Cerebral vasospasm in children with subarachnoid hemorrhage: frequency, diagnosis, and therapeutic management.

BACKGROUND: The present study explores the frequency, diagnostic approach, and therapeutic management of cerebral vasospasm in a cohort of children with moderate-to-severe traumatic and nontraumatic subarachnoid hemorrhage (SAH). METHODS: This was a single-center retrospective study performed over a 10-year period, from January 2010 to December 2019. Children aged from one month to 18 years who were admitted to the pediatric or adult intensive care unit with a diagnosis of SAH were eligible. Cerebral vasospasm could be suspected by clinical signs or transcranial Doppler (TCD) criteria (mean blood flow velocity > 120 cm/s or an increase in mean blood flow velocity by > 50 cm/s within 24 h) and then confirmed on cerebral imaging (with a reduction to less than 50% of the caliber of the cerebral artery). RESULTS: Eighty patients aged 8.6 years (3.3-14.8 years, 25-75th centiles) were admitted with an initial Glasgow Coma Scale score of 8 (4-12). SAH was nontraumatic in 21 (26%) patients. A total of 14/80 patients (18%) developed cerebral vasospasm on brain imaging on day 6 (5-10) after admission, with a predominance of nontraumatic SAH (12/14). The diagnosis of cerebral vasospasm was suspected on clinical signs and/or significant temporal changes in TCD monitoring (7 patients) and then confirmed on cerebral imaging. Thirteen of 14 patients with vasospasm were successfully treated using a continuous intravenous infusion of milrinone. The Pediatric Cerebral Performance Category score at discharge from the intensive care unit was comparable between children with vasospasm (score of 2 [1-4]) vs. children without vasospasm (score of 4 [2-4]) (p = 0.09). CONCLUSIONS: These findings indicate that cerebral vasospasm exists in pediatrics, particularly after nontraumatic SAH. The use of TCD and milrinone may help in the diagnostic and therapeutic management of cerebral vasospasm.

Clinical applications of transcranial Doppler in non-trauma critically ill children: a scoping review.

BACKGROUND: Many applications of transcranial Doppler (TCD) as a diagnosis or monitoring tool have raised interest in the last decades. It is important that clinicians know when and how to perform TCD in this population, what parameter to assess and monitor and how to interpret it. OBJECTIVE: This review aims to describe the emerging clinical applications of TCD in critically ill children excluding those suffering from trauma. METHODS: Databases Web of Science, Cochrane and PubMed were searched in May 2020. We considered all publications since the year 2000 addressing the use of TCD as a prognostic, diagnostic or follow-up tool in children aged 0 to 15 years admitted to intensive care or emergency units, excluding neonatology and traumatic brain injury. Two independent reviewers selected 82 abstracts and full-text articles from the 2011 unique citations identified at the outset. RESULTS: TCD provides crucial additional information at bedside about cerebrovascular hemodynamics. Many clinical applications include the diagnosis and management of various medical and surgical neurologic conditions (central nervous system infections, arterial ischemic stroke, subarachnoid hemorrhage and vasospasm, brain death, seizures, metabolic disease, hydrocephalus) as well as monitoring the impact systemic conditions on brain perfusion (hemodynamic instability, circulatory assistance). CONCLUSION: To conclude, TCD has become an invaluable asset for non-invasive neuromonitoring in critically ill children excluding those suffering from trauma. However, the scope of TCD remains unclearly defined yet and reference values in critically ill children are still lacking.

Impact of Head-of-Bed Posture on Brain Oxygenation in Patients with Acute Brain Injury: A Prospective Cohort Study.

BACKGROUND: Therapeutic head positioning plays a role in the management of patients with acute brain injury. Although intracranial pressure (ICP) is typically lower in an upright posture than in a flat position, limited data exist concerning the effect of upright positioning on brain oxygenation and circulation. We sought to determine the impact of supine (0°) and semirecumbent (15° and 30°) postures on ICP, brain oxygenation, and brain circulation. METHODS: An observational cohort study was conducted between February 2012 and September 2015. Twenty-three patients with severe acute brain injury were successively observed at head elevations of 30°, 15°, and 0°. Postural-induced changes in ICP, cerebral perfusion pressure, brain tissue oxygenation pressure, and transcranial Doppler findings were simultaneously measured during three repeated experiments: 24 h after admission to the intensive care unit (exp1), 24 h later (exp2), and 96 h later (exp3). Cerebral perfusion pressure, arterial blood gases, hemoglobin content, and body temperature remained unchanged during the three experiments. RESULTS: Using linear random-slope mixed models, we found that during the early phase of acute brain injury (exp1), lowering the head posture from 30° to 15°, and then to 0°, was associated with a gradual mean ICP increase of 2.6 mm Hg (1.4-3.7 mm Hg; P < 0.001); and from 30° to 0°, an increase of 7.4 mm Hg (6.3-8.6 mm Hg; P < 0.001). Furthermore, brain tissue oxygenation pressure and mean blood flow velocity improved when the head posture was lowered from 30° to 0° by 1.2 mm Hg (0.2-2.3 mm Hg) and 4.1 cm/s (0.0-8.2 cm/s), respectively (both P < 0.05). CONCLUSIONS: Changing the positioning of stable patients with acute brain injury resulted in opposite changes of ICP versus brain oxygenation and circulation. This information supports the concept of an individualized approach to head positioning that is based on the multimodal monitoring of brain parameters.

Using Pupillary Pain Index to Assess Nociception in Sedated Critically Ill Patients.

BACKGROUND: Pupillary reflex dilation is a reliable indicator of response to noxious stimulation. In a proof of concept study, we investigated the performance of pupillary pain index, a new score derived from pupillary reflex dilation measurements, to predict nociceptive response to endotracheal suctioning in sedated critically ill patients. METHODS: Twenty brain-injured and 20 non-brain-injured patients were studied within 48 hours of admission (T1) in the intensive care unit and at 48-72 hours later (T2). Video-based pupillometer was used to determine pupillary reflex dilation during tetanic stimulation. The tetanic stimulation (100 Hz) was applied to the skin area innervated by the ulnar nerve and was stepwise increased from 10 to 60 mA until pupil size had increased by 13% compared to baseline. The maximum intensity value allowed the determination of a pupillary pain index score ranging from 1 (no nociception) to 9 (high nociception). The Behavioral Pain Scale response to endotracheal suctioning was measured thereafter. RESULTS: Behavioral Pain Scale responses to endotracheal suctioning and pupillary pain index scores were positively correlated at T1 and T2 (both P < .01). After adjustments for repeated measurements and group of patients, the area under the receiver operating characteristic curve of pupillary pain index to predict Behavioral Pain Scale response to endotracheal suctioning was of 0.862 (95% CI, 0.714-0.954). In the combined set of patients, a pupillary pain index score of ≤4 could predict no nociceptive response to endotracheal suctioning with a sensitivity of 88% (95% CI, 68%-97%) and a specificity of 79% (95% CI, 66%-88%). By contrast with endotracheal suctioning, tetanic stimulation had no effect on intracranial pressure in the brain-injured group. CONCLUSIONS: These results are a proof of concept. The nociceptive response to endotracheal suctioning could be accurately predicted using the determination of pupillary pain index score in sedated critically ill patients whether they have brain injury or not.

mcr-1 Colistin Resistance in ESBL-Producing Klebsiella pneumoniae, France.

We report intestinal carriage of an extended-spectrum ß-lactamase-producing Klebsiella pneumoniae strain with high-level resistance to colistin (MIC 24 mg/L) in a patient in France who had been hospitalized for fungal meningitis. The strain had the mcr-1 plasmid gene and an inactivated mgrB gene, which are associated with colistin resistance.

Using external lumbar CSF drainage to treat communicating external hydrocephalus in adult patients after acute traumatic or non-traumatic brain injury.

BACKGROUND: Despite various treatments to control intracranial pressure (ICP) after brain injury, patients may present a late onset of high ICP or a poor response to medications. External lumbar drainage (ELD) can be considered a therapeutic option if high ICP is due to communicating external hydrocephalus. We aimed at describing the efficacy and safety of ELD used in a cohort of traumatic or non-traumatic brain-injured patients. METHODS: In this multicentre retrospective analysis, patients had a delayed onset of high ICP after the initial injury and/or a poor response to ICP treatments. ELD was considered in the presence of radiological signs of communicating external hydrocephalus. Changes in ICP values and side effects following the ELD procedure were reported. RESULTS: Thirty-three patients with a median age of 51 years (25-75th percentile: 34-61 years) were admitted after traumatic (n = 22) or non-traumatic (n = 11) brain injuries. Their initial Glasgow Coma Scale score was 8 (4-11). Eight patients underwent external ventricular drainage prior to ELD. Median time to ELD insertion was 5 days (4-8) after brain insult. In all patients, ELD was dramatically effective in lowering ICP: 25 mmHg (20-31) before versus 7 mmHg (3-10) after (p < 0.001). None of the patients showed adverse effects such as pupil changes or intracranial bleeding after the procedure. One patient developed an ELD-related infection. CONCLUSIONS: These findings indicate that ELD may be considered potentially effective in controlling ICP, remaining safe if a firm diagnosis of communicating external hydrocephalus has been made.

Dynamics of clinical recovery during the early phase of rehabilitation in patients with severe traumatic and non-traumatic brain injury.

PURPOSE: Our aim was to describe the changes in the functional outcome at the early phase of rehabilitation following severe brain injury and to identify the factors associated with faster recovery. METHODS: This retrospective analysis included 182 patients who were transferred from the intensive care unit (ICU) to a post-ICU neurorehabilitation unit following traumatic brain injury (TBI) (n = 82) or cerebrovascular accident (CVA) (n = 100). Admission, discharge and changes in scores were calculated for the Functional Independent Measurement (FIM) and the Wessex Head Injury Matrix (WHIM). Patients with high dynamics of clinical recovery were defined by delta FIM scores ≥22. RESULTS: Upon admission to the neurorehabilitation unit, 97% of patients had a FIM score <50 and 41% a WHIM score <32. Patients showed significantly improved FIM (+17 points; 7-37) and WHIM (+11 points; 3-19) scores with an over 22-day stay (14-38). Those with faster recovery (45%) were more likely those with high FIM and WHIM scores at admission. The nature and severity of the brain insult were not associated with the dynamics of recovery. CONCLUSIONS: Within a 2-6 week stay in a post-ICU neurorehabilitation unit, patients with severe disability could achieve partial functional independence and showed cognitive improvements.

Automated drug dispensing systems in the intensive care unit: a financial analysis.

INTRODUCTION: To evaluate the economic impact of automated-drug dispensing systems (ADS) in surgical intensive care units (ICUs). A financial analysis was conducted in three adult ICUs of one university hospital, where ADS were implemented, one in each unit, to replace the traditional floor stock system. METHOD: Costs were estimated before and after implementation of the ADS on the basis of floor stock inventories, expired drugs, and time spent by nurses and pharmacy technicians on medication-related work activities. A financial analysis was conducted that included operating cash flows, investment cash flows, global cash flow and net present value. RESULTS: After ADS implementation, nurses spent less time on medication-related activities with an average of 14.7 hours saved per day/33 beds. Pharmacy technicians spent more time on floor-stock activities with an average of 3.5 additional hours per day across the three ICUs. The cost of drug storage was reduced by €44,298 and the cost of expired drugs was reduced by €14,772 per year across the three ICUs. Five years after the initial investment, the global cash flow was €148,229 and the net present value of the project was positive by €510,404. CONCLUSION: The financial modeling of the ADS implementation in three ICUs showed a high return on investment for the hospital. Medication-related costs and nursing time dedicated to medications are reduced with ADS.

Intracranial pressure monitoring with and without brain tissue oxygen pressure monitoring for severe traumatic brain injury in France (OXY-TC): an open-label, randomised controlled superiority trial.

BACKGROUND: Optimisation of brain oxygenation might improve neurological outcome after traumatic brain injury. The OXY-TC trial explored the superiority of a strategy combining intracranial pressure and brain tissue oxygen pressure (PbtO2) monitoring over a strategy of intracranial pressure monitoring only to reduce the proportion of patients with poor neurological outcome at 6 months. METHODS: We did an open-label, randomised controlled superiority trial at 25 French tertiary referral centres. Within 16 h of brain injury, patients with severe traumatic brain injury (aged 18-75 years) were randomly assigned via a website to be managed during the first 5 days of admission to the intensive care unit either by intracranial pressure monitoring only or by both intracranial pressure and PbtO2 monitoring. Randomisation was stratified by age and centre. The study was open label due to the visibility of the intervention, but the statisticians and outcome assessors were masked to group allocation. The therapeutic objectives were to maintain intracranial pressure of 20 mm Hg or lower, and to keep PbtO2 (for those in the dual-monitoring group) above 20 mm Hg, at all times. The primary outcome was the proportion of patients with an extended Glasgow Outcome Scale (GOSE) score of 1-4 (death to upper severe disability) at 6 months after injury. The primary analysis was reported in the modified intention-to-treat population, which comprised all randomly assigned patients except those who withdrew consent or had protocol violations. This trial is registered with ClinicalTrials.gov, NCT02754063, and is completed. FINDINGS: Between June 15, 2016, and April 17, 2021, 318 patients were randomly assigned to receive either intracranial pressure monitoring only (n=160) or both intracranial pressure and PbtO2 monitoring (n=158). 27 individuals with protocol violations were not included in the modified intention-to-treat analysis. Thus, the primary outcome was analysed for 144 patients in the intracranial pressure only group and 147 patients in the intracranial pressure and PbtO2 group. Compared with intracranial pressure monitoring only, intracranial pressure and PbtO2 monitoring did not reduce the proportion of patients with GOSE score 1-4 (51% [95% CI 43-60] in the intracranial pressure monitoring only group vs 52% [43-60] in the intracranial pressure and PbtO2 monitoring group; odds ratio 1·0 [95% CI 0·6-1·7]; p=0·95). Two (1%) of 144 participants in the intracranial pressure only group and 12 (8%) of 147 participants in the intracranial pressure and PbtO2 group had catheter dysfunction (p=0.011). Six patients (4%) in the intracranial pressure and PbtO2 group had an intracrebral haematoma related to the catheter, compared with none in the intracranial pressure only group (p=0.030). No significant difference in deaths was found between the two groups at 12 months after injury. At 12 months, 33 deaths had occurred in the intracranial pressure group: 25 (76%) were attributable to the brain trauma, six (18%) were end-of-life decisions, and two (6%) due to sepsis. 34 deaths had occured in the intracranial pressure and PbtO2 group at 12 months: 25 (74%) were attributable to the brain trauma, six (18%) were end-of-life decisions, one (3%) due to pulmonary embolism, one (3%) due to haemorrhagic shock, and one (3%) due to cardiac arrest. INTERPRETATION: After severe non-penetrating traumatic brain injury, intracranial pressure and PbtO2 monitoring did not reduce the proportion of patients with poor neurological outcome at 6 months. Technical failures related to intracerebral catheter and intracerebral haematoma were more frequent in the intracranial pressure and PbtO2 group. Further research is needed to assess whether a targeted approach to multimodal brain monitoring could be useful in subgroups of patients with severe traumatic brain injury-eg, those with high intracranial pressure on admission. FUNDING: The French National Program for Clinical Research, La Fondation des Gueules Cassées, and Integra Lifesciences.

Diffusion tensor imaging of diffuse axonal injury in a rat brain trauma model.

Diffusion tensor imaging (DTI) was used to study traumatic brain injury. The impact-acceleration trauma model was used in rats. Here, in addition to diffusivities (mean, axial and radial), fractional anisotropy (FA) was used, in particular, as a parameter to characterize the cerebral tissue early after trauma. DTI was implemented at 7 T using fast spiral k-space sampling and the twice-refocused spin echo radiofrequency sequence for eddy current minimization. The method was carefully validated on different phantom measurements. DTI of a trauma group (n = 5), as well as a sham group (n = 5), was performed at different time points during 6 h following traumatic brain injury. Two cerebral regions, the cortex and corpus callosum, were analyzed carefully. A significant decrease in diffusivity in the trauma group versus the sham group was observed, suggesting the predominance of cellular edema in both cerebral regions. No significant FA change was detected in the cortex. In the corpus callosum of the trauma group, the FA indices were significantly lower. A net discontinuity in fiber reconstructions in the corpus callosum was observed by fiber tracking using DTI. Histological analysis using Hoechst, myelin basic protein and Bielschowsky staining showed fiber disorganization in the corpus callosum in the brains of the trauma group. On the basis of our histology results and the characteristics of the impact-acceleration model responsible for the presence of diffuse axonal injury, the detection of low FA caused by a drastic reduction in axial diffusivity and the presence of fiber disconnections of the DTI track in the corpus callosum were considered to be related to the presence of diffuse axonal injury.

Reduced brain edema and functional deficits after treatment of diffuse traumatic brain injury by carbamylated erythropoietin derivative.

OBJECTIVE: To investigate the effects of carbamylated erythropoietin, a modified erythropoietin lacking erythropoietic activity, on brain edema and functional recovery in a model of diffuse traumatic brain injury. DESIGN: Adult male Wistar rats. SETTING: Neurosciences and physiology laboratories. INTERVENTIONS: Thirty minutes after diffuse traumatic brain injury (impact-acceleration model), rats were intravenously administered with either a saline solution (traumatic brain injury-saline) or carbamylated erythropoietin (50 µg/kg; traumatic brain injury-carbamylated erythropoietin). A third group received no traumatic brain injury insult (sham-operated). MEASUREMENTS AND MAIN RESULTS: Three series of experiments were conducted to investigate: 1) the effect of carbamylated erythropoietin on brain edema before and 1 hr after traumatic brain injury using diffusion-weighted magnetic resonance imaging and measurements of apparent diffusion coefficient (n = 10 rats per group), and the phosphorylation level of brain extracellular-regulated kinase-1/-2 was also determined to indicate the presence of an activated cell signaling pathway; 2) the time course of brain edema using magnetic resonance imaging between 4 and 6 hrs postinjury and the gravimetric technique at 6 hrs (n = 10 rats per group); and 3) motor and cognitive function over 10 days post traumatic brain injury, testing acute somatomotor reflexes, adhesive paper removal, and two-way active avoidance (n = 8 rats per group). Compared to traumatic brain injury-saline rats, rats receiving traumatic brain injury-carbamylated erythropoietin showed a significant reduction in brain edema formation at 1 hr that was sustained until 6 hrs when results were comparable with sham-operated rats. This antiedematous effect of carbamylated erythropoietin was possibly mediated through an early inhibition of extracellular-regulated kinase-1/-2 phosphorylation. Compared to traumatic brain injury-saline rats, traumatic brain injury-carbamylated erythropoietin rats showed improved functional recovery of the acute somatomotor reflexes post traumatic brain injury, took less time to remove adhesive from the forelimbs, and showed higher percentages of correct avoidance responses. CONCLUSION: Our findings indicate that early posttraumatic administration of carbamylated erythropoietin reduces brain edema development until at least 6 hrs postinjury and improves neurologic recovery. Carbamylated erythropoietin can thus be considered as a potential agent in the treatment of traumatic brain injury-induced diffuse edema.

Comparison of strategies for monitoring and treating patients at the early phase of severe traumatic brain injury: the multicentre randomised controlled OXY-TC trial study protocol.

