10.1016/j.wneu.2016.02.110
Reference:
WNEU 3812
To appear in:
World Neurosurgery
Received Date: 31 December 2015 Revised Date:
24 February 2016
Accepted Date: 25 February 2016
Please cite this article as: Lu X-Y, Sun H, Li Q-Y, Lu P-S, Progesterone for traumatic brain injury: a meta-narrative review of randomized controlled trials, World Neurosurgery (2016), doi: 10.1016/ j.wneu.2016.02.110. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Unmarked revised Progesterone for traumatic brain injury: a meta-narrative review of randomized controlled trials
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Xin-Yu Lu1, M.D., Ph.D., Hui Sun2*, M.B., Qiao-Yu Li1, M.D., Ph.D., Pei-Song Lu1, M.D., Ph.D.
Department of Neurosurgery, People’s Hospital Affiliated of Jiangsu University,
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1
Zhenjiang, Jiangsu 212001, China
Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China
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*Corresponding author: Hui Sun, Department of Plastic Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China. Tel: +86-511-88915090;
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Email: [email protected]
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RUNNING HEAD: Progesterone in traumatic brain injury
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Abstract Objective: The ability of progesterone treatment to reduce mortality and improve neurological outcome in traumatic brain injury (TBI) is controversial. Thus, the aim
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of this study was to conduct a meta-analysis to determine whether progesterone, compared with placebo or no treatment, influences mortality and neurological outcome in TBI.
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Methods: To identify eligible studies, systematic searches for randomized controlled trials (RCTs) of progesterone treatment in TBI were conducted in PubMed, Web of
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Science, EMBASE, Cochrane library, and clinicaltrials.gov databases. The search yielded 8 studies that were included in the meta-analysis. The data included the study characteristics, patient demographics, baseline characteristics, progesterone treatment protocol, main outcome of mortality, and secondary neurological outcome evaluated using the Glasgow Outcome Scale (GOS).
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Outcome: The eight included studies comprised 2585 patients. The meta-analysis indicated that there was no evidence that progesterone treatment decreased the risk of mortality in TBI patients; the overall risk ratio (RR) was 0.852 (95% confidence
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interval (CI) 0.632-1.144, P=0.284). In the secondary outcome analysis, progesterone had no neuroprotective role in improving neurological outcome; the overall RR was
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1.151 (95% CI 0.0991-1.338, P=0.06). Subgroup analysis according to the injury degree assessed by the Glasgow Coma Scale (GCS) also demonstrated similar results. Conclusion: This study is the largest meta-analysis conducted to date to determine whether progesterone is effective in the treatment of TBI. The findings indicate that progesterone treatment does not decrease mortality or improve neurological outcome in TBI patients. Keywords: traumatic brain injury; progesterone; mortality; outcome; meta-analysis 2
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Introduction Traumatic brain injury (TBI) is a worldwide public health problem and is the major cause of mortality and morbidity in individuals <35 years of age (9). It is estimated
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that 1.7 million individuals suffer TBI each year in the United States, and approximately 25% of these injuries result in long-term disabilities that cause significant familial, social, and economic burdens (1, 17). The clinical treatment of
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TBI has been greatly improved following progress in diagnosis, neuroradiology, and neurosurgical care in recent years. Nevertheless, there are no effective options for the
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treatment of extensive TBI in limiting disability following injury. Consequently, it is of critical importance to develop more effective treatment strategies for these patients. Progesterone, an endogenous steroid hormone, has long been merely regarded as a female reproductive hormone; however, increasing evidence has indicated that progesterone may have a neuroprotective role after TBI. Previous work has indicated
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that progesterone administration after TBI has a neuroprotective role on cerebral edema and secondary neuronal death. Furthermore, progesterone has been demonstrated to attenuate inflammation and apoptosis after TBI (4, 12, 13, 26).
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Several phase II, randomized, double-blind, placebo-controlled clinical trials have also demonstrated that progesterone may improve the neurological outcome of acute
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TBI (6, 11); however, there have been increasing debates regarding the neuroprotective role of progesterone after TBI. Two recently published, multicenter clinical trials demonstrated that there was no benefit of progesterone compared with placebo in the improvement of outcome in patients with acute TBI (7, 8). To comprehensively evaluate the effectiveness of progesterone administration in reducing mortality and morbidity in patients with TBI, we searched global published randomized controlled trials (RCTs) and used the Cochrane systematic review method 3
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(www.cochranelibrary.com) to perform a quantitative analysis of a large sample of patients with TBI, which can ultimately be used to develop an evidence-based
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conclusion regarding the efficacy of progesterone for clinical treatment.
Methods Data sources and search strategy
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To identify eligible studies, systematic searches regarding TBI and progesterone were
performed using the PubMed, Web of Science, EMBASE, Cochrane library, and
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clinicaltrials.gov databases. The following search terms were used: progesterone, progestins, gonadal steroid hormones, estrogens, craniocerebral trauma, Glasgow Outcome Scale (GOS), traumatic brain injury, brain injury, head injury, and head trauma. We also manually searched the reference lists of all relevant studies for any
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additional trials.
Inclusion/exclusion criteria
The inclusion criteria comprised published RCTs of progesterone versus placebo or no
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treatment for the treatment of all severities of TBI, irrespective of dose, by any route of administration and any duration. If an institution or author had published multiple
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studies, only the report with the largest sample size was included in the analysis. If an author had reported outcomes for two or more different follow-up time points, we used the data from the longest follow-up point for each trial. No limits were set regarding the date of publication or the duration of follow-up. We excluded studies that lacked key information or for which the estimated risk ratio (RR) could not be determined either by the available data or after a request was sent to the authors via email and no response was obtained. 4
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Selection of studies and data extraction Two review authors independently examined the titles and abstracts of all references
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and determined whether they were likely eligible for inclusion in the review. The full texts of all relevant studies were obtained, and it was determined whether the studies met the pre-defined inclusion criteria. Data extraction was conducted and
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cross-checked independently by two reviewers. The type of intervention, patient characteristics, follow-up time, and relevant outcome of each study were recorded.
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Disagreements were resolved by discussion or arbitration from Hui Sun. The primary outcome was mortality; the secondary outcome was neurological function, which was evaluated according to the GOS or the expanded Glasgow Outcome Scale (EGOS). The GOS is a scale that classifies TBI patients into groups that provide standardized descriptions of the objective degree of recovery based on different neurological
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outcomes (16). To improve the data analysis, we dichotomized the neurological function into favorable outcomes and unfavorable outcomes. Unfavorable outcomes were defined as death, vegetative state, or severe disability (GOS 1-3 or EGOS 1-4),
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and favorable outcomes were defined as moderate disability and good recovery (GOS
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4-5 or EGOS 5-8).
Risk of bias assessment for the included studies Two independent authors assessed the risk of bias for each trial using the risk of bias assessment tool in Revman Software (2011; Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark), including random sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other sources of bias. We assessed the risk of bias for each domain as 5
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low risk, unclear risk, or high risk. Sensitivity analyses Based on the quality assessment, a sensitivity analysis was carried out, which
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included studies with a low risk of bias to identify the reliability of the meta-analysis results and determine the potential impact of studies with poor qualities on the results.
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Statistical analysis
A meta-analysis was performed for the eight included studies. We calculated the RR
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with its 95% confidence interval (CI) for mortality and favorable outcome (moderate disability, good recovery, GOS 4-5 or EGOS 5-8). A RR <1 indicated that progesterone decreased the risk of mortality or increased the favorable outcome. The overall RR was computed with Comprehensive Meta-Analysis 2.0 Software (Borenstein M, Hedges L, Higgins J, Rothstein H. Comprehensive Meta-analysis
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Version 2, Biostat, Englewood, NJ, USA, 2005). P-values <0.05 were considered statistically significant. The data were synthesized using a fixed effect model, and the heterogeneity was assessed by considering the I2 method with the Chi2 p value. An
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I2>50% and a Chi2 test P<0.1 indicated that there was substantial heterogeneity; a random-effects model was subsequently applied to synthesize the data for each trial. A
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subgroup analysis was also performed that compared the severe TBI subgroup (Glasgow Coma Scale (GCS) ≤8) and moderate TBI subgroup (GCS 9-12).
