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.

BACKGROUND: Early 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. METHODS: This 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. RESULTS: 1767 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). CONCLUSION: TXA 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 NUMBER: ISRCTN15088122.

Value of Shock Index in prognosticating the short-term outcome of death for patients presenting with severe sepsis and septic shock in the emergency department.

INTRODUCTION: The importance of early recognition and treatment of sepsis and its effects on short-term survival outcome have long been recognized. Having reliable indicators and markers that would help prognosticate the survival of these patients is invaluable and would subsequently assist in the course of effective dynamic triaging and goal directed management. STUDY OBJECTIVES: To determine the prognosticative value of Shock Index (SI), taken upon arrival to the emergency department and after 2 hours of resuscitation on the shortterm outcome of severe sepsis and septic shock patients. METHODOLOGY: This is a retrospective observational study involving 50 patients admitted to the University of Malaya Medical Centre between June 2009 and June 2010 who have been diagnosed with either severe sepsis or septic shock. Patients were identified retrospectively from the details recorded in the registration book of the resuscitation room. 50 patients were selected for this pilot study. The population comprised 19 males (38%) and 31 females (62%). The median (min, max) age was 54.5 (17.0, 84.0) years. The number of severe sepsis and septic shock cases were 31 (62%), and 19 (38%) respectively. There were 17 (34%) cases of pneumonias, 13 (26%) cases of urological sepsis, 8 (16%) cases of gastro intestinal tract related infections and 12 (24%) cases of other infections. There were a total of 23 (46%) survivors and 27 (54%) deaths. The value of the shock index is defined as systolic blood pressure divided by heart rate was calculated. Shock Index on presentation to ED (SI 1) and after 2 hours of resuscitation in the ED (SI 2). The median, minimum and maximum variables were tested using Mann-Whitney U and Chi square analysis. The significant parameters were re-evaluated for sensitivity, specificity and cut-off points. ROC curves and AUC values were generated among these variables to assess prognostic utility for outcome. RESULTS: Amongst all 7 variables tested, 2 were tested to be significant (p: < 0.05). From the sensitivity, specificity and ROC analysis, the best predictor for death was (SI 2) with a sensitivity of 80.8%, specificity of 79.2%, AUC value of 0.8894 [CI 95 0.8052, 0.9736] at a cut-off point of > or = 1.0. CONCLUSION: (SI 2) may potentially be utilized as a reliable predictor for death in patients presenting with septic shock and severe sepsis in an emergency department. This parameters should be further analyzed in a larger scale prospective study to determine its validity.