Evidence Of Bleeding Research Articles

9332 Breathless Struggle: Unraveling The Interplay Between DKA And Acute Respiratory Distress Syndrome

Abstract Disclosure: S. Zahra: None. R. Subramani: None. M. Abbas: None. K.Y. Hasan: None. F. Manas: None. C. Bajracharya: None. Introduction: Diabetic Ketoacidosis (DKA) is a life threatening emergency with mortality rate of 0.15%-0.30%. Acute Respiratory Distress Syndrome (ARDS) is a rare complication of DKA which presents as a sudden onset of dyspnea and progressive hypoxia. It is an inflammatory process that damages the alveolar-capillary membrane leading to the fluid leakage into the alveolar space. The incidence of ARDS in DKA remains unknown. It is more commonly seen in adolescents and young adults. The exact pathogenesis of ARDS in DKA is currently unknown. Some proposed mechanisms are that a severe metabolic acidosis in DKA along with increased cytokines production due to long standing hyperglycemia leads to increased capillary membrane permeability allowing fluid to accumulate in the alveolar space. TNF-a and IL-6 along with other pro-inflammatory cytokines are known to cause endothelial damage and increase pulmonary permeability leading to pulmonary edema. However most DKA patients with severe metabolic acidosis do not develop ARDS. Case Presentation:Case 1: A 19 year old male with uncontrolled type I diabetes mellitus presented with altered mental status. On examination, he was tachycardic and tachypneic with dry mucous membranes. Lab workup revealed leukocytosis, severe hyperglycemia, and severe anion gap metabolic acidosis with beta hydroxybutyrate level of 14.20 mmol/L (normal: 0.02-0.27 mmol/L). He was diagnosed with DKA and started on intravenous fluids, and insulin as per institutional DKA protocol. Approximately 12 hours post-admission, the patient experienced sudden-onset dyspnea with deteriorating hypoxia, necessitating emergent intubation and mechanical ventilation. Chest radiography displayed bilateral patchy ground-glass opacifications consistent with acute respiratory distress syndrome (ARDS). Despite the administration of 8 liters of intravenous fluids, the patient exhibited a negative net fluid balance of 2.3 liters, implicating fluid shift. Further investigations, including bronchoscopy and bronchoalveolar lavage, revealed an unobstructed airway, minimal secretions, and no evidence of hemorrhage or infection. Comprehensive infectious work-ups yielded negative results as well, reinforcing the diagnosis of DKA as the underlying cause of ARDS. Conclusion: Acute Respiratory Distress Syndrome is a rare but potentially fatal complication of Diabetic Ketoacidosis. Early recognition of this serious pulmonary complication of DKA and its prompt management is essential to prevent respiratory failure and mortality. Presentation: 6/1/2024

Hemorrhagic versus non-hemorrhagic presentation of presumed reversible cerebral vasoconstriction syndrome (RCVS): Presentations and outcomes

Introduction Reversible cerebral vasoconstriction syndrome (RCVS) can present with hemorrhage, ischemia, or both. We aim to compare the differences in presentation and outcomes between patients with RCVS. Methods The hemorrhagic presentation group had 58 patients, and the non-hemorrhagic presentations had 30 patients. Subgroup analysis compared patients with evidence of one or more types of hemorrhage ( n = 53), no evidence of hemorrhage or infarction ( n = 23), evidence of infarction only ( n = 7), and combination of hemorrhage and infarction ( n = 5). Clinical and radiographic data were analyzed. Results Migraine ( p = 0.030) and intracranial tumors ( p = 0.004) were more frequent in non-hemorrhagic presentation. Seizures on admission ( p = 0.047) and higher than average C-reactive protein (CRP) ( p = 0.037) were seen at a higher rate in patients with hemorrhagic presentation. RCVS2 scores were not unexpectedly higher in patients with hemorrhage than non-hemorrhagic presentations ( p = 0.010). Outcomes between the hemorrhagic and non-hemorrhagic groups were comparable. Subgroup analysis found a higher subset of patients with opiate use ( p = 0.046) in the hemorrhage-only group. Patients with hemorrhage presented with a thunderclap headache ( p < 0.001) more often when compared to the other three groups. RCVS2 score was not unexpectedly higher in the hemorrhage-only group compared with the other groups ( p = 0.004). Conclusion A history of migraines was associated with ischemia, while intracranial tumor was significantly associated with evidence of either an infarct, or no changes on imaging. Exposure to opiates, and seizures or thunderclap headache on presentation were associated with hemorrhage. If our data are reproducible, the RCVS2 score may benefit from inclusion of other, small hemorrhages as criterion for diagnosis for RCVS.

