scholarly journals Effect of tranexamic acid on intracranial haemorrhage and infarction in patients with traumatic brain injury: a pre-planned substudy in a sample of CRASH-3 trial patients

2020 ◽  
pp. emermed-2020-210424
Author(s):  
Abda Mahmood ◽  
Kelly Needham ◽  
Haleema Shakur-Still ◽  
Tim Harris ◽  
Sabariah Faizah Jamaluddin ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Clinical Practice ◽  
Brain Injury ◽  
Head Injury ◽  
Tranexamic Acid ◽  
Intracranial Haemorrhage ◽  
Routine Clinical Practice ◽  
Intraparenchymal Haemorrhage ◽  
Scan Data ◽  
Post Randomisation

BackgroundEarly tranexamic acid (TXA) treatment reduces head injury deaths after traumatic brain injury (TBI). We used brain scans that were acquired as part of the routine clinical practice during the CRASH-3 trial (before unblinding) to examine the mechanism of action of TXA in TBI. Specifically, we explored the potential effects of TXA on intracranial haemorrhage and infarction.MethodsThis is a prospective substudy nested within the CRASH-3 trial, a randomised placebo-controlled trial of TXA (loading dose 1 g over 10 min, then 1 g infusion over 8 hours) in patients with isolated head injury. CRASH-3 trial patients were recruited between July 2012 and January 2019. Participants in the current substudy were a subset of trial patients enrolled at 10 hospitals in the UK and 4 in Malaysia, who had at least one CT head scan performed as part of the routine clinical practice within 28 days of randomisation. The primary outcome was the volume of intraparenchymal haemorrhage (ie, contusion) measured on a CT scan done after randomisation. Secondary outcomes were progressive intracranial haemorrhage (post-randomisation CT shows >25% of volume seen on pre-randomisation CT), new intracranial haemorrhage (any haemorrhage seen on post-randomisation CT but not on pre-randomisation CT), cerebral infarction (any infarction seen on any type of brain scan done post-randomisation, excluding infarction seen pre-randomisation) and intracranial haemorrhage volume (intraparenchymal + intraventricular + subdural + epidural) in those who underwent neurosurgical haemorrhage evacuation. We planned to conduct sensitivity analyses excluding patients who were severely injured at baseline. Dichotomous outcomes were analysed using relative risks (RR) or hazard ratios (HR), and continuous outcomes using a linear mixed model.Results1767 patients were included in this substudy. One-third of the patients had a baseline GCS (Glasgow Coma Score) of 3 (n=579) and 24% had unilateral or bilateral unreactive pupils. 46% of patients were scanned pre-randomisation and post-randomisation (n=812/1767), 19% were scanned only pre-randomisation (n=341/1767) and 35% were scanned only post-randomisation (n=614/1767). In all patients, there was no evidence that TXA prevents intraparenchymal haemorrhage expansion (estimate=1.09, 95% CI 0.81 to 1.45) or intracranial haemorrhage expansion in patients who underwent neurosurgical haemorrhage evacuation (n=363) (estimate=0.79, 95% CI 0.57 to 1.11). In patients scanned pre-randomisation and post-randomisation (n=812), there was no evidence that TXA reduces progressive haemorrhage (adjusted RR=0.91, 95% CI 0.74 to 1.13) and new haemorrhage (adjusted RR=0.85, 95% CI 0.72 to 1.01). When patients with unreactive pupils at baseline were excluded, there was evidence that TXA prevents new haemorrhage (adjusted RR=0.80, 95% CI 0.66 to 0.98). In patients scanned post-randomisation (n=1431), there was no evidence of an increase in infarction with TXA (adjusted HR=1.28, 95% CI 0.93 to 1.76). A larger proportion of patients without (vs with) a post-randomisation scan died from head injury (38% vs 19%: RR=1.97, 95% CI 1.66 to 2.34, p<0.0001).ConclusionTXA may prevent new haemorrhage in patients with reactive pupils at baseline. This is consistent with the results of the CRASH-3 trial which found that TXA reduced head injury death in patients with at least one reactive pupil at baseline. However, the large number of patients without post-randomisation scans and the possibility that the availability of scan data depends on whether a patient received TXA, challenges the validity of inferences made using routinely collected scan data. This study highlights the limitations of using routinely collected scan data to examine the effects of TBI treatments.Trial registration numberISRCTN15088122.

scholarly journals Tranexamic acid for significant traumatic brain injury (The CRASH-3 trial): Statistical analysis plan for an international, randomised, double-blind, placebo-controlled trial