INTRODUCTION: Intracranial hypertension is considered as an independent risk factor of mortality and neurological disabilities after severe traumatic brain injury (TBI). However, clinical studies have demonstrated that episodes of brain ischaemia/hypoxia are common despite normalisation of intracranial pressure (ICP). This study assesses the impact on neurological outcome of guiding therapeutic strategies based on the monitoring of both brain tissue oxygenation pressure (PbtO2) and ICP during the first 5 days following severe TBI. METHODS AND ANALYSIS: Multicentre, open-labelled, randomised controlled superiority trial with two parallel groups in 300 patients with severe TBI. Intracerebral monitoring must be in place within the first 16 hours post-trauma. Patients are randomly assigned to the ICP group or to the ICP + PbtO2 group. The ICP group is managed according to the international guidelines to maintain ICP≤20 mm Hg. The ICP + PbtO2 group is managed to maintain PbtO2 ≥20 mm Hg in addition to the conventional optimisation of ICP. The primary outcome measure is the neurological status at 6 months as assessed using the extended Glasgow Outcome Scale. Secondary outcome measures include quality-of-life assessment, mortality rate, therapeutic intensity and incidence of critical events during the first 5 days. Analysis will be performed according to the intention-to-treat principle and full statistical analysis plan developed prior to database freeze. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Board of Sud-Est V (14-CHUG-48) and from the National Agency for Medicines and Health Products Safety (Agence Nationale de Sécurité du Médicament et des produits de santé) (141 435B-31). Results will be presented at scientific meetings and published in peer-reviewed publications.The study was registered with ClinTrials NCT02754063 on 28 April 2016 (pre-results).

Which Protocol for Milrinone to Treat Cerebral Vasospasm Associated With Subarachnoid Hemorrhage?

BACKGROUND: Milrinone has emerged as an option to treat delayed cerebral ischemia after subarachnoid hemorrhage. However, substantial variation exists in the administration of this drug. We retrospectively assessed the effectiveness of 2 protocols in patients with angiographically proven cerebral vasospasm. METHODS: During 2 successive periods, milrinone was administered using either a combination of intra-arterial milrinone infusion followed by intravenous administration until day 14 after initial bleeding (IA+IV protocol), or a continuous intravenous milrinone infusion for at least 7 days (IV protocol). The primary endpoint was the reversion rate of vasospastic arterial segments following the first IA infusion of milrinone (IA+IV protocol) compared with the reversion rate during the first week of IV infusion (IV protocol). RESULTS: There were 24 and 77 consecutive patients in IA+IV and IV protocols, respectively. The reversion rate was comparable between the 2 protocols: 71% (95% confidence interval [CI], 59%-83%) in the IA+IV protocol versus 64% (95% CI, 58%-71%) in the IV protocol (P=0.36). Rescue procedures for persistence or recurrence of vasospasm, that is, mechanical angioplasty and/or IA milrinone infusion, were similar between the 2 protocols. Patients with a good neurological outcome at 1 year, that is, modified Rankin Scale scores 0-2, were comparable between the 2 protocols. Side effects of milrinone were uncommon and equally distributed within the 2 protocols. CONCLUSIONS: These findings indicate that a continuous IV infusion of milrinone was as efficient as combined IA+IV infusion and suggest that this modality could be considered as a first easy-to-use option to treat patients with CVS.

Equimolar doses of mannitol and hypertonic saline in the treatment of increased intracranial pressure.

OBJECTIVE: To compare the effects of equimolar doses of 20% mannitol solution and of 7.45% hypertonic saline solution (HSS) in the treatment of patients with sustained elevated intracranial pressure (ICP). DESIGN: Parallel, randomized, controlled trial. SETTING: Two intensive care units in a university hospital. PATIENTS: A total of 20 stable patients with a sustained ICP of >20 mm Hg secondary to traumatic brain injury (n = 17) or stroke (n = 3). INTERVENTIONS: A single equimolar infusion (255 mOsm dose) of either 231 mL of 20% mannitol (mannitol group; n = 10 patients) or 100 mL of 7.45% hypertonic saline (HSS group; n = 10 patients) during 20 mins of administration. MEASUREMENTS: ICP, arterial blood pressure, cerebral perfusion pressure, blood flow velocities of middle cerebral artery using continuous transcranial Doppler, brain tissue oxygen tension, serum sodium and osmolality, and urine output during a study period of 120 mins. MAIN RESULTS: The two treatments equally and durably reduced ICP during the experiment. At 60 mins after the start of the infusion, ICP was reduced by 45% +/- 19% of baseline values (mean +/- sd) in the mannitol group vs. 35% +/- 14% of baseline values in the HSS group. Cerebral perfusion pressure and diastolic and mean blood flow velocities were durably increased in the mannitol group, resulting in lower values of pulsatility index at the different times of the experiment (p < .01 vs. HSS). No major changes in brain tissue oxygen tension were found after each treatment. Mannitol caused a significantly greater increase in urine output (p < .05) than HSS, although there was no difference in the vascular filling requirement between the two treatments. HSS caused a significant elevation of serum sodium and chloride at 120 mins after the start of the infusion (p < .01). CONCLUSIONS: A single equimolar infusion of 20% mannitol is as effective as 7.45% HSS in decreasing ICP in patients with brain injury. Mannitol exerts additional effects on brain circulation through a possible improvement in blood rheology. Pretreatment factors, such as serum sodium, systemic hemodynamics, and brain hemodynamics, thus should be considered when choosing between mannitol and HSS for patients with increased ICP.

Characterization and quantification of cerebral edema induced by synchrotron x-ray microbeam radiation therapy.

Cerebral edema is one of the main acute complications arising after irradiation of brain tumors. Microbeam radiation therapy (MRT), an innovative experimental radiotherapy technique using spatially fractionated synchrotron x-rays, has been shown to spare radiosensitive tissues such as mammal brains. The aim of this study was to determine if cerebral edema occurs after MRT using diffusion-weighted MRI and microgravimetry. Prone Swiss nude mice's heads were positioned horizontally in the synchrotron x-ray beam and the upper part of the left hemisphere was irradiated in the antero-posterior direction by an array of 18 planar microbeams (25 mm wide, on-center spacing 211 mm, height 4 mm, entrance dose 312 Gy or 1000 Gy). An apparent diffusion coefficient (ADC) was measured at 7 T 1, 7, 14, 21 and 28 days after irradiation. Eventually, the cerebral water content (CWC) was determined by microgravimetry. The ADC and CWC in the irradiated (312 Gy or 1000 Gy) and in the contralateral non-irradiated hemispheres were not significantly different at all measurement times, with two exceptions: (1) a 9% ADC decrease (p < 0.05) was observed in the irradiated cortex 1 day after exposure to 312 Gy, (2) a 0.7% increase (p < 0.05) in the CWC was measured in the irradiated hemispheres 1 day after exposure to 1000 Gy. The results demonstrate the presence of a minor and transient cellular edema (ADC decrease) at 1 day after a 312 Gy exposure, without a significant CWC increase. One day after a 1000 Gy exposure, the CWC increased, while the ADC remained unchanged and may reflect the simultaneous presence of cellular and vasogenic edema. Both types of edema disappear within a week after microbeam exposure which may confirm the normal tissue sparing effect of MRT.

Lethal cerebral hemorrhage after ticagrelor intoxication: a specific antidote is urgently needed.

BACKGROUND: Ticagrelor is a direct and reversible competitive antagonist of the P2Y12 receptor and inhibits platelet activation. Although adverse bleeding is common, fatal intoxication has never been documented. CASE DESCRIPTION: A 47-year-old man died from a severe cerebral hemorrhage secondary to a fall and cranial trauma 4 d after the massive intake of ticagrelor. Iterative platelet transfusions did not improve his condition. Toxicological analyses by liquid chromatography tandem mass spectrometry (LC-MS/MS) revealed high plasma concentrations of ticagrelor (3343 µg/L) and its active metabolite AR-C124910XX (656 µg/L) 10 h after intake. The approximate ingested dose was extrapolated to 1677 mg. Assessment of ADP-induced platelet aggregation and platelet Vasodilator Stimulated Phosphoprotein phosphorylation (VASP), 2 and 3 d after admission, respectively, showed the persistence of platelet inhibition. DISCUSSION: To the best of our knowledge, no prior fatal cases have been reported and documented with both ticagrelor and AR-C124910XX concentrations. Our findings highlight the need for a specific antidote to manage such complications resulting from ticagrelor overdose.