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Corticosteroids have been used to treat head injuries for more than 30 years. In 1997, findings of a systematic review suggested that these drugs reduce risk of death by 1-2%. The CRASH trial--a multicentre international collaboration--aimed to confirm or refute such an effect by recruiting 20000 patients. In May, 2004, the data monitoring committee disclosed the unmasked results to the steering committee, which stopped recruitment. 10008 adults with head injury and a Glasgow coma score (GCS) of 14 or less within 8 h of injury were randomly allocated 48 h infusion of corticosteroids (methylprednisolone) or placebo. Primary outcomes were death within 2 weeks of injury and death or disability at 6 months. Prespecified subgroup analyses were based on injury severity (GCS) at randomisation and on time from injury to randomisation. Analysis was by intention to treat. Effects on outcomes within 2 weeks of randomisation are presented in this report. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN74459797. Compared with placebo, the risk of death from all causes within 2 weeks was higher in the group allocated corticosteroids (1052 [21.1%] vs 893 [17.9%] deaths; relative risk 1.18 [95% CI 1.09-1.27]; p=0.0001). The relative increase in deaths due to corticosteroids did not differ by injury severity (p=0.22) or time since injury (p=0.05). Our results show there is no reduction in mortality with methylprednisolone in the 2 weeks after head injury. The cause of the rise in risk of death within 2 weeks is unclear.

Objective. This study is aimed at exploring the effect of ulinastatin combined with Xingnaojing injection on severe traumatic craniocerebral injury and its influence on oxidative stress response and inflammatory response in patients. Methods. A total of 100 patients with severe traumatic craniocerebral injury admitted to our hospital from January 2018 to January 2020 were selected and equally assigned into a study group (50 cases) and a control group (50 cases) according to a random sampling method. Patients in study group received treatment of ulinastatin combined with Xingnaojing injection, while those in control group were treated with ulinastatin only. The study compared the two groups on the oxidative stress response, inflammatory response, the therapeutic effect, and the incidence rate of adverse reactions. Results. It is observed that patients in study group obtained lower levels of free cortisol (FC) and norepinephrine (NE) in the serum and higher level of total thyroxine (TT4) after treatment compared with those in control group with significant difference (P<0.05); in the meantime, they were examined to have significantly fewer oxidative stress response products, lower serum inflammatory factor level, and serum indicator levels of craniocerebral injury as opposed to those in control group, suggesting significant differences (P<0.05); study group demonstrated higher treatment response rate and lower incidence rate of adverse reactions compared with control group with a significant difference (P<0.05). Conclusion. The study found that ulinastatin combined with Xingnaojing infection has a significant effect in the treatment of severe traumatic craniocerebral injury, which can reduce the degree of craniocerebral injury and the level of inflammatory factors in the serum of patients. It is worthy of being promoted and applied clinically.

MRC CRASH is a randomised controlled trial (ISRCTN74459797) of the effect of corticosteroids on death and disability after head injury. We randomly allocated 10 008 adults with head injury and a Glasgow Coma Scale score of 14 or less, within 8 h of injury, to a 48-h infusion of corticosteroid (methylprednisolone) or placebo. Data at 6 months were obtained for 9673 (96·7%) patients. The risk of death was higher in the corticosteroid group than in the placebo group (1248 [25·7%] vs 1075 [22·3%] deaths; relative risk 1·15, 95% CI 1·07–1·24; p=0·0001), as was the risk of death or severe disability (1828 [38·1%] vs 1728 [36·3%] dead or severely disabled; 1·05, 0·99–1·10; p=0·079). There was no evidence that the effect of corticosteroids differed by injury severity or time since injury. These results lend support to our earlier conclusion that corticosteroids should not be used routinely in the treatment of head injury.

