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Background In severe traumatic brain injury (TBI), sedatives are often used to control intracranial pressure (ICP), to reduce brain metabolism, to allow for other treatments such as mechanical ventilation or targeted temperature management, or to control paroxysmal sympathetic hyperactivity. Prolonged sedation is often necessary. The most commonly used sedatives in TBI are propofol and midazolam, often in combination, but both have significant side effects when used at high doses for several days. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, provides sedation and analgesia with minimal respiratory depression or haemodynamic instability. However, ketamine carries a US Food and Drug Administration (FDA) precaution regarding its use in patients with pre-anaesthetic elevated cerebrospinal fluid pressure, which discourages its use in TBI patients. Several observational studies and two large meta-analyses do not suggest that the use of ketamine as an induction agent or sedative in sedated and mechanically ventilated TBI patients would increase the ICP. Off-label use of ketamine for this indication is increasing worldwide. To date, no prospective randomized clinical trial (RCT) has demonstrated the safety of ketamine in TBI patients. Methods The Brain Injury and Ketamine (BIKe) study is a prospective multicentre double-blind placebo-controlled RCT, to evaluate the safety, and effect on therapeutic intensity to reduce ICP, of ketamine as an adjunct to a standard sedation regimen in patients with severe TBI. Adult TBI patients, admitted to the intensive care unit (ICU), requiring sedation and ICP monitoring within 72 h of admission, will be randomized to ketamine or placebo. The study drug will be started within 6 h of randomization. The dose of the investigational medicinal product (IMP) is 1 mg/kg/h, by continuous infusion. The IMP will be stopped when the last ICP control sedative is discontinued. Data collection will stop when the patient is discharged from the ICU. All patients will be followed for 6 months post-trauma. The study is powered for the safety endpoint of detecting a clinically relevant increase of two episodes in the median number of episodes of high intracranial pressure episodes per ICU stay. A total of 100 patients are required to meet these objectives. We hypothesize a clinically relevant reduction in the therapeutic intensity level (TIL) score of at least 3 points. Discussion This study is the first prospective RCT to investigate the safety of ketamine as an adjunct to a standard sedation regimen in TBI patients. Trial registration ClinicalTrials.gov NCT05097261. Registered on October 28, 2021.

Background Cognitive function can be affected in conditions with raised intracranial pressure (ICP) such as idiopathic intracranial hypertension (IIH). Drugs used off label to treat raised ICP also have cognitive side effects, underscoring the unmet need for effective therapeutics which reduce ICP without worsening cognition. The Glucagon Like Peptide-1 (GLP-1) receptor agonist, exenatide, has been shown to significantly reduce ICP in IIH, therefore this study aimed to determine the effects of exenatide on cognition in IIH. Methods This was an exploratory study of the IIH:Pressure trial (ISTCRN 12678718). Women with IIH and telemetric ICP monitors (n = 15) were treated with exenatide (n = 7) or placebo (n = 8) for 12 weeks. Cognitive function was tested using the National Institute of Health Toolbox Cognitive Battery at baseline and 12 weeks. Results Cognitive performance was impaired in fluid intelligence ((T-score of 50 = population mean), mean (SD) 37.20 (9.87)), attention (33.93 (7.15)) and executive function (38.07 (14.61)). After 12-weeks there was no evidence that exenatide compromised cognition (no differences between exenatide and placebo). Cognition improved in exenatide treated patients in fluid intelligence (baseline 38.4 (8.2), 12 weeks 52.9 (6.6), p  = 0.0005), processing speed (baseline 43.7 (9.4), 12 weeks 58.4 (10.4), p  = 0.0058) and episodic memory (baseline 49.4 (5.3), 12 weeks 62.1 (13.2), p  = 0.0315). Conclusions In patients with raised ICP due to IIH, exenatide, a drug emerging as an ICP lowering agent, does not adversely impact cognition. This is encouraging and has potential to be relevant when considering prescribing choices to lower ICP.