2018 ◽  
Vol 3 ◽  
pp. 86 ◽  
Author(s):  
Ian Roberts ◽  
Antonio Belli ◽  
Amy Brenner ◽  
Rizwana Chaudhri ◽  
Bukola Fawole ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Statistical Analysis ◽  
Brain Injury ◽  
Head Injury ◽  
Blood Loss ◽  
Tranexamic Acid ◽  
Statistical Analysis Plan ◽  
Intracranial Bleeding ◽  
Injury Death ◽  
Reliable Evidence

Background: Worldwide, traumatic brain injury (TBI) kills or hospitalises over 10 million people each year. Early intracranial bleeding is common after TBI, increasing the risk of death and disability. Tranexamic acid reduces blood loss in surgery and death due to bleeding in trauma patients with extra-cranial injury. Early administration of tranexamic acid in TBI patients might limit intracranial bleeding, reducing death and disability. The CRASH-3 trial aims to provide reliable evidence on the effect of tranexamic acid on death and disability in TBI patients. We will randomly allocate about 13,000 TBI patients to an intravenous infusion of tranexamic acid or matching placebo in addition to usual care. This paper presents a protocol update (version 2.1) and statistical analysis plan for the CRASH-3 trial. Results: The primary outcome is head injury death in hospital within 28 days of injury for patients treated within 3 hours of injury (deaths in patients treated after 3 hours will also be reported). Because there are strong scientific reasons to expect that tranexamic acid will be most effective in patients treated immediately after injury and less effective with increasing delay, the effect in patients treated within one hour of injury is of particular interest. Secondary outcomes are all-cause and cause-specific mortality, vascular occlusive events (myocardial infarction, pulmonary embolism, deep vein thrombosis, stroke), disability based on the Disability Rating Scale and measures suggested by patient representatives, seizures, neurosurgical intervention, neurosurgical blood loss, days in intensive care and adverse events. Sub-group analyses will examine the effect of tranexamic acid on head injury death stratified by time to treatment, severity of TBI and baseline risk. Conclusion: The CRASH-3 trial will provide reliable evidence of the effectiveness and safety of tranexamic acid in patients with acute TBI. Registration: International Standard Randomised Controlled Trials registry (ISRCTN15088122) 19/07/2011, and ClinicalTrials.gov (NCT01402882) 25/07/2011.

scholarly journals Tranexamic acid to reduce head injury death in people with traumatic brain injury: the CRASH-3 international RCT

2021 ◽  
Vol 25 (26) ◽  
pp. 1-76
Author(s):  
Ian Roberts ◽  
Haleema Shakur-Still ◽  
Amy Aeron-Thomas ◽  
Danielle Beaumont ◽  
Antonio Belli ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Head Injury ◽  
Confidence Interval ◽  
Tranexamic Acid ◽  
Risk Ratio ◽  
Group Versus ◽  
Acid Group ◽  
Injury Death ◽  
Moderate Traumatic Brain Injury

Background Tranexamic acid safely reduces mortality in traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury and can cause brain herniation and death. We assessed the effects of tranexamic acid in traumatic brain injury patients. Objective To assess the effects of tranexamic acid on death, disability and vascular occlusive events in traumatic brain injury patients. We also assessed cost-effectiveness. Design Randomised trial and economic evaluation. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, caregivers and those assessing outcomes were masked to allocation. All analyses were by intention to treat. We assessed the cost-effectiveness of tranexamic acid versus no treatment from a UK NHS perspective using the trial results and a Markov model. Setting 175 hospitals in 29 countries. Participants Adults with traumatic brain injury within 3 hours of injury with a Glasgow Coma Scale score of ≤ 12 or any intracranial bleeding on computerised tomography scan, and no major extracranial bleeding, were eligible. Intervention Tranexamic acid (loading dose 1 g over 10 minutes then infusion of 1 g over 8 hours) or matching placebo. Main outcome measures Head injury death in hospital within 28 days of injury in patients treated within 3 hours of injury. Secondary outcomes were early head injury deaths, all-cause and cause-specific mortality, disability, vascular occlusive events, seizures, complications and adverse events. Results Among patients treated within 3 hours of injury (n = 9127), the risk of head injury death was 18.5% in the tranexamic acid group versus 19.8% in the placebo group (855/4613 vs. 892/4514; risk ratio 0.94, 95% confidence interval 0.86 to 1.02). In a prespecified analysis excluding patients with a Glasgow Coma Scale score of 3 or bilateral unreactive pupils at baseline, the results were 12.5% in the tranexamic acid group versus 14.0% in the placebo group (485/3880 vs. 525/3757; risk ratio 0.89, 95% confidence interval 0.80 to 1.00). There was a reduction in the risk of head injury death with tranexamic acid in those with mild to moderate head injury (166/2846 vs. 207/2769; risk ratio 0.78, 95% confidence interval 0.64 to 0.95), but in those with severe head injury (689/1739 vs. 685/1710; risk ratio 0.99, 95% confidence interval 0.91 to 1.07) there was no apparent reduction (p-value for heterogeneity = 0.030). Early treatment was more effective in mild and moderate head injury (p = 0.005), but there was no obvious impact of time to treatment in cases of severe head injury (p = 0.73). The risk of disability, vascular occlusive events and seizures was similar in both groups. Tranexamic acid is highly cost-effective for mild and moderate traumatic brain injury (base case of £4288 per quality-adjusted life-year gained). Conclusion Early tranexamic acid treatment reduces head injury deaths. Treatment is cost-effective for patients with mild or moderate traumatic brain injury, or those with both pupils reactive. Future work Further trials should examine early tranexamic acid treatment in mild head injury. Research on alternative routes of administration is needed. Limitations Time to treatment may have been underestimated. Trial registration Current Controlled Trials ISRCTN15088122, ClinicalTrials.gov NCT01402882, EudraCT 2011-003669-14, Pan African Clinical Trial Registry PACTR20121000441277. Funding The project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 26. See the NIHR Journals Library website for further project information. In addition, funding was provided by JP Moulton Charitable Trust, Joint Global Health Trials (Medical Research Council, Department for International Development and the Wellcome Trust). This project was funded by the NIHR Global Health Trials programme.