Results
Study selection Six hundred eighty-three studies were initially identified using the search strategy previously described. After 67 duplicated studies were excluded, 616 studies were 6
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screened. After screening the titles and abstracts, 593 studies were excluded, and 23 studies were retrieved and subjected to detailed evaluation. Based on the inclusion and exclusion criteria, 14 articles were excluded. One publication comprised only a
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conference abstract with insufficient information for inclusion; we attempted to contact the author of the article to obtain the study details but did not receive a
response. The article was therefore excluded (21). Thus, eight studies were included
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in the meta-analysis (Fig. 1).
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Study characteristics
The eight included RCTs comprised 2585 patients (2, 6-8, 11, 14, 18, 19). There were 1324 patients assigned to the progesterone group and 1261 patients assigned to the control group. One of the eight RCTs comprised a conference proceeding for which the full text was not available; however, the abstract supplied the necessary
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information regarding the patients and treatment and was thus included (14). The sample size of the eight RCTs ranged from 59 to 1179 individuals, whereas the follow-up time ranged from 30 days to 6 months. All studies compared the efficacy of
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progesterone to a control, with the exception of one study that divided patients into three groups (placebo, progesterone, and progesterone-vitamin D) to examine the
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effect of vitamin D and progesterone on brain injury treatment after brain trauma. We extracted the data separately regarding the control and progesterone only groups. Seven studies enrolled severe to moderate injury patients (GCS 3-12); one RCT (14) did not present the injury degree, and only indicated that the GCS score of the enrolled patients was >8. The characteristics of the included studies are shown in Table 1. All studies reported mortality at the end of the follow-up with the exception of Abokhabar 2012, which only reported the neurological outcome and duration of 7
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ICU stay. Xiao 2007 reported the mean GOS at three months post-injury for the progesterone and control groups, but the data could not be dichotomized into favorable and unfavorable outcomes; thus, the neurological outcome data were not
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included in the meta-analysis. One study (14) enrolled patients whose GOS scores were >8, two studies (6, 7) enrolled moderate-severe patients with GOS scores 4-12 and reported the outcome according to moderate (9-12) and severe (4-8) TBI groups,
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whereas the remaining five studies accessed the neuroprotective role of progesterone in severe injury patients (GOS 3-8). The characteristics of the included studies are
Risk of bias in included studies
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shown in Table 1.
One study (14) comprised a report of the 25th Annual Congress of the European Society of Intensive Care Medicine, and only the abstract was available. Thus, the
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random sequence generation, allocation concealment, blinding, and incomplete outcome data could not be determined. Four studies (6-8, 11) provided detailed information regarding random sequence generation, allocation concealment, blinding
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method, and no selective reporting. In the remaining studies, various degrees of methodological bias were identified. Two studies (2, 18) reported the random
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sequence generation; however, the allocation concealment and blinding were not described. One study (6) was randomized but not reported as double-blind, and no information was reported regarding withdrawals, drop-outs, attrition between groups, or losses to follow-up. The risk of bias across the eight studies is summarized in Figs. 2 and 3.
Meta-analysis results 8
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Mortality Seven studies reported the mortality rate after progesterone treatment. Heterogeneity clearly existed in these studies and could not be eliminated by subgroup analysis
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according to the injury degree. The heterogeneity among trials was a result of the different injury severities, varying follow-up periods, and difference in the initiation treatment time, as well as the difference in progesterone doses, which resulted in the
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application of a random-effects model during data analysis. The pooled RR of
mortality at the end of the follow-up was 0.852 with a 95% CI of 0.632-1.144. This
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meta-analysis provides no evidence that progesterone decreased the mortality of patients with TBI (Fig. 4). Similarly, a sensitivity analysis also suggested that progesterone decreased the mortality of TBI patients when the low quality studies by Xiao 2007 were deleted (RR=0.855, 95% CI=0.635-1.153). An additional subgroup analysis was performed to assess the efficacy of progesterone in the severe subgroup;
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the pooled RR of mortality at the end of the follow-up was 0.817 with a 95% CI of 0.592-1.127, and the heterogeneity evaluated by I2 was 59.005, P=0.023. For the moderate subgroup, the pooled RR of mortality was 1.301, with a 95% CI of
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0.703-2.410. Thus, there was no substantial evidence of heterogeneity (I2=0, P=0.914) (Figs. 5 and 6). Overall, the findings indicated that there was no significant difference
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in the mortality rates between the progesterone and control groups, and progesterone treatment did not decrease the mortality in the severe or moderate subgroups.