Objective:To prospectively study S-100B and neuron specific enolase (NSE) levels in subjects treated for severe head injury (sTBI), and investigate the prognostic value of these biomarkers.Methods:Subjects included in a prospective double blind randomised study for sTBI. Inclusion criteria: Glasgow Coma Score (GCS) ⩽8, age 15–70 years, first recorded cerebral perfusion pressure of >10 mm Hg and arrival <24 h after trauma. Subjects were treated with an intracranial pressure (ICP) targeted therapy. Blood samples for S-100B and NSE were drawn immediately after arrival and every 12 h for 5 days. Outcome was evaluated as Glasgow Outcome Scale (GOS) by independent staff at 3 and 12 months.Results:48 subjects, mean age 35.5 years, and median GCS 6 were included. The first blood sample was drawn at 15.6 (1.4) h after injury. Initial concentration of S-100B was 1.04 (0.21) μg/l and for NSE 18.94 (2.32) μg/l. The biomarkers were significantly higher in subjects with GCS 3 and in those who died compared with those with GCS 4–8 and GOS 2–5, respectively. Receiver operated characteristic curve analyses of the initial S-100B and NSE levels to GOS dichotomised as unfavourable (GOS 1–3) and favourable (GOS 4–5) showed a weak correlation: AUC 0.585 and 0.555, respectively. Using the dichotomisation dead (GOS 1)/alive (GOS 2–5), the AUC values were 0.687 and 0.734, respectively. Furthermore, a correlation was found between the biomarkers themselves and the biomarkers and ICP.Conclusion:At 3 and 12 months after trauma, no differences in prognostic values between the markers were apparent nor was there any clinical significant value of the markers as predictors of clinical outcome.

In this randomized trial of hypothermia in children with severe traumatic brain injury, severe disability, a persistent vegetative state, or death occurred in 31% of patients who were treated with hypothermia for 24 hours and in 22% of controls. These findings suggest that hypothermia is not a beneficial therapy for children with traumatic brain injury. In this randomized trial of hypothermia in children with severe traumatic brain injury, severe disability, a persistent vegetative state, or death occurred in 31% of patients who were treated with hypothermia for 24 hours and in 22% of controls. Hypothermia therapy significantly improves survival and the neurologic outcome in rodent models of traumatic brain injury. 1 , 2 An early case series involving 18 children suggested that hypothermia therapy could improve survival and the neurologic outcome among children with traumatic brain injury. 3 These observations led to two randomized trials involving children. 4 , 5 In these two trials, investigators analyzed a total of 96 children with severe traumatic brain injury and reported that hypothermia therapy appeared to be safe and caused no significant increase in serious adverse events; however, these trials were not powered to detect significant improvements in survival or neurologic recovery. . . .

There are no therapies shown to improve outcome after severe traumatic brain injury (TBI) in humans, a leading cause of morbidity and mortality. We sought to verify brain exposure of the systemically administered antioxidant N-acetylcysteine (NAC) and the synergistic adjuvant probenecid, and identify adverse effects of this drug combination after severe TBI in children. IRB-approved, randomized, double-blind, placebo controlled Phase I study in children 2 to 18 years-of-age admitted to a Pediatric Intensive Care Unit after severe TBI (Glasgow Coma Scale [GCS] score ≤8) requiring an externalized ventricular drain for measurement of intracranial pressure (ICP). Patients were recruited from November 2011-August 2013. Fourteen patients (n = 7/group) were randomly assigned after obtaining informed consent to receive probenecid (25 mg/kg load, then 10 mg/kg/dose q6h×11 doses) and NAC (140 mg/kg load, then 70 mg/kg/dose q4h×17 doses), or placebos via naso/orogastric tube. Serum and CSF samples were drawn pre-bolus and 1-96 h after randomization and drug concentrations were measured via UPLC-MS/MS. Glasgow Outcome Scale (GOS) score was assessed at 3 months. There were no adverse events attributable to drug treatment. One patient in the placebo group was withdrawn due to adverse effects. In the treatment group, NAC concentrations ranged from 16,977.3±2,212.3 to 16,786.1±3,285.3 in serum and from 269.3±113.0 to 467.9±262.7 ng/mL in CSF, at 24 to 72 h post-bolus, respectively; and probenecid concentrations ranged from 75.4.3±10.0 to 52.9±25.8 in serum and 5.4±1.0 to 4.6±2.1 μg/mL in CSF, at 24 to 72 h post-bolus, respectively (mean±SEM). Temperature, mean arterial pressure, ICP, use of ICP-directed therapies, surveillance serum brain injury biomarkers, and GOS at 3 months were not different between groups. Treatment resulted in detectable concentrations of NAC and probenecid in CSF and was not associated with undesirable effects after TBI in children. ClinicalTrials.gov NCT01322009.

The potential superiority of hypertonic saline (HTS) over mannitol (MTL) for control of intracranial pressure (ICP) following traumatic brain injury (TBI) is still debated. Forty-seven severe TBI patients with increased ICP were prospectively recruited in two university hospitals and randomly treated with equiosmolar infusions of either MTL 20% (4 mL/kg; n=25 patients) or HTS 7.5% (2 mL/kg; n=22 patients). Serum sodium, hematocrit, ICP, arterial blood pressure, cerebral perfusion pressure (CPP), shear rate, global indices of cerebral blood flow (CBF) and metabolism were measured before, and 30 and 120 min following each infusion during the course of illness. Outcome was assessed at 6 months. Both HTS and MTL effectively and equally reduced ICP levels with subsequent elevation of CPP and CBF, although this effect was significantly stronger and of longer duration after HTS and correlated with improved rheological blood properties induced by HTS. Further, effect of HTS on ICP appeared to be more robust in patients with diffuse brain injury. In contrast, oxygen and glucose metabolic rates were left equally unaffected by both solutions. Accordingly, there was no significant difference in neurological outcome between the two groups. In conclusion, MTL was as effective as HTS in decreasing ICP in TBI patients although both solutions failed to improved cerebral metabolism. HTS showed an additional and stronger effect on cerebral perfusion of potential benefit in the presence of cerebral ischemia. Treatment selection should therefore be individually based on sodium level and cerebral hemodynamics.

Background To investigate whether the administration of intravenous propofol before endotracheal suctioning (ES) in patients with severe brain disease can reduce the sputum suction response, improve prognosis, and accelerate recovery. Methods A total of 208 severe brain disease patients after craniocerebral surgery were enrolled in the study. The subjects were randomly assigned to the experimental group ( n  = 104) and the control group ( n  = 104). The experimental group was given intravenous propofol (10 ml propofol with 1 ml 2% lidocaine), 0.5–1 mg/kg, before ES, while the control group was subjected to ES only. Changes in vital signs, sputum suction effect, the fluctuation range of intracranial pressure (ICP) before and after ES, choking cough response, short-term complications, length of stay, and hospitalization cost were evaluated. Additionally, the Glasgow Outcome Scale (GOS) prognosis score was obtained at 6 months after the operation. Results At the baseline, the characteristics of the two groups were comparable ( P  > 0.05). The increase of systolic blood pressure after ES was higher in the control group than in the experimental group ( P  < 0.05). The average peak value of ICP in the experimental group during the suctioning (15.57 ± 12.31 mmHg) was lower than in the control group (18.24 ± 8.99 mmHg; P  < 0.05). The percentage of patients experiencing cough reaction- during suctioning in the experimental group was lower than in the control group ( P  < 0.05), and the fluctuation range of ICP was increased ( P  < 0.0001). The effect of ES was achieved in both groups. The incidence of short-term complications in the two groups was comparable ( P  > 0.05). At 6 months after the surgery, the GOS scores were significantly higher in the experimental than in the control group (4–5 points, 51.54% vs. 32.64%; 1–3 points, 48.46% vs. 67.36%; P  < 0.05). There was no significant difference in the length of stay and hospitalization cost between the two groups. Conclusions Propofol sedation before ES could reduce choking cough response and intracranial hypertension response. The use of propofol was safe and improved the long-term prognosis. The study was registered in the Chinese Clinical Trial Registry on May 16, 2015 (ChiCTR-IOR-15006441).