scholarly journals Tranexamic acid for significant traumatic brain injury (The CRASH-3 trial): Statistical analysis plan for an international, randomised, double-blind, placebo-controlled trial

2018 ◽  
Vol 3 ◽  
pp. 86 ◽  
Author(s):  
Ian Roberts ◽  
Antonio Belli ◽  
Amy Brenner ◽  
Rizwana Chaudhri ◽  
Bukola Fawole ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Statistical Analysis ◽  
Brain Injury ◽  
Head Injury ◽  
Blood Loss ◽  
Tranexamic Acid ◽  
Statistical Analysis Plan ◽  
Intracranial Bleeding ◽  
Injury Death ◽  
Risk Of Death

Background: Worldwide, traumatic brain injury (TBI) kills or hospitalises over 10 million people each year. Early intracranial bleeding is common after TBI, increasing the risk of death and disability. Tranexamic acid reduces blood loss in surgery and death due to bleeding in trauma patients with extra-cranial injury. Early administration of tranexamic acid in TBI patients might limit intracranial bleeding, reducing death and disability. The CRASH-3 trial aims to provide evidence on the effect of tranexamic acid on death and disability in TBI patients. We will randomly allocate about 13,000 TBI patients (approximately 10,000 within 3 hours of injury) to an intravenous infusion of tranexamic acid or matching placebo in addition to usual care. This paper presents a protocol update (version 2.1) and statistical analysis plan for the CRASH-3 trial. Results: The primary outcome is head injury death in hospital within 28 days of injury for patients treated within 3 hours of injury (deaths in patients treated after 3 hours will also be reported). Because there are reasons to expect that tranexamic acid will be most effective in patients treated immediately after injury and less effective with increasing delay, the effect in patients treated within one hour of injury is of particular interest. Secondary outcomes are all-cause and cause-specific mortality, vascular occlusive events, disability based on the Disability Rating Scale and measures suggested by patient representatives, seizures, neurosurgical intervention, neurosurgical blood loss, days in intensive care and adverse events. Sub-group analyses will examine the effect of tranexamic acid on head injury death stratified by time to treatment, severity of TBI and baseline risk. Conclusion: The CRASH-3 trial will provide reliable evidence of the effectiveness and safety of tranexamic acid in patients with acute TBI. Registration: International Standard Randomised Controlled Trials registry ( ISRCTN15088122) 19/07/2011, and ClinicalTrials.gov ( NCT01402882) 25/07/2011.

scholarly journals Prospective Analysis of Coagulopathy Associated with Isolated Traumatic Brain Injury and Clinical Outcome

2021 ◽  
Author(s):  
Gopal Krishna ◽  
Varun Aggarwal ◽  
Ishwar Singh
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Head Injury ◽  
Clinical Outcome ◽  
Road Traffic ◽  
Statistical Significance ◽  
Platelet Counts ◽  
Coagulation Abnormalities ◽  
The Mean ◽  
D Dimer

Abstract Introduction Traumatic brain injury (TBI) affects the coagulation pathway in a distinct way than does extracranial trauma. The extent of coagulation abnormalities varies from bleeding diathesis to disseminated thrombosis. Design Prospective study. Methods The study included 50 patients of isolated TBI with cohorts of moderate (MHI) and severe head injury (SHI). Coagulopathy was graded according to the values of parameters in single laboratory. The incidence of coagulopathy according to the severity of TBI and correlation with disseminated intravascular coagulation (DIC) score, platelets, prothrombin time (PT), activated partial thromboplastin time (APTT), D-dimer, and fibrinogen was observed. The comparison was also made between expired and discharged patients within each group. It also compared coagulation derailments with clinical presentation (Glasgow Coma Scale [GCS]) and outcome (Glasgow Outcome Scale [GOS]). Results Road traffic accident was the primary (72%) mode of injury. Fifty-two percent had MHI and rest had SHI. Eighty-four percent of cases were managed conservatively. The mean GCS was 12.23 and 5.75 in MHI and SHI, respectively. Sixty-two percent of MHI and 96% of the patients with SHI had coagulation abnormalities. On statistical analysis, DIC score (p < 0.001) strongly correlated with the severity of head injury and GOS. PT and APTT were also significantly associated with the severity of TBI. In patients with moderate TBI, D-dimer and platelet counts showed association with clinical outcome. Fibrinogen levels did not show any statistical significance. The mean platelet counts remained normal in both the groups of TBI. The mean GOS was 1.54 and 4.62 in SHI and MHI, respectively. Conclusion Coagulopathy is common in isolated TBI. The basic laboratory parameters are reliable predictors of coagulation abnormalities in TBI. Coagulopathy is directly associated with the severity of TBI, GCS, and poor outcome.

scholarly journals Differential Leukocyte and Platelet Profiles in Distinct Models of Traumatic Brain Injury

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 500
Author(s):  
William Brad Hubbard ◽  
Meenakshi Banerjee ◽  
Hemendra Vekaria ◽  
Kanakanagavalli Shravani Prakhya ◽  
Smita Joshi ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Head Injury ◽  
Closed Head Injury ◽  
Diffuse Brain Injury ◽  
Blood Brain ◽  
Closed Head ◽  
Leukocyte Counts ◽  
Neutrophil Aggregation ◽  
Blood Leukocyte

Traumatic brain injury (TBI) affects over 3 million individuals every year in the U.S. There is growing appreciation that TBI can produce systemic modifications, which are in part propagated through blood–brain barrier (BBB) dysfunction and blood–brain cell interactions. As such, platelets and leukocytes contribute to mechanisms of thromboinflammation after TBI. While these mechanisms have been investigated in experimental models of contusion brain injury, less is known regarding acute alterations following mild closed head injury. To investigate the role of platelet dynamics and bioenergetics after TBI, we employed two distinct, well-established models of TBI in mice: the controlled cortical impact (CCI) model of contusion brain injury and the closed head injury (CHI) model of mild diffuse brain injury. Hematology parameters, platelet-neutrophil aggregation, and platelet respirometry were assessed acutely after injury. CCI resulted in an early drop in blood leukocyte counts, while CHI increased blood leukocyte counts early after injury. Platelet-neutrophil aggregation was altered acutely after CCI compared to sham. Furthermore, platelet bioenergetic coupling efficiency was transiently reduced at 6 h and increased at 24 h post-CCI. After CHI, oxidative phosphorylation in intact platelets was reduced at 6 h and increased at 24 h compared to sham. Taken together, these data demonstrate that brain trauma initiates alterations in platelet-leukocyte dynamics and platelet metabolism, which may be time- and injury-dependent, providing evidence that platelets carry a peripheral signature of brain injury. The unique trend of platelet bioenergetics after two distinct types of TBI suggests the potential for utilization in prognosis.

scholarly journals Development of a Prognostic Model to Predict Mortality after Traumatic Brain Injury in Intensive Care Setting in a Developing Country

2021 ◽  
Vol 12 (02) ◽  
pp. 368-375
Author(s):  
Mini Jayan ◽  
Dhaval Shukla ◽  
Bhagavatula Indira Devi ◽  
Dhananjaya I. Bhat ◽  
Subhas K. Konar
Keyword(s):  
Traumatic Brain Injury ◽  
Intensive Care ◽  
Brain Injury ◽  
Hospital Mortality ◽  
Prognostic Model ◽  
Third Ventricle ◽  
The Third ◽  
Scan Data ◽  
Gcs Score ◽  
Basal Cisterns