Neurological outcome As previously discussed, Xiao 2007 reported the mean GOS at three months
post-injury, which was significantly different between the progesterone (5.0±1.7) and control (4.0±1.9) groups (P<0.05). The author argued that progesterone can improve 9
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the neurological outcome of TBI. The other seven studies reported the neurological outcome evaluated by the GOS at the end of the 30 days to six months follow-up period. We dichotomized the GOS scores into favorable outcome (moderate disability,
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good recovery; GOS 4-5 or EGOS 5-8) and unfavorable outcome (death, vegetative state, severe disability; GOS 1-3 or EGOS 1-4). The pooled RR of the favorable neurological outcome at the end of the follow-up was 1.151 with a 95% CI of
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0.0991-1.338. The findings indicated that there was no significant difference between the progesterone and control groups (Fig. 7), which was confirmed by the results of
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the sensitivity analysis when the low quality studies by Abokhar 2012 were deleted (RR = 1.101, 95% CI=0.952-1.272). An additional subgroup analysis was also conducted to assess the efficacy of progesterone. In the severe subgroup, the pooled RR of the favorable outcome rate at the end of the follow-up was 1.1084, with a 95% CI of 0.928-1.267, and the heterogeneity evaluated by I2 was 43.427, P=0.116. In the
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moderate subgroup, the pooled RR of the favorable outcome rate was 1.229, with a 95% CI of 0.838-1.802 (Figs. 8 and 9). Overall, the findings indicated that there was no significant difference in the favorable outcome rate between the progesterone and
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Discussion
To the best of our knowledge, the current study represents the largest meta-analysis to date to determine the efficacy of progesterone in the treatment of TBI. Ma et al. conducted a meta-analysis regarding the efficacy of progesterone in the treatment of TBI (20) and identified a 39% lower mortality rate and 23% more favorable outcome in the patients who received progesterone treatment; however, this previous 10
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meta-analysis only included three small single-center studies. Furthermore, it only focused on moderate-severe TBI patients, whereas the current study included TBI patients with any severity and duration of illness. The current systematic review and
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meta-analysis investigated the association between progesterone treatment and outcome in a large sample of patients with TBI across 8 RCTs. Seven studies reported
the mortality in TBI in progesterone treatment and placebo groups, whereas seven
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studies reported the neurological outcome measured by the GCS after various lengths
of follow up. The results of the meta-analysis demonstrated there was no evidence
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that progesterone has a protective role in TBI patients. Furthermore, the subgroup analysis also indicated that progesterone did not decrease mortality in severe or moderate TBI patients.