Microhemorrhages in diquat-induced encephalopathy identified using susceptibility-weighted imaging

Introduction Intracerebral bleeding that predominantly affects the pons, midbrain, cerebral peduncle, basal ganglia, and thalamus may occur in severe diquat poisoning. We employed magnetic resonance-susceptibility-weighted imaging to highlight the presence of microhemorrhages in a patient with diquat poisoning. Case summary: A 15-year-old female patient presented with kidney and liver damage after ingesting diquat. Three days later, she developed coma. She received seven sessions of hemoperfusion and was discharged with residual cognitive impairment and right limb muscle weakness after 66 days of hospitalization. Images: Cranial computed tomography on day 5 and magnetic resonance imaging on day 8 revealed swelling in the pons, midbrain, and thalamus without evidence of hemorrhage. However, susceptibility-weighted imaging on day 8 demonstrated multiple punctate low signals, suggesting the presence of microhemorrhages. Conclusion Susceptibility-weighted imaging is a useful technique for detecting microhemorrhages in patients with diquat-induced encephalopathy, as microhemorrhages are often not detectable on computed tomography or conventional magnetic resonance imaging.

SURG-07. A PHASE I STUDY EXAMINING THE FEASIBILITY OF INTERMITTENT CONVECTION-ENHANCED DELIVERY (CED) OF MTX110 FOR THE TREATMENT OF CHILDREN WITH NEWLY DIAGNOSED DIFFUSE MIDLINE GLIOMAS

Abstract BACKGROUND Histone deacetylase inhibitors have been found preclinically to be among the most active agents against Diffuse Midline Gliomas (DMGs), however, they are clinically ineffective with systemic delivery due to low blood brain barrier penetration and systemic toxicity. Using an implantable subcutaneous pump connected with a catheter directly implanted into the pons we have conducted a phase I, 3 + 3 dose escalation study to investigate the safety and feasibility of repeated infusions of MTX110 (Biodexa Ltd), a water-soluble formulation of panobinostat, via CED. METHODS Eligible patents were between 3 and 18 years of age with newly diagnosed DMG following radiation therapy, without evidence of hemorrhage or cyst in the tumor, and having normal organ function. First, patients underwent tumor biopsy and device implantation, then received two 48-hour-infusion pulses 7 days apart. Three dose levels of MTX110 infusions (30, 60, 90 mcM) were studied. The infusion pump was prefilled with MTX110 (and gadolinium for co-infusion as a contrast agent), which was then administered using the wireless N’Vision clinical programmer at a rate of 0.2 mL/hr. RESULTS Nine patients were treated in the study (30 mcM group, n=3; 60 mcM group, n=4; 90 mcM group, n=2). All patients had an H3K27M mutated tumor. All but one patient had adequate tumor coverage with the infusate. One patient suffered a severe adverse event related to the infusion and tumor anatomy. Four patients had Grade 2 transient neurological deficits related to biopsy (n=1) or infusion (n=3). We observed one objective response. Median PFS was 10 months from diagnosis (range 8 to 20 months) while median OS was 16.5 months (range 12 to 35 months). CONCLUSIONS The study has demonstrated safety and feasibility of repeated infusions of MTX110 via CED in DMG patients with a favorable trend in overall survival warranting further trials with higher number of infusion pulses.

Magnetic resonance imaging-guided focused ultrasound thalamotomy for essential tremor in a patient with von Willebrand disease: perioperative optimization for patients with coagulopathies. Illustrative case.

Essential tremor (ET) is one of the most common movement disorders worldwide. In medically refractory ET, deep brain stimulation (DBS) of the ventral intermediate nucleus of the thalamus is the current standard of care. However, DBS carries an inherent 2% to 3% risk of hemorrhage, a risk that can be much higher in patients with concomitant coagulopathy. Magnetic resonance imaging-guided focused ultrasound (MRgFUS) thalamotomy is a surgical alternative that is highly effective in treating ET, with no reports of intracranial hemorrhage to date. This is the first documented case of successful MRgFUS thalamotomy in a patient with von Willebrand disease (VWD). A 60-year-old left-handed male had medically refractory ET, VWD type 2B, and a family history of clinically significant hemorrhage after DBS. He underwent right-sided MRgFUS thalamotomy and received a perioperative course of VONVENDI (recombinant von Willebrand factor) to ensure appropriate hemostasis. Postprocedure imaging confirmed a focal lesion in the right thalamus without evidence of hemorrhage. The patient reported 90% improvement of his left-hand tremor and significant improvement in his quality of life without obvious side effects. MRgFUS thalamotomy with peri- and postoperative hematological management is a promising alternative to DBS for patients with underlying coagulopathies.

Predicting Progression of Intracranial Hemorrhage in the Prehospital TXA for TBI Trial.

