ABSTRACT
BACKGROUND: Andexanet alfa, a novel anticoagulation reversal agent for factor Xa inhibitors, was recently approved. Traumatic intracranial hemorrhage presents a prime target for this drug. The Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors study established the efficacy of andexanet alfa in reversing factor Xa inhibitors. However, the association between anticoagulation reversal and traumatic intracranial hemorrhage progression is not well understood. The objective of this study was to determine progression rates of patients with traumatic intracranial hemorrhage on factor Xa inhibitors prior to hospitalization who were managed without the use of andexanet alfa. METHODS: A retrospective cohort study was performed between 2016 and 2019 at a single institution. An institutional traumatic brain injury (TBI) registry was queried. Patients with recorded use of apixaban or rivaroxaban <18 hours before injury were included. The primary study outcome was <35% increase in hemorrhage volume or thickness on repeated head computed tomography (CT) scans. RESULTS: We identified 25 patients meeting the inclusion criteria. Two patients were excluded because of a lack of necessary CT data. Twelve patients (52%) were receiving apixaban, and 11 were (48%) on rivaroxaban. On admission CT scan, 14 patients had subdural hematoma, 6 had traumatic intraparenchymal hemorrhage, and 3 had subarachnoid hemorrhage. Anticoagulation reversal was attempted in 17 patients (74%), primarily using 4-factor prothrombin complex concentrate. Twenty patients (87%) were adjudicated as having excellent or good hemostasis on repeat imaging. CONCLUSIONS: Our results indicate that patients on factor Xa inhibitors with complicated mild TBI have a similar intracranial hemorrhage progression rate to patients who are not anticoagulated or anticoagulated with a reversible agent. The hemostatic outcomes in our cohort were similar to those reported after andexanet alfa administration.
Subject(s)
Blood Coagulation Factors/therapeutic use , Factor Xa Inhibitors/adverse effects , Factor Xa/therapeutic use , Intracranial Hemorrhage, Traumatic/drug therapy , Recombinant Proteins/therapeutic use , Aged , Aged, 80 and over , Atrial Fibrillation/drug therapy , Cerebral Hemorrhage, Traumatic/diagnostic imaging , Cerebral Hemorrhage, Traumatic/drug therapy , Cerebral Hemorrhage, Traumatic/physiopathology , Cohort Studies , Disease Progression , Factor Xa Inhibitors/therapeutic use , Female , Glasgow Coma Scale , Hematoma, Subdural, Intracranial/diagnostic imaging , Hematoma, Subdural, Intracranial/drug therapy , Hematoma, Subdural, Intracranial/physiopathology , Hemostasis , Humans , Intracranial Hemorrhage, Traumatic/diagnostic imaging , Intracranial Hemorrhage, Traumatic/physiopathology , Male , Middle Aged , Plasma , Platelet Transfusion , Pyrazoles/adverse effects , Pyrazoles/therapeutic use , Pyridones/adverse effects , Pyridones/therapeutic use , Retrospective Studies , Risk , Risk Factors , Rivaroxaban/adverse effects , Rivaroxaban/therapeutic use , Subarachnoid Hemorrhage, Traumatic/diagnostic imaging , Subarachnoid Hemorrhage, Traumatic/drug therapy , Subarachnoid Hemorrhage, Traumatic/physiopathology , Tomography, X-Ray Computed , Venous Thromboembolism/drug therapy , Venous Thromboembolism/prevention & controlABSTRACT
Aneurysmal subarachnoid hemorrhage (SAH) is a severe cerebrovascular disease with very poor prognosis. The aim of the present study was to evaluate the protective effects of atorvastatin on early brain injury (EBI) after SAH using a perforation SAH model. Male Sprague-Dawley rats were randomly divided into four groups: the sham group, the SAH group (model group), SAH + 10 mg.kg-1day-1 atorvastatin (low atorvastatin group), and SAH + 20 mg.kg-1day-1 atorvastatin (high atorvastatin group). Atorvastatin was administered orally by gastric gavage for 15 days before operation. At 24 h after SAH, we evaluated the effects of atorvastatin on brain water content, apoptosis by TUNEL assay and scanning electron microscope (SEM), and the expression of apoptosis-related proteins by immunofluorescence and Western blotting analysis. Compared with the sham group, we observed increased brain water content, significant apoptosis, and elevated levels of apoptosis-related proteins including caspase-3, CCAAT enhancer-binding protein homologous protein (CHOP), the 78-kDa glucose-regulated protein (GRP78), and aquaporin-4 (AQP4) in the SAH group. Atorvastatin administration under all doses could significantly reduce brain water content, apoptosis, and the expression levels of caspase-3, CHOP, GRP78, and AQP4 at 24 h after SAH. Our data show that early treatment with atorvastatin effectively ameliorates EBI after SAH through anti-apoptotic effects and the effects might be associated inhibition of caspase-3 and endoplasmic reticulum (ER) stress related proteins CHOP and GRP78.
Subject(s)
Anticholesteremic Agents/pharmacology , Apoptosis/drug effects , Atorvastatin/pharmacology , Brain Injuries/prevention & control , Endoplasmic Reticulum Stress/drug effects , Neuroprotective Agents/pharmacology , Subarachnoid Hemorrhage, Traumatic/drug therapy , Administration, Oral , Animals , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Aquaporin 4/genetics , Aquaporin 4/metabolism , Brain/drug effects , Brain/metabolism , Brain/pathology , Brain Injuries/genetics , Brain Injuries/metabolism , Brain Injuries/pathology , Caspase 3/genetics , Caspase 3/metabolism , Disease Models, Animal , Drug Repositioning , Gene Expression Regulation , Heat-Shock Proteins/genetics , Heat-Shock Proteins/metabolism , Male , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Rats , Rats, Sprague-Dawley , Subarachnoid Hemorrhage, Traumatic/genetics , Subarachnoid Hemorrhage, Traumatic/metabolism , Subarachnoid Hemorrhage, Traumatic/pathology , Transcription Factor CHOP/genetics , Transcription Factor CHOP/metabolism , Water/analysis , Water/metabolismABSTRACT
BACKGROUND: Blood-brain barrier (BBB) disruption and neural apoptosis are thought to promote early brain injury (EBI) after subarachnoid hemorrhage (SAH). Previous studies have demonstrated that valproic acid (VPA) decreased brain injury in a prechiasmatic injection model of SