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.
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.
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.
Traumatic brain injury is a leading cause of death and disability worldwide, with over 60 million new cases each year. When the head is injured there is often bleeding inside the brain, which can continue for some time and worsen after hospital admission. This bleeding increases pressure inside the skull, causing further damage to the brain, which can be fatal or result in serious disability. Tranexamic acid is a cheap drug that reduces bleeding in other conditions. A large trial of accident victims (other than those with head injury) found that it reduced the chances of bleeding to death. We wanted to find out if tranexamic acid would also reduce deaths among patients with head injuries. We studied just under 13,000 patients with traumatic brain injury who did not have other major injuries to their bodies from 175 hospitals across 29 countries. Patients were assigned at random to receive either tranexamic acid or a dummy medicine called a placebo. Neither the clinical team nor the patient knew which medicine the patient received. All patients received the usual treatments given to head-injured patients. Outcomes from 9127 participants were analysed. Among patients treated early, within 3 hours, the rate of head injury death was 18.5% (855/4613) in the tranexamic acid group and 19.8% (892/4514) in the placebo group. We found no evidence of an effect of tranexamic acid overall. However, in patients with mild or moderate traumatic brain injury, there was a 20% reduction in deaths. There were no side effects and no increase in disability in survivors when the drug was used. The economic analysis shows that tranexamic acid represents value for money for patients with mild or moderate traumatic brain injury.
Cohen presents his credentials early in the article ("I have taken LSD many times"), and a note reveals that he spent some time at Timothy Leary and Richard Alpert's Castalia Foundation. But then, when the acid-heads know he's on their side of the chasm: pow.
Model representation of lipin 1 binding to PA. Phosphorylated Ser/Thr residues are identified by number, where brackets indicate either or both residues may be phosphorylated, NLIP and CLIP are conserved NH2- and COOH-LIP in homology domains, HAD is haloacid dehalogenase-like domain identified by DxDxT, NLS/PBD is the nuclear localization sequence/polybasic domain with the sequence shown below, SRD is the serine-rich domain previously identified to bind to 14-3-3, and b is the 33-amino acid alternatively spliced exon.
Lipin 1 is clearly required for phospholipid and neutral lipid synthesis. Insulin stimulation promotes triacylglycerol synthesis in adipose tissue (37). It may seem paradoxical that insulin stimulation increases lipin 1 phosphorylation and decreases its interaction with membranes and thus its enzymatic activity (4). However, a second major driving force for this reaction is increased fatty acid availability. This provides a feed-forward stimulus through the accumulation of fatty acids and PA in membranes that promotes the translocation of lipins to the endoplasmic reticulum and enables cells to match their rates of triacylglycerol synthesis to the fatty acid supply. This occurs during β-adrenergic stimulation of adipocytes, which promotes lipolysis, increases fatty acid accumulation, and increases lipin 1 membrane association, resulting in increased fatty acid esterification (4, 38, 39). This translocation would be favored by low insulin stimulated phosphorylation of lipin 1.
It is also possible that alterations in intracellular pH, combined with the effect of pH on the ability of lipin 1 to bind to PA, could contribute to the observations in vivo. To use adipocytes as an example, during insulin stimulation, lipin 1 is highly phosphorylated. Presumably this will decrease lipin 1 affinity for PA. However, adipocytes also increase fatty acid esterification to PA during the influx of fatty acids from lipoprotein lipase postprandially. Therefore, the concentration of PA at the ER will increase, overcoming the inhibitory effect of phosphorylation. On the other hand, stimulation of adipocytes with a catecholamine, such as epinephrine, causes a profound induction of triacylglycerol lipolysis. The high levels of fatty acids flooding the cell decrease intracellular pH (40). At the same time, insulin signaling pathways are inhibited, particularly the mTORC1 pathway (41). Thus, the reduction in pH decreases lipin 1 affinity for PA, yet at the same time lipin 1 phosphorylation is inhibited, thereby increasing its affinity for PA. We postulate that lipin 1 phosphorylation is a necessary counterbalance to maintain PAP activity during changes in intracellular pH, alterations in PC:PE ratios, and possibly intracellular fatty acid accumulation. Maintaining a relatively similar degree of lipin 1 affinity for PA could be important because allowing lipin 1 to have a high affinity for PA at any pH could promote lipin 1-mediated hydrolysis of PA generated via insulin stimulation of PLD at the plasma membrane or other membrane surfaces outside of the ER. In addition, lipin 1 might show increasing phosphorylation because of the importance of preventing lipin 1 from binding to the inner leaflet of the plasma membrane, an important site for the PA role in insulin-stimulated GLUT4 vesicle fusion (42, 43). Thus, as the intracellular pH changes, increasing or decreasing lipin 1 affinity for PA, phosphorylation is reciprocally regulated to maintain a relatively constant affinity for PA. We should point out that biochemical fractionation may not be an accurate measure of lipin 1 microsomal association, as changing the intracellular pH to the pH of the buffer during homogenization may artificially change lipin 1 association with membranes.
Gastroesophageal reflux disease (GERD) is the most common esophageal disease. Besides the typical presentation of heartburn and acid regurgitation, either alone or in combination, GERD can cause atypical symptoms. An estimated 20 to 60 percent of patients with GERD have head and neck symptoms without any appreciable heartburn. While the most common head and neck symptom is a globus sensation (a lump in the throat), the head and neck manifestations can be diverse and may be misleading in the initial work-up. Thus, a high index of suspicion is required. Laryngoscopy can confirm the diagnosis of laryngopharyngeal reflux. Erythema of the posterior larynx may be seen, and the true vocal cords may be edematous. Treatment should be initiated with a histamine H2 receptor blocker or proton pump inhibitor. Lifestyle changes are also beneficial. Untreated, GERD can lead to chronic laryngitis, dysphonia, chronic sore throat, chronic cough, constant throat clearing, granuloma of the true vocal cords and other problems.
The pathophysiology of GERD in patients with gastrointestinal symptoms differs from that in patients with head and neck symptoms. Patients with gastrointestinal symptoms have esophageal dysmotility and dysfunction of the lower esophageal sphincter, whereas patients with head and neck manifestations have dysfunction of the upper esophageal sphincter but good esophageal motility.2 Patients with gastrointestinal symptoms usually experience esophageal reflux when they are supine, whereas patients with head and neck manifestations have laryngopharyngeal reflux during the daytime when they are upright. Interestingly, one study revealed that only 18 percent of patients with head and neck manifestations of GERD had esophagitis.2 041b061a72