Progression of intracranial hemorrhage is a common, potentially devastating complication after moderate/severe traumatic brain injury (TBI). Clinicians have few tools to predict which patients with traumatic intracranial hemorrhage on their initial head computed tomography (hCT) scan will progress. The objective of this investigation was to identify clinical, imaging, and/or protein biomarkers associated with progression of intracranial hemorrhage (PICH) after moderate/severe TBI and to create an accurate predictive model of PICH based on clinical features available at presentation. We analyzed a subset of subjects from the phase II double-blind, multi-center, randomized "Prehospital Tranexamic Acid Use for TBI" trial. This subset was limited to the placebo arm of the parent trial with evidence of hemorrhage on the initial hCT and a follow-up hCT 6 h after. PICH was defined as an increase in hemorrhage size by 30% or more, or the development of new hemorrhage in the intra- and extra-axial intracranial vault between the initial and the follow-up hCT. Two independent radiologists evaluated each hCT, and conflicts were adjudicated by a third. Clinical and radiographic characteristics were collected, along with plasma protein biomarkers at admission. Principal component analysis (PCA) was performed, and each principal component (PC) was interrogated for its association with PICH. Finally, expert opinion and recursive feature extraction (RFE) were used to select input features for the construction of several supervised classification models. Their ability to predict PICH was quantified and compared. In this subset of subjects (n = 104), 46% (n = 48) demonstrated PICH. Univariate analyses showed no association between PICH and age, sex, admission Glasgow Coma Scale (GCS), GCS motor subscore, presence of midline shift, admission platelet count or admission INR. Radiographic severity scores (Marshall score [p = 0.007], Rotterdam score [p = 0.004]), and initial hematoma volume [p = 0.005] were associated with PICH. Higher levels of admission glial fibrillary acidic protein (p < 0.001) and MAP (p = 0.011) were also associated with PICH. Of the PCs, PC1 was significantly associated with PICH (p = 0.0125). Using multimodal data input, machine learning classifiers successfully discriminated patients with or without PICH. Models composed of machine-selected features performed better than models composed of expert-selected variables (reaching an average of 77% accuracy, AUC = 0.78 versus AUC = 0.68 for the expert-selected variables). Predictive models utilizing variables measured at admission can accurately predict PICH, confirmed by the 6-hour follow-up hCT. Our best-performing models must now be externally validated in a separate cohort of TBI patients with low GCS and initial hCT positive for hemorrhage.

Anticoagulant Rodenticide Toxicity in Terrestrial Raptors: Tools to Estimate the Impact on Populations in North America and Globally.

Anticoagulant rodenticides (ARs) have caused widespread contamination and poisoning of predators and scavengers. The diagnosis of toxicity proceeds from evidence of hemorrhage, and subsequent detection of residues in liver. Many factors confound the assessment of AR poisoning, particularly exposure dose, timing and frequency of exposure, and individual and taxon-specific variables. There is a need, therefore, for better AR toxicity criteria. To respond, we compiled a database of second-generation anticoagulant rodenticide (SGAR) residues in liver and postmortem evaluations of 951 terrestrial raptor carcasses from Canada and the United States, 1989 to 2021. We developed mixed-effects logistic regression models to produce specific probability curves of the toxicity of ∑SGARs at the taxonomic level of the family, and separately for three SGARs registered in North America, brodifacoum, bromadiolone, and difethialone. The ∑SGAR threshold concentrations for diagnosis of coagulopathy at 0.20 probability of risk were highest for strigid owls (15 ng g-1 ) lower and relatively similar for accipitrid hawks and eagles (8.2 ng g-1 ) and falcons (7.9 ng g-1 ), and much lower for tytonid barn owls (0.32 ng g-1 ). These values are lower than those we found previously, due to compilation and use of a larger database with a mix of species and source locations, and also to refinements in the statistical methods. Our presentation of results on the family taxonomic level should aid in the global applicability of the numbers. We also collated a subset of 440 single-compound exposure events and determined the probability of SGAR-poisoning symptoms as a function of SGAR concentration, which we then used to estimate relative SGAR toxicity and toxic equivalence factors: difethialone, 1, brodifacoum, 0.8, and bromadiolone, 0.5. Environ Toxicol Chem 2024;00:1-11. © 2024 His Majesty the King in Right of Canada and The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC Reproduced with the permission of the Minister of Environment and Climate Change Canada.

Accuracy, Hemorrhagic Complications and CT Radiation Dose of Emergency External Ventricular Drain (EVD) Placement in Pediatric Patients: A 15-Year Retrospective Analysis.

To assess accuracy, the frequency of hemorrhagic complications and computed tomography (CT) radiation dose parameters in pediatric patients undergoing landmark-guided external ventricular drain (EVD) placement in an emergency setting. Retrospective analysis comprised 36 EVD placements with subsequent CT control scans in 29 patients (aged 0 to 17 years) in our university hospital from 2008 to 2022. The position of the EVD as well as the presence and extension of bleeding were classified according to previously established grading schemes. Dose length product (DLP), volume-weighted CT dose index (CTDIvol) and scan length were extracted from the radiation dose reports and compared to the diagnostic reference values (DRLs) issued by the German Federal Office for Radiation Protection. After the initial EVD placement, optimal positioning of the catheter tip into the ipsilateral frontal horn or third ventricle (Grade I), or a functional positioning in the contralateral lateral ventricle or the non-eloquent cortex (Grade II), was achieved in 28 and 8 cases, respectively. In 32 of 36 procedures, no evidence of hemorrhage was present in the control CT scan. Grade 1 (<1 mL) and Grade 2 (≥1 to 15 mL) bleedings were detected after 3 and 1 placement(s), respectively. For control scans after EVD placements, CTDIvol (median [25%; 75% quartile]) was 39.92 [30.80; 45.55] mGy, DLP yielded 475.50 [375.00; 624.75] mGy*cm and the scan length result was 136 [120; 166] mm. Exceedances of the DRL values were observed in 14.5% for CTDIvol, 12.7% for DLP and 65.6% for the scan length. None of these values was in the range requiring a report to the national authorities. Landmark-based emergency EVD placement in pediatric patients yielded an optimal position in most cases already after the initial insertion. Complications in terms of secondary hemorrhages are rare. CT dose levels associated with the intervention are below the reportable threshold of the national DRLs in Germany.