Background Despite recent advances in neuroimaging and neurocritical care, severe traumatic brain injury (TBI) is still a major cause of severe disability and mortality, with increasing incidence worldwide. Antisecretory factor (AF), commercially available as Salovum®, has been shown to lower intracranial pressure (ICP) in experimental models of, e.g., TBI and herpes encephalitis. The aim of this study is to assess the effect of antisecretory factors in adult patients with severe TBI on ICP and inflammatory mediators in extracellular fluid and plasma. Methods/design This is a single-center, randomized, placebo-controlled clinical phase 2 trial, investigating the clinical superiority of Salovum® given as a food supplement during 5 days to adults with severe TBI (Glasgow Coma Scale (GCS) < 9), admitted to the neurocritical intensive care unit (NICU) at Skane university hospital, Lund, Sweden. All patients with GCS < 9 and clinical indication for insertion of ICP-monitor and microdialysis catheter will be screened for inclusion and assigned to either the treatment group ( n  = 10) or placebo group ( n  = 10). In both groups, the primary outcome will be ICP (mean values and change from baseline during intervention), registered from high-frequency data monitoring for 5 days. Secondary outcomes will be inflammatory mediators in plasma and intracerebral microdialysis perfusate days 1, 3, and 5 during trial treatment. Trial registration ClinicalTrials.gov NCT04117672 . Registered on September 17, 2017. Protocol version 6 from October 24, 2023.

The use of programmed intermittent epidural bolus for postoperative analgesia may have greater analgesic efficacy than continuous epidural infusion. However, the rapid delivery speed used with an epidural bolus is more likely to increase intracranial pressure. We compared the effects of lumbar epidural bolus versus continuous infusion epidural analgesia on intracranial pressure in children using optic nerve sheath diameter as a marker. We randomly assigned 40 paediatric patients to bolus or infusion groups. Epidural analgesia (0.15% ropivacaine 0.3 ml·kg −1 ) was administered via bolus or infusion. Ultrasonography was used to measure the optic nerve sheath diameter before (T0), at 3 min (T1), 10 min (T2), and 70 min (T3) after starting the pump. There were statistically significant between-group differences in optic nerve sheath diameter over time (P Group x Time  = 0.045). From T0–T3, the area under the curve values were similar between the two groups. Although there were differences in the patterns of optic nerve sheath diameter change according to the delivery mode, the use of lumbar epidural bolus did not increase the risk of intracranial pressure increase over that of continuous infusion. Further research is needed to investigate intracranial pressure changes after continuous application of each delivery mode.

Traumatic brain injury (TBI) is an important cause of death and disability. Safety and pharmacodynamics of 4-amino-tetrahydrobiopterin (VAS203), a nitric oxide (NO)-synthase inhibitor, were assessed in TBI in an exploratory Phase IIa study (NOSynthase Inhibition in TRAumatic brain injury=NOSTRA). The study included 32 patients with TBI in six European centers. In a first open Cohort, eight patients received three 12-h intravenous infusions of VAS203 followed by a 12-h infusion-free interval over 3 days (total dose 15 mg/kg). Patients in Cohorts 2 and 3 (24) were randomized 2:1 to receive either VAS203 or placebo as an infusion for 48 or 72 h, respectively (total dose 20 and 30 mg/kg). Effects of VAS203 on intracranial pressure (ICP), cerebral perfusion pressure (CPP), brain metabolism using microdialysis, and the therapy intensity level (TIL) were end points. In addition, exploratory analysis of the extended Glasgow Outcome Score (eGOS) after 6 months was performed. Metabolites of VAS203 were detected in cerebral microdialysates. No significant differences between treatment and placebo groups were observed for ICP, CPP, and brain metabolism. TIL on day 6 was significantly decreased (p<0.04) in the VAS203 treated patients. The eGOS after 6 months was significantly higher in treated patients compared with placebo (p<0.01). VAS203 was not associated with hepatic, hematologic, or cardiac toxic effects. At the highest dose administered, four of eight patients receiving VAS203 showed transitory acute kidney injury (stage 2–3). In conclusion, the significant improvement in clinical outcome indicates VAS203-mediated neuroprotection after TBI. At the highest dose, VAS203 is associated with a risk of acute kidney injury.