Progesterone, an endogenous steroid hormone, is well known for its role in the menstrual cycle. Its neuroprotective effects were identified in an animal TBI model in
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1987 in which pseudo-pregnant animals exhibited less impairment and brain edema after frontal cortex lesions compared with their normal cycling counterparts (3). It was subsequently confirmed that cox-2 and caspase-3 expression in TBI mice treated with
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progesterone was significantly lower than the control group, and TBI rats with progesterone treatment had shorter latencies, more platform crossings, and spent more
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time swimming compared with TBI rats (25). Progesterone has also been demonstrated to reduce cell death, pro-inflammatory cytokines, such as IL-6 and TNF-α, and oxidative stress in rodent models of TBI (5, 22, 28). Furthermore, a phase II proTECT RCT recruited 77 TBI patients to investigate the role of progesterone in TBI and demonstrated that progesterone caused no discernible harm and had a lower 30-day mortality rate compared with the controls (6). A Chinese team reported similar findings that progesterone treatment decreased the mortality rate at a 6-month 11
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follow-up and improved neurological outcome (19). Based on these two studies, two multi-center phase III clinical trials (7, 8) of progesterone for severe TBI were conducted; however, the findings indicated that progesterone had no protective role in
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TBI. Despite the considerable supportive evidence that progesterone exhibited a
protective role in animal TBI models, it is difficult to translate experimental data to
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the clinical context of TBI in human patients. There are several potential reasons for the negative results regarding progesterone treatment. First, there is substantial
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heterogeneity in human TBI in accordance with the nature of the injury (e.g., diffuse, focal), different parenchymal lesion locations, and highly diverse injury mechanisms. However, animal studies elude the complexities linked to heterogeneity in human studies. When one animal TBI model is adopted, the injury mechanism and exposure time are the same. Second, the individual response to human TBI varies substantially
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depending on age and coexisting conditions; thus, it is difficult and impossible to fully replicate the complexities of human TBI in animal trauma models in which the animals used are healthy and young with significant comorbid conditions (10, 23, 27).
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Finally, in a widely cited article in which Ioannidis explained why most published positive research findings are less likely to be true, he argued that the studies
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conducted in the field are smaller; thus, the effect sizes are smaller, and unrecognized bias and low odds of a true relationship exist prior to the start of the research, which may all contribute to these findings (15). Thus, Schwamm (15, 24) suggested that research in this area requires radical changes in the culture of investigation and funding; TBI research should include the creation of collaborative research networks, more rigorous reporting and pooling of preclinical data, coordinated and sequential exploratory phase 2 trials in which standardized outcomes are measured, and phase 3 12
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trials designed to test well-vetted hypotheses. In future TBI trials, more strict inclusion criteria should be adopted to further reduce the impact of comorbid conditions and varying clinical characteristics. Patients should be grouped according
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to age, sex, pupillary reaction, CT findings, comorbidities, biomarkers, or genotypes. In addition, to more properly assess drug efficacy, the pharmacokinetics, optimal dosage, and time suitability of different drugs should be considered together.
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Several factors may explain the significant heterogeneity in our study. With the exception of two multi-center phase III studies, six studies comprised small single
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center studies and one study was a conference article with limited data available. Second, there were different follow up periods that ranged from 30 days to six months. Third, the dosage and treatment routine of progesterone varied across studies. Fourth, the included TBI patient conditions varied across studies; one study enrolled TBI patients with GCS scores >8, five studies included severe TBI patients (GCS <8), and
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two studies included moderate-severe TBI patients (GCS <12). Although subgroup analyses were performed, heterogeneity still existed; thus, a random-effects model was employed, but there are no differences between the random-model and fixed
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A major strength of our study is the systematic and standardized methodology
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employed to perform a systematic review and meta-analysis. Moreover, the thorough and methodical research design included various databases without limitations regarding publication date or language, and a comprehensive analytical method was implemented. Nevertheless, the number of included studies in the systematic review was limited, and the quality of the included studies was variable according to the quality assessment, especially the studies by Xiao 2007 and Abokhar 2012, which represent key limitations of this systematic review. Furthermore, the heterogeneity 13
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among the studies was obvious for all outcomes of interest. Finally, we analyzed the GOS scores to determine neurological function outcome in this meta-analysis; however, the GOS may not completely reflect the patients’ neurological function
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condition. It is critical for future studies to identify sensitive parameters that may be used to assess the outcome of TBI. Moreover, modified functional independence measure scores and cognitive dysfunction assessment may also be helpful to include
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Conclusions
This study comprises the largest systematic review and meta-analysis of progesterone treatment in TBI to date, which included eight studies and 2585 patients. The current clinical evidence indicates that progesterone treatment does not decrease mortality or
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improve neurological function outcome in patients with acute TBI.
Disclosure
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in thispaper.