Regression discontinuity (RD) is a quasi-experimental design that may provide valid estimates of treatment effects in case of continuous outcomes. We aimed to evaluate validity and precision in the RD design for dichotomous outcomes. We performed validation studies in three large randomized controlled trials (RCTs) (Corticosteroid Randomization After Significant Head injury [CRASH], the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries [GUSTO], and PROspective Study of Pravastatin in elderly individuals at risk of vascular disease [PROSPER]). To mimic the RD design, we selected patients above and below a cutoff (e.g., age 75 years) randomized to treatment and control, respectively. Adjusted logistic regression models using restricted cubic splines (RCS) and polynomials and local logistic regression models estimated the odds ratio (OR) for treatment, with 95% confidence intervals (CIs) to indicate precision. In CRASH, treatment increased mortality with OR 1.22 [95% CI 1.06–1.40] in the RCT. The RD estimates were 1.42 (0.94–2.16) and 1.13 (0.90–1.40) with RCS adjustment and local regression, respectively. In GUSTO, treatment reduced mortality (OR 0.83 [0.72–0.95]), with more extreme estimates in the RD analysis (OR 0.57 [0.35; 0.92] and 0.67 [0.51; 0.86]). In PROSPER, similar RCT and RD estimates were found, again with less precision in RD designs. We conclude that the RD design provides similar but substantially less precise treatment effect estimates compared with an RCT, with local regression being the preferred method of analysis.

Severe traumatic brain injury (TBI) has a major role in mortality rate among the other types of trauma. The aim of this clinical study was to assess the effect of progesterone on the improvement of neurologic outcome in patients with acute severe TBI. A total of 76 patients who had arrived within 8h of injury with a Glasgow Coma Score ≤8 were enrolled in the study. In a randomized style 38 received progesterone (1mg/kg per 12h for 5 days) and 38 did not. There was a better recovery rate and GOS score for the patients who were given progesterone than for those in the control group in a 3-months follow-up period (50% vs. 21%); subgroup analysis showed a significant difference in the percentage of favorable outcome between the two groups with GCS of 5–8 (p=0.03). The use of progesterone may significantly improve neurologic outcome of patients suffering severe TBI up to 3 months after injury, especially those with 5≤GCS≤8, providing a potential benefit to the treatment of acute severe TBI patients. Considering this drug had no significant side effects, so progesterone could be used in patients with severe TBI as a neuro-protective drug.

To explore the pharmacokinetics and pharmacodynamics of dopamine and norepinephrine. Prospective, controlled, trial. Neurosciences critical care unit. Eight patients with a head injury, requiring dopamine or norepinephrine infusions to support cerebral perfusion pressure (CPP). Patients received in randomised order, either dopamine or norepinephrine to achieve and maintain a CPP of 70 mmHg, and then, following a 30-min period of stable haemodynamics, a CPP of 90 mmHg. Data were then acquired using the second agent. Haemodynamic measurements were made during each period and a blood sample was obtained at the end of each study period for analysis of plasma catecholamine concentrations Plasma levels of norepinephrine and dopamine were significantly related to infusion rates but did not have a simple linear relationship to haemodynamic parameters. However, there was a significant quadratic relationship between the infusion rate of dopamine and cardiac index (r2=0.431), and systemic vascular resistance index (r2=0.605), with a breakpoint (at which cardiac index reduced and SVRI increased) at a dopamine plasma level of approximately 50 nM/l (corresponding to an infusion rate of approximately 15 microg.kg(-1).min(-1)). Norepinephrine and dopamine have predictable pharmacokinetics; however, those of dopamine do not fit a simple first-order kinetic model. The pharmacodynamic effects of dopamine and norepinephrine show much inter-individual variability and unpredictability. Plasma levels of dopamine appear to relate to variations in adrenergic receptor effects with break points that reflect expectations from infusion-rate related pharmacodynamics.

Traumatic brain injury (TBI) remains the most common cause of death in persons under age 45 in the Western world. Recent evidence from animal studies suggests that supplementation with omega-3 fatty acids (O3FA) improves functional outcomes following focal neural injury. The purpose of this study is to determine the benefits of DHA supplementation following diffuse axonal injury in rats. Four groups of 10 adult male Sprague-Dawley rats were subjected to an impact acceleration injury and then received 30 days of supplementation with either 10 mg/kg/d or 40 mg/kg/d of docosahexaenoic acid (DHA). Serum fatty acid levels were determined from the isolated plasma phospholipids prior to injury and at the end of the 30 days of DHA supplementation. Following sacrifice, brainstem white matter tracts underwent fluorescent immunohistochemical processing for labeling of β-amyloid precursor protein (APP), a marker of axonal injury. Dietary supplementation with either 10 mg/kg/d or 40 mg/kg/d of DHA for 30 days results in significantly (p < 0.05) increased DHA serum levels of 123% and 175% over baseline, respectively. Immunohistochemical analysis reveals significantly (p < 0.05) decreased numbers of APP-positive axons in animals receiving dietary supplementation with DHA, 26.1 (SD 5.3) for 10 mg/kg/d, and 19.6 (SD 4.7) for 40 mg/kg/d axons per mm2, versus 147.7 (SD 7.1) axons in unsupplemented animals. Sham-injured animals had 6.4 (SD 13.9) APP positive axons per mm2. Dietary supplementation with DHA increases serum levels in a dose-dependent manner. DHA supplementation significantly reduces the number of APP-positive axons at 30 days post-injury, to levels similar to seen those in uninjured animals. DHA is safe, affordable, and readily available worldwide to potentially reduce the burden of TBI.

Patients in emergency situations with impaired consciousness are unable to give informed consent to participate in clinical trials. In this situation, some ethics committees ask that consent is obtained from a relative or a legal representative. Others however, waive the need for informed consent and allow the doctor in charge to take responsibility for entering such patients. This study used data from the MRC CRASH Trial, an international randomised controlled trial of corticosteroids in head injury, to assess whether the practice of waiving consent results in earlier administration of the trial treatment. It was found that time from injury to randomisation was significantly reduced (1.2 hours, 95% CI 0.7 to 1.8 hours) and patient recruitment was higher in hospitals where consent was waived compared with those that required relatives consent.

The correlation between chronic direct oral anticoagulants (DOACs) intake and the incidence of intracranial complications after minor head injury (MHI) is still not well defined. This study examined the incidence of complications in patients receiving vitamin K antagonists (VKA) or DOACs observed in the emergency department (ED) for MHI. Two hundred twenty-five patients affected by MHI and receiving oral anticoagulants were recorded between January and December 2016, distinguishing those treated with VKA (118) from those receiving DOACs (107). All patients underwent a CT scan and were observed for 24h in the ED. Follow-up was performed up to 1month after the head trauma. The rate of intracranial hemorrhage was significantly lower in patients treated with DOACs than in patients treated with VKA. We recorded 2 deaths among the 12 patients who experienced intracranial complications in the VKA group. DOACs seem to have a more favorable safety profile than VKA in patients affected by MHI. This observation is important in light of the increasing number of elderly patients who are receiving anticoagulant therapy.

Head injuries frequently occur in combat. Tactical Combat Casualty Care (TCCC) guidelines recommend pre-hospital use of ketamine for analgesia. Yet the use of this medication in patients with head injuries remains controversial, particularly among pediatric patients. We compare survival to hospital discharge rates among pediatric head injury subjects who received prehospital ketamine versus those who did not. We queried the Department of Defense Trauma Registry (DODTR) for all pediatric (<18 years of age) subjects from January 2007 to January 2016. We performed a sub-analysis of subjects with an abbreviated injury severity score for the head of 3 (serious) or higher and at least one documented Glasgow Coma Score (GCS) ≤13. Of the 3439 pediatric patients within our dataset, 555 subjects met inclusion criteria for head injury – 36 (6.5%) received prehospital ketamine versus 519 (93.5%) who did not. There was no significant difference noted between groups regarding median age (10 versus 8, p = 0.259), percent male gender (72.2% versus 76.3%, p = 0.579), mechanism of injury (p = 0.143), median composite injury scores (22 versus 20, p = 0.082), median ventilator-free days (28 versus 27, p = 0.068), median ICU-free days (27.5 versus 27, p = 0.767), median hospital days (3.5 versus 4, p = 0.876) or survival to discharge (66.7% versus 70.7%, p = 0.607). Within this data set, we were unable to detect any differences in mortality among pediatric head trauma subjects administered ketamine compared to subjects not receiving this medication in the prehospital setting.