Nuclear translocation of beta catenin in patients with Rathke cleft cysts—clinical and imaging characteristics and risk of recurrence

PurposeAlthough Rathke cleft cysts (RCC) are benign lesions of the sellar region, recurrence is frequent after surgical treatment. Nuclear translocation of ß-catenin (NTßC), a key effector of the wnt-signaling pathway that is responsible for cell renewal, has been shown to act as a proto-oncogene and is considered to be a potential risk factor for increased recurrence in RCC. In this study, we analyzed a surgically treated cohort into patients with and without NTßC expression in order to identify clinical and imaging differences and further evaluate the risk of recurrence.MethodsPatients with resection of RCC between 04/2001 and 11/2020 were included. Histological specimens were immunohistochemically stained for ß-catenin. Study endpoints were time to cyst recurrence (TTR) and functional outcome. Functional outcome included ophthalmological and endocrinological data. Furthermore, MRI data were assessed.ResultsSeventy-three patients (median age 42.3 years) with RCC underwent mainly transsphenoidal cyst resection (95.9%), 4.1% via transcranial approach. Immunohistochemical staining for ß-catenin was feasible in 61/73 (83.6%) patients, with nuclear translocation detected in 13/61 cases (21.3%). Patients with and without NTßC were equally likely to present with endocrine dysfunction before surgery (p = 0.49). Postoperative new hypopituitarism occurred in 14/73 (19.2%) patients. Preoperative visual impairment was equal in both groups (p = 0.52). Vision improved in 8/21 (33.3%) patients and visual field deficits in 22/34 (64.7%) after surgery. There was no difference in visual and perimetric outcome between patients with and without NTßC (p = 0.45 and p = 0.23, respectively). On preoperative MRI, cyst volume (9.9 vs. 8.2 cm3; p = 0.4) and evidence of hemorrhage (30.8% vs. 35.4%; p = 0.99) were equal and postoperative cyst volume decreased significantly in both groups (0.7 vs. 0.5 cm3; p < 0.0001 each). Cyst progression occurred in 13/73 (17.8%) patients after 39.3 ± 60.3 months. Cyst drainage with partial removal of the cyst wall resulted in improved recurrence-free survival without increasing the risk of complications compared with cyst fenestration alone. Patients with postoperative diabetes insipidus had an increased risk for recurrence according to multivariate analysis (p = 0.005). NTßC was evident in 4/15 patients (26.7%) and was not associated with a higher risk for recurrence (p = 0.67).ConclusionTransnasal transsphenoidal cyst drainage with partial removal of the cyst wall reduces the risk of recurrence without increasing the risk of complications compared with fenestration of the cyst alone. Patients with postoperative diabetes insipidus seem to have an increased risk for recurrence. In contrast, NTßC was not associated with a higher risk of recurrence and did not provide stratification for clinically distinct patients.

Rathke's cleft cyst presenting with recurrent aseptic meningitis and inflammatory apoplexy: illustrative case.

Rathke's cleft cyst (RCC) is a benign sellar/suprasellar lesion often discovered incidentally. Rarely, symptomatic cases can present with headache and may exhibit concomitant aseptic meningitis or apoplexy. The authors describe a patient with an RCC presenting with recurring episodes of aseptic meningitis and ultimately inflammatory-type apoplexy. A 30-year-old female presented with three episodes of intractable headaches over 2 months. Each episode's clinical picture was consistent with meningitis though cerebrospinal fluid cultures, and viral tests remained negative. Imaging demonstrated a sellar lesion, initially thought to be coincidental. On the third presentation, there was rapid interval growth of the lesion, adjacent cerebritis, and new endocrinopathy. Resection was then performed via an endoscopic endonasal approach. Pathology showed an RCC with acute and chronic inflammation and no evidence of hemorrhage. Cultures were negative for organisms. The patient received several weeks of antibiotic treatment with the resolution of all symptoms and no recurrence. Recurrent aseptic meningitis with apoplexy-like symptoms is a rare presentation of RCC. The authors propose the term inflammatory apoplexy to describe such a presentation without evidence of abscess, necrosis, or hemorrhage. The mechanism is unclear although may be due to intermittent microleakage of cyst contents into the subarachnoid space.

Biomarkers of lung alveolarization and microvascular maturation in response to intermittent hypoxia and/or early antioxidant/fish oil supplementation in neonatal rats.