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Author contributions to the study and manuscript preparation include the following. Acquisition of data: XinYu Lu, Qiaoyu Li. Analysis and interpretation of data: XinYu Lu, Pei-Song Lu. Drafting the article: XinYu Lu, Hui Sun. Critically
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revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Sun. Study supervision: Sun.
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15. Ioannidis JP: Why most published research findings are false. PLOS MED. 2:e124, 2005. 16. Jennett B, Bond M: Assessment of outcome after severe brain damage. LANCET. 1:480-484, 1975. 17. Langlois JA, Rutland-Brown W, Wald MM: The epidemiology and impact of traumatic brain injury: a brief overview. J Head Trauma Rehabil. 21:375-378, 2006.
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Figure legends Fig. 1. Flow diagram of the search for relevant references. Of the 683 studies initially identified from our electronic search, 8 studies met the inclusion criteria and were
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included in the meta-analysis.
Fig. 2. Risk of bias summary: review of the authors’ judgments regarding each risk of bias item for each included study.
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Fig. 3. Risk of bias graph: review of the authors’ judgments regarding each risk of
bias item presented as percentages across all included studies. Four studies are
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included in this review.
Fig. 4. Progesterone versus placebo for the mortality rates in all TBI patients at the end of the follow-up period.
Fig. 5. Progesterone versus placebo for the mortality rates in severe TBI patients at the end of the follow-up period.
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Fig. 6. Progesterone versus placebo for the mortality rates in moderate TBI patients at the end of the follow-up period.
Fig. 7. Progesterone versus placebo for the favorable neurological outcome rates in all
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TBI patients at the end of the follow-up period. Fig. 8. Progesterone versus placebo for the favorable neurological outcome rates in
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severe TBI patients at the end of the follow-up period. Fig. 9. Progesterone versus placebo for the favorable neurological outcome rates in moderate TBI patients at the end of the follow-up period.
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Follow-up 30 days
Matching placebo
GCS, GOS, mortality
3 months
1 mg/kg progesterone via nasogastric tube every 12 h for five days
No placebo
GOS, mortality
3 months
five days of
Matching
GOS at 3 and 6 months,
6 months
Skolnick 2014
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Outcome Glasgow Outcome Scale (GOS), duration of ICU stay
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N=40, males=28, females=12 GCS<8 for all patients Inclusion criteria: brain trauma and diffuse axonal injury within 8 h of injury and GCS <8 Exclusion criteria: lack of consent by patient’s legal representative N=76 male adults (>18 years old) GCS ≤8 for all patients Inclusion criteria: adult male patients with head trauma and diagnosis of diffuse axonal injury victims within 8 h of injury and GCS <8. Exclusion criteria: hormonal drug use 30 days prior to enrollment, male patients <18 years old N=1179 adults (>18 years old),
Comparison Matching placebo
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Aminmansour 2012
Intervention 1 mg/kg progesterone via intramuscular injection within 8 h of admission and then every 12 h for five consecutive days 1 mg/kg progesterone via intramuscular injection every 12 h for five days
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Patients N=100 Inclusion criteria: Glasgow Coma Scale (GCS) >8 Exclusion criteria: not available
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Study Abokhabar 2012
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mortality at 1 and 6 months, intracranial pressure, cerebral perfusion pressure, and therapeutic intensity levels, CT scan on day 6, and the 36-Item Short-Form Health Survey (SF-36) scale at 3 and 6 months
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intravenous placebo treatment; First h: 0.71 mg/kg/h; Next 119 h: 0.50 mg/kg/h
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three days of intravenous progesterone treatment; First h: 0.71 mg/kg at 14 mL/h; Next 11 h: 10 ml/h to deliver 0.5 mg/kg/h; Next five additional 12 h
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males=927, females=252 GCS ≤8 for all patients Inclusion criteria: adult blunt trauma victims within 8 h of injury and GCS≤8 Exclusion criteria: GCS=3 and bilaterally fixed and dilated pupils, a life expectancy of <24 h, prolonged or uncorrectable hypoxemia, hypotension, spinal cord injury, pregnancy, only an isolated epidural hematoma, or coma that was suspected to be primarily the result of other causes N=100 adults (>18 years old), males=71, females=29, GCS 4-8 n=72, GCS >9 n=28 Inclusion criteria: adult blunt trauma victims within 11 h of injury and GCS=4-12 Exclusion criteria: blood alcohol concentration >250 mg/dl, penetrating brain injury, <18 years of age, GCS <4 or >12, indeterminate time of injury, pregnancy, a family-reported history of active cancer, acute stroke, a
Matching placebo
Mortality, GOS, Disability 30 days Rating Score (DRS), duration of coma, duration of post-traumatic amnesia, intracranial pressure, temperature, blood pressure during the first 3 days of treatment and for 1 day afterwards, adverse events
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GOS, mortality, DRS score, adverse events
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Matching Placebo
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of maintenance infusions: standard rate of 10 ml/h four days of intravenous progesterone treatment; First h: 14.3 ml/h; Next 71 h: 10 ml/h; Last 24 h: 2.5 ml/h every 8 h
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family-reported history of older stroke with residual motor deficits, or acute or chronic spinal cord injury with neurological deficits N=882 adults (>18 years old), males=650, females=232 GCS 4-8 n=628, GCS >9 n=254 Inclusion criteria: adult blunt trauma victims within 4 h of injury and GCS=4-12 Exclusion criteria: bilateral, dilated, unresponsive pupils; cardio-pulmonary resuscitation, hypoxemia, hypotension, spinal cord injury, epilepticus status, pregnancy, prisoner or ward of the state, severe intoxication (ethanol level, >249 mg/dl), known history of reproductive cancer, allergy to progesterone or a fat-emulsion vehicle, a blood-clotting disorder, active myocardial infarction, ischemic stroke, pulmonary embolism, or deep-vein thrombosis
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Table 1. Characteristics of the studies included in the meta-analysis.
Mortality, intracranial pressure, GCS score, complications during treatment, verbal and motor function at 10 days and 3 months after injury
3 months
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Matching placebo
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80 mf progesterone via intramuscular injection when admitted followed by one dose every 12 h for five consecutive days five days of N=159 adults (>18 years old), progesterone via males=115, females=44 intramuscular GCS≤8 for all patients injection; Inclusion criteria: adult blunt trauma First dose at 1.0 victims within 8 h of injury and GCS mg/kg via <8 intramuscular Exclusion criteria: previous use of injection investigational drugs 30 days prior to enrollment, severe anoxic intracerebral followed by one dose every 12 h damage or brain death, clinical for five condition was unstable (partial consecutive days pressure of oxygen <60 mmHg, a systolic blood pressure <90 mmHg, or both), pregnancy, lactation, acute or chronic spinal cord injury
N=56 adults Inclusion criteria: adult blunt trauma victims within 24 h of injury and GCS=5-8 Exclusion criteria: previous use of investigational drugs, pregnancy, lactation, severe chronic disease
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Xiao 2007
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GOS, modified Functional Independence Measure (FIM) score, mortality
6 months
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0 additional records identified through other source
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683 articles screened
reduplicated 67 articles excluded
616 articles screened
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593 articles excluded because of
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23 articles screened
14 of full text articles excluded because violation of inclusion criteria
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9 of articles assessed for eligibility
8 studies included in the systematic review and meta-analysis
1 article excluded because of no data availeble
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Highlight 1) Progesterone treatment did not decrease the mortality after TBI.
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2) Progesterone treatment could not improve the neurological outcome after TBI.
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Conflict of interest statement: declare
with
other people
work,
there
that
is
we
have
no
financial
or organizations that
no professional
can
and
personal
inappropriately
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our
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or other personal interest of any nature or
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the position presented in, or the review of, the manuscript entitled.
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Abbreviations: traumatic brain injury
RCTs
randomized controlled trials
GOS
Glasgow Outcome Scale
RR
risk ratio
GCS
Glasgow Coma Scale
EGOS
expanded Glasgow Outcome Scale
CI
confidence interval
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TBI