Abstract Objectives We aimed to develop a prognostic model for the prediction of in-hospital mortality in patients with traumatic brain injury (TBI) admitted to the neurosurgery intensive care unit (ICU) of our institute. Materials and Methods The clinical and computed tomography scan data of consecutive patients admitted after a diagnosis TBI in ICU were reviewed. Construction of the model was done by using all the variables of Corticosteroid Randomization after Significant Head Injury and International Mission on Prognosis and Analysis of Clinical Trials in TBI models. The endpoint was in-hospital mortality. Results A total of 243 patients with TBI were admitted to ICU during the study period. The in-hospital mortality was 15.3%. On multivariate analysis, the Glasgow coma scale (GCS) at admission, hypoxia, hypotension, and obliteration of the third ventricle/basal cisterns were significantly associated with mortality. Patients with hypoxia had eight times, with hypotensions 22 times, and with obliteration of the third ventricle/basal cisterns three times more chance of death. The TBI score was developed as a sum of individual points assigned as follows: GCS score 3 to 4 (+2 points), 5 to 12 (+1), hypoxia (+1), hypotension (+1), and obliteration third ventricle/basal cistern (+1). The mortality was 0% for a score of “0” and 85% for a score of “4.” Conclusion The outcome of patients treated in ICU was based on common admission variables. A simple clinical grading score allows risk stratification of patients with TBI admitted in ICU.

scholarly journals Outcome Prediction in Patients of Traumatic Brain Injury Based on Midline Shift on CT Scan of Brain

2021 ◽  
Author(s):  
Shrikant Govindrao Palekar ◽  
Manish Jaiswal ◽  
Mandar Patil ◽  
Vijay Malpathak
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Head Injury ◽  
Ct Scan ◽  
Treatment Protocol ◽  
Emergency Setting ◽  
Midline Shift ◽  
Ct Head ◽  
Clinical Tools ◽  
Gcs Score

Abstract Background Clinicians treating patients with head injury often take decisions based on their assessment of prognosis. Assessment of prognosis could help communication with a patient and the family. One of the most widely used clinical tools for such prediction is the Glasgow coma scale (GCS); however, the tool has a limitation with regard to its use in patients who are under sedation, are intubated, or under the influence of alcohol or psychoactive drugs. CT scan findings such as status of basal cistern, midline shift, associated traumatic subarachnoid hemorrhage (SAH), and intraventricular hemorrhage are useful indicators in predicting outcome and also considered as valid options for prognostication of the patients with traumatic brain injury (TBI), especially in emergency setting. Materials and Methods 108 patients of head injury were assessed at admission with clinical examination, history, and CT scan of brain. CT findings were classified according to type of lesion and midline shift correlated to GCS score at admission. All the subjects in this study were managed with an identical treatment protocol. Outcome of these patients were assessed on GCS score at discharge. Result Among patients with severe GCS, 51% had midline shift. The degree of midline shift in CT head was a statistically significant determinant of outcome (p = 0.023). Seventeen out of 48 patients (35.4%) with midline shift had poor outcome as compared with 8 out of 60 patients (13.3%) with no midline shift. Conclusion In patients with TBI, the degree of midline shift on CT scan was significantly related to the severity of head injury and resulted in poor clinical outcome.

scholarly journals The role of salivary vesicles as a potential inflammatory biomarker to detect traumatic brain injury in mixed martial artists

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rani Matuk ◽  
Mandy Pereira ◽  
Janette Baird ◽  
Mark Dooner ◽  
Yan Cheng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Head Injury ◽  
Injury Severity ◽  
Expression Profiles ◽  
High Impact ◽  
Impact Mechanism ◽  
Inflammatory Biomarker ◽  
Potential Biomarker

AbstractTraumatic brain injury (TBI) is of significant concern in the realm of high impact contact sports, including mixed martial arts (MMA). Extracellular vesicles (EVs) travel between the brain and oral cavity and may be isolated from salivary samples as a noninvasive biomarker of TBI. Salivary EVs may highlight acute neurocognitive or neuropathological changes, which may be particularly useful as a biomarker in high impact sports. Pre and post-fight samples of saliva were isolated from 8 MMA fighters and 7 from controls. Real-time PCR of salivary EVs was done using the TaqMan Human Inflammatory array. Gene expression profiles were compared pre-fight to post-fight as well as pre-fight to controls. Largest signals were noted for fighters sustaining a loss by technical knockout (higher impact mechanism of injury) or a full match culminating in referee decision (longer length of fight), while smaller signals were noted for fighters winning by joint or choke submission (lower impact mechanism as well as less time). A correlation was observed between absolute gene information signals and fight related markers of head injury severity. Gene expression was also significantly different in MMA fighters pre-fight compared to controls. Our findings suggest that salivary EVs as a potential biomarker in the acute period following head injury to identify injury severity and can help elucidate pathophysiological processes involved in TBI.

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