Extremely preterm infants experience frequent intermittent hypoxia (IH) episodes during oxygen therapy which causes significant damage to the lungs and curtails important signaling pathways that regulate normal lung alveolarization and microvascular maturation. We tested the hypothesis that early supplementation with fish oil and/or antioxidants in rats exposed to neonatal IH improves expression of lung biomarkers of alveolarization and microvascular maturation, and reduces IH-induced lung injury. From birth (P0) to P14, rat pups were exposed to room air (RA) or neonatal IH during which they received daily oral supplementation with either: (1) olive oil (OO) (control); (2) Coenzyme Q10 (CoQ10) in OO; (3) fish oil; (4) glutathione nanoparticles (nGSH); or (5) fish oil +CoQ10. At P14 pups were placed in RAuntil P21 with no further treatment. RA controls were similarly treated. Lung growth and alveolarization, histopathology, apoptosis, oxidative stress and biomarkers of alveolarization and microvascular maturation were determined. Neonatal IH was associated with reduced lung weights and severe histopathological outcomes. These effects were curtailed with fish oil and nGSH. nGSH was also protective against apoptosis, while CoQ10 prevented IH-induced ROS production. Of all treatments, nGSH and CoQ10 + fish oil-induced vascular endothelial growth factor165 and CD31 (Platelet endothelial cell adhesion molecule-1), which are associated with angiogenesis. CoQ10 + fish oil improved alveolarization in RA and IH despite evidence of hemorrhage. The benefits of nGSH and CoQ10 + fish oil suggest an antioxidant effect which may be required to curtail IH-induced lung injury. Further clinical assessment of the effectiveness of nGSH is warranted.

Vascular anomaly, lipoma, and polymicrogyria associated with schizencephaly: developmental and diagnostic insights. Illustrative case.

Schizencephaly is an uncommon central nervous system malformation. Intracranial lipomas are also rare, accounting for approximately 0.1% of brain "tumors." They are believed to be derived from a persistent meninx primitiva, a neural crest-derived mesenchyme that develops into the dura and leptomeninges. The authors present a case of heterotopic adipose tissue and a nonshunting arterial vascular malformation arising within a schizencephalic cleft in a 22-year-old male. Imaging showed right frontal gray matter abnormality and an associated suspected arteriovenous malformation with evidence of hemorrhage. Brain magnetic resonance imaging revealed right frontal polymicrogyria lining an open-lip schizencephaly, periventricular heterotopic gray matter, fat within the schizencephalic cleft, and gradient echo hypointensity concerning for prior hemorrhage. Histological assessment demonstrated mature adipose tissue with large-bore, thick-walled, irregular arteries. Mural calcifications and subendothelial cushions suggesting nonlaminar blood flow were observed. There were no arterialized veins or direct transitions from the arteries to veins. Hemosiderin deposition was scant, and hemorrhage was not present. The final diagnosis was consistent with ectopic mature adipose tissue and arteries with meningocerebral cicatrix. This example of a complex maldevelopment of derivatives of the meninx primitiva in association with cortical maldevelopment highlights the unique challenges from both a radiological and histological perspective during diagnostic workup.

Evaluating the Performance of the IMPACT Model in the Prehospital TXA for TBI Trial (P14-7.001)

<h3>Objective:</h3> To test the IMPACT model’s performance in a contemporary clinical trial population. <h3>Background:</h3> The International Mission on Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) prognostic model predicts functional outcome after moderate-severe traumatic brain injury (TBI). Our previous work suggested that glial fibrillary acidic protein (GFAP) may improve the discrimination of outcome when added to prognostic models. <h3>Design/Methods:</h3> We analyzed data from a subset subjects from the phase II double-blind, multicenter randomized controlled trial, “Prehospital Tranexamic Acid Use for Traumatic Brain Injury.” This subset was limited to subjects in the placebo arm of the parent trial with evidence of hemorrhage on initial head computed tomographic (CT) scan. All 3 versions (core, extended, lab) of the IMPACT model were evaluated against 6-month mortality, plus an exploratory 4^th version (lab+GFAP). We compared our results to previously published validation results from the CENTER-TBI cohort. <h3>Results:</h3> Within the subset (n=166), 127 subjects had complete 6-month outcome data. Predictor variables were missing &lt;10% (0–9.4%) of cases, and were imputed (GCS motor score, pupillary reactivity, serum glucose, serum hemoglobin, hypoxia, and Marshall CT score). GFAP was associated with mortality (p=0.004). The core model discriminated poorly in the subset (AUC 0.60 [95% CI: 0.48–0.71], p=0.096). The extended model discriminated well (AUC 0.73 [95% CI: 0.64–0.82], p&lt;0.001). The lab model discriminated non-significantly better (AUC 0.76 [95% CI: 0.66–0.86], p=0.167). Adding GFAP to the lab model improved discrimination further (AUC 0.83 [95% CI: 0.76–0.90], p=0.004). All 4 models overestimated mortality compared with the observed rate (n=31, 24% v. 26–82%). <h3>Conclusions:</h3> In comparison with the observational CENTER-TBI validation cohort, the IMPACT models (core/extended/lab) discriminated mortality less well in a subset of the TXA trial. The addition of GFAP improved discrimination for mortality, but further work is needed to optimize its addition to the lab model. <b>Disclosure:</b> Dr. Hinson has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Hinson has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for UCSF. Dr. Hinson has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Heart Association. Shannon McWeeney has nothing to disclose. Adam Ferguson has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Spine X Inc. Adam Ferguson has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Neuronasal Inc.. The institution of Adam Ferguson has received research support from NIH/NINDS. The institution of Adam Ferguson has received research support from VA RR&amp;D. The institution of Adam Ferguson has received research support from VA BLR&amp;D. The institution of Adam Ferguson has received research support from Wings for Life Foundation/Craig H Neilsen Foundation. The institution of Adam Ferguson has received research support from Wings for Life Foundation. The institution of Adam Ferguson has received research support from DoD/CDMRP. The institution of Adam Ferguson has received research support from DARPA. The institution of Adam Ferguson has received research support from DoE. Adam Ferguson has received personal compensation in the range of $500-$4,999 for serving as a Reviewer with NIH/CSR. Dr. Schreiber has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for CSL Behring. Dr. Schreiber has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Harmonetics. Dr. Schreiber has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Tricol. Dr. Schreiber has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Trauma Textbook. Dr. Schreiber has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Lawyers. The institution of Dr. Schreiber has received research support from DoD. Dr. Rowell has nothing to disclose.

Presumed pituitary apoplexy in 26 dogs: Clinical findings, treatments, and outcomes

Pituitary apoplexy refers to hemorrhage or infarction within the pituitary gland resulting in acute neurological abnormalities. This condition is poorly described in dogs. To document presenting complaints, examination findings, endocrinopathies, magnetic resonance imaging (MRI), treatments, and outcomes of dogs with pituitary apoplexy. Twenty-six client-owned dogs with acute onset of neurological dysfunction. Retrospective case series. Dogs were diagnosed with pituitary apoplexy if MRI or histopathology documented an intrasellar or suprasellar mass with evidence of hemorrhage or infarction in conjunction with acute neurological dysfunction. Clinical information was obtained from medical records and imaging reports. Common presenting complaints included altered mentation (16/26, 62%) and gastrointestinal dysfunction (14/26, 54%). Gait or posture changes (22/26, 85%), mentation changes (18/26, 69%), cranial neuropathies (17/26, 65%), cervical or head hyperpathia (12/26, 46%), and hyperthermia (8/26, 31%) were the most frequent exam findings. Ten dogs (38%) lacked evidence of an endocrinopathy before presentation. Common MRI findings included T1-weighted hypo- to isointensity of the hemorrhagic lesion (21/25, 84%), peripheral enhancement of the pituitary mass lesion (15/25, 60%), brain herniation (14/25, 56%), and obstructive hydrocephalus (13/25, 52%). Fifteen dogs (58%) survived to hospital discharge. Seven of these dogs received medical management alone (median survival 143 days; range, 7-641 days) and 8 received medications and radiation therapy (median survival 973 days; range, 41-1719 days). Dogs with pituitary apoplexy present with a variety of acute signs of neurological disease and inconsistent endocrine dysfunction. Dogs that survive to discharge can have a favorable outcome.

A canine thromboembolic model of anterior circulation large vessel occlusion stroke

PurposeTo develop a large animal preclinical model of thromboembolic stroke with stable, protracted large vessel occlusion (LVO) utilizing an autologous clot. Materials and methodsA reproducible canine model of large vessel occlusion stroke was established by endovascular placement of an autologous clot into the middle cerebral artery (MCA) of six adult hounds and confirmed using digital subtraction angiography (DSA). Infarct volume and evidence of hemorrhage were determined by magnetic resonance imaging (MRI) 7 h after occlusion and Thrombolysis in Cerebral Infarction scale (TICI) was assessed before and after clot placement and at 1, 6, 7, and 9 h after middle cerebral artery occlusion (MCAO). Heart rate (HR) and blood pressure (BP) were monitored continuously and invasively through an arterial sheath throughout the procedures and complete blood count and blood gas analysis completed at time of sacrifice. Histopathological findings at time of sacrifice were used to confirm stroke volume and hemorrhage. ResultsMCAO with resulting TICI 0 flow was observed in all six animals, verified by serial DSA, and lack of collateral flow persisted for 9 h after clot placement until time of sacrifice. The mean infarct volume was 47.0 ± 6.7% of the ipsilateral hemisphere and no events of spontaneous recanalization or clot autolysis were observed. ConclusionWe demonstrate a thromboembolic canine model of MCAO that is both feasible and results in consistent infarct volumes to generate a clinically relevant LVO. This model is important to evaluate treatment of LVO in acute ischemic stroke (AIS) outside the established 4.5 h recombinant tissue plasminogen activator (rTPA) therapeutic window utilizing a prolonged occlusive thrombus.

Retrospective evaluation of fresh platelet concentrate administration in dogs: Patient characteristics, outcomes, and transfusion practices in 189 transfusion episodes (2008-2019).

To describe patient characteristics, underlying disease processes, clinical outcomes, transfusion dose and type (therapeutic or prophylactic), platelet count changes, and adverse events associated with platelet concentrate (PC) administration in dogs. Retrospective study. University teaching hospital. A total of 149 dogs, representing 189 PC transfusion episodes. None. In this population, 39 of 149 dogs (26.2%) were diagnosed with primary immune-mediated thrombocytopenia, 22 of 149 (14.8%) had decreased bone marrow production, 12 of 149 (8.0%) received PC during a massive transfusion, 3 of 149 (2.0%) had congenital thrombocytopathia, 59 of 149 (39.6%) had severe thrombocytopenia of other causes, and 14 of 149 (9.4%) underwent transfusion for miscellaneous causes without a documented severe thrombocytopenia. In 117 of 149 dogs (78.5%), >1 site of hemorrhage was noted. The most common sites of hemorrhage were the gastrointestinal (GI) tract in 89 of 149 (59.7%) and the skin in 78 of 149 (52.3%). Overall survival to discharge was 59.1% (88/149). The median PC dose was 0.8 units per 10kg of body weight per transfusion episode (range: 0.2-6.7). Of 189 episodes, 29 of 189 (15.7%) were prophylactic, and 158 of 189 (83.6%) were therapeutic. For 99 of 189 transfusion episodes, paired pre- and postplatelet counts were available within 24hours. The median platelet count change was 5.0×109 /L (5000/μL; range: -115×109 /L to 158×109 /L [-115,000 to 158,000/μL]); the posttransfusion platelet count was significantly higher than pretransfusion (P<0.0001). The increase in platelet count after transfusion was greater in the prophylactic group than the therapeutic group (P=0.0167). Transfusion reactions were suspected during 2 of 168 episodes (1.2%). Immune-mediated thrombocytopenia was the most common disease process that resulted in PC transfusion. PC was more frequently administered to animals with active hemorrhage rather than prophylactically, and most dogs had evidence of hemorrhage in multiple organ systems, particularly the GI tract and skin. PC transfusions typically appeared safe, and the median platelet count increased after transfusion.

MODL-28. DEVELOPING A STRATEGY FOR MODELING HIGH-GRADE GLIOMA IN GӦTTINGEN MINIPIGS

Abstract BACKGROUND The current literature does not describe a reproducible large animal model of intracranial high-grade glioma (HGG). Prior work has demonstrated the feasibility of inducing HGG de-novo in rodents by targeting specific oncogenic pathways. Here we report our approach to the production of supratentorial HGG in a series of minipigs through lentiviral gene transfer and subsequent initial characterization of a porcine glioma cell line. METHODS Four minipigs received injections into the subcortical white matter using a combination of lentiviral vectors expressing platelet-derived growth factor beta (PDGF-B), HRAS, and shRNA-p53. Animals underwent behavioral monitoring through porcine neurobehavioral scoring (PNS) and veterinary monitoring. Magnetic resonance imaging (MRI) was conducted at endpoint prior to necropsy. Post-mortem tissue biopsies underwent tissue culture and neuropathologic evaluation with hematoxylin and eosin (H&amp;E) staining, immunohistochemistry, and immunofluorescent staining. Data are presented using appropriate statistical tests where relevant and descriptive statistics. RESULTS Two pigs received 50ul injections and reached endpoint by the end of post-operative week 1 and 2. Two pigs received 25 ul injections and were asymptomatic until a pre-determined endpoint of 4 weeks. MRI scans at endpoint demonstrated contrast enhancing, mass forming lesions at the site of injection with evidence of hemorrhage and perilesional edema, consistent with high-grade glioma. On H&amp;E staining high-grade glioma growth was identified in 100% of animals. We observed immunopositivity for tumor markers GFAP, OLIG2, NG2, SOX2, and PDGFRA, as well as redox markers, and microenvironmental features consistent with high-grade glioma. Porcine glioma cell cultures were found to have significantly greater proliferative rate compared to control, and demonstrated GFAP, OLIG2, PDGFRA, and CD68 immunopositivity. CONCLUSIONS Lentiviral gene transfer represents a feasible strategy for glioma modeling in the Gӧttingen minipig. With our described methodology, we present a realistic strategy for reproducible modeling of intracranial glioma as a platform for preclinical neurosurgical development programs.

Association of Early Norepinephrine Administration With 24-Hour Mortality Among Patients With Blunt Trauma and Hemorrhagic Shock

Hemorrhagic shock is a common cause of preventable death after injury. Vasopressor administration for patients with blunt trauma and hemorrhagic shock is often discouraged. To evaluate the association of early norepinephrine administration with 24-hour mortality among patients with blunt trauma and hemorrhagic shock. This retrospective, multicenter, observational cohort study used data from 3 registries in the US and France on all consecutive patients with blunt trauma from January 1, 2013, to December 31, 2018. Patients were alive on admission with hemorrhagic shock, defined by prehospital or admission systolic blood pressure less than 100 mm Hg and evidence of hemorrhage (ie, prehospital or resuscitation room transfusion of packed red blood cells, receipt of emergency treatment for hemorrhage control, transfusion of >10 units of packed red blood cells in the first 24 hours, or death from hemorrhage). Blunt trauma was defined as any exposure to nonpenetrating kinetic energy, collision, or deceleration. Statistical analysis was performed from January 15, 2021, to February 22, 2022. Continuous administration of norepinephrine in the prehospital environment or resuscitation room prior to hemorrhage control, according to European guidelines. The primary outcome was 24-hour mortality, and the secondary outcome was in-hospital mortality. The average treatment effect (ATE) of early norepinephrine administration on 24-hour mortality was estimated according to the Rubin causal model. Inverse propensity score weighting and the doubly robust approach with 5 distinct analytical strategies were used to determine the ATE. A total of 52 568 patients were screened for inclusion, and 2164 patients (1508 men [70%]; mean [SD] age, 46 [19] years; median Injury Severity Score, 29 [IQR, 17-36]) presented with acute hemorrhage and were included. A total of 1497 patients (69.1%) required emergency hemorrhage control, 128 (5.9%) received a prehospital transfusion of packed red blood cells, and 543 (25.0%) received a massive transfusion. Norepinephrine was administered to 1498 patients (69.2%). The 24-hour mortality rate was 17.8% (385 of 2164), and the in-hospital mortality rate was 35.6% (770 of 2164). None of the 5 analytical strategies suggested any statistically significant association between norepinephrine administration and 24-hour mortality, with ATEs ranging from -4.6 (95% CI, -11.9 to 2.7) to 2.1 (95% CI, -2.1 to 6.3), or between norepinephrine administration and in-hospital mortality, with ATEs ranging from -1.3 (95% CI, -9.5 to 6.9) to 5.3 (95% CI, -2.1 to 12.8). The findings of this study suggest that early norepinephrine infusion was not associated with 24-hour or in-hospital mortality among patients with blunt trauma and hemorrhagic shock. Randomized clinical trials that study the effect of early norepinephrine administration among patients with trauma and hypotension are warranted to further assess whether norepinephrine is safe for patients with hemorrhagic shock.

Correlation of MRI signal characteristics of intracranial melanoma metastases with BRAF mutation status.

BRAF V600 mutations (BRAF mut ) are associated with more pigmentation in primary melanomas, but data on melanin content of metastases are limited. This study compares signal characteristics of BRAF mut and BRAF-wildtype (BRAF wt ) intracranial melanoma metastases (IMM). MRI brain examinations at first diagnosis of IMM were identified, all performed at 3-Tesla including 1 mm volumetric pre- and postcontrast T1-weighted imaging and susceptibility-weighted imaging (SWI). Individual metastases were assessed by a neuroradiologist, stratified by size (≥10 mm, 'larger', vs. 2-9 mm, 'small'; up to 10 per group); presence of intrinsic T1-hyperintensity (T1H) and, if present, whether confidently attributable to melanin as opposed to haemorrhage; evidence of haemorrhage; presence of central necrosis. A total of 267 IMM in 73 patients were assessed (87 larger IMM, 180 small). The proportion of larger IMM was similar in both groups (31% BRAF mut and 36% BRAF wt ). In small IMM, MRI evidence of melanin was more common in BRAF mut patients (42% vs. 26%; P = 0.038). Haemorrhage was more common in larger IMM (51%, vs. 20% of small IMM; P < 0.0001), but did not differ based on BRAF status. Central necrosis was more common in larger IMM (44% vs. 7%; P < 0.0001) and in BRAF mut IMM (23% vs. 11%; P = 0.011). In the BRAF mut cohort, central necrosis was more common in patients without previous anti-BRAF therapy (33% vs. 7%; P = 0.0001). T1H attributable to melanin is only slightly more common in BRAF mut IMM than BRAF wt . Higher rates of central necrosis in BRAF mut patients without previous anti-BRAF therapy suggest that anti-BRAF therapy may affect the patterns of IMM growth.

The clinical spectrum of haemorrhagic CNS inflammatory demyelinating lesions

Background: Haemorrhagic demyelinating lesions are rare, and little is known about the demyelinating diseases with which they are associated, or how lesional haemorrhage affects treatment and outcomes. Objective: To examine the clinical characteristics and outcomes of patients with demyelinating lesions and magnetic resonance imaging (MRI) evidence of haemorrhage seen at the Mayo clinic between 1990 and 2018. Methods: The Mayo Clinic’s medical-record diagnostic-linkage system was used to identify patients with CNS demyelinating disease and parenchymal haemorrhage on brain MRI cross-referenced against a database of patients with pathologically confirmed CNS demyelinating disease. The clinical characteristics, diagnosis, MRI findings, brain histopathology, and outcomes of these patients were reviewed. Results: Ten patients with haemorrhagic demyelination were identified, including three patients who underwent a brain biopsy. The main findings were that haemorrhagic demyelinating lesions most often occur in atypical forms of demyelination, especially acute haemorrhagic leukoencephalitis (AHL, or Weston–Hurst disease) and tumefactive demyelination, and rarely in multiple sclerosis. A spectrum of outcomes was observed for these patients ranging from complete remission through to high level disability. Conclusion: Lesional haemorrhage is uncommon in demyelinating disease where it is most closely associated with AHL. Bleeding within a demyelinating lesion does not always herald a poor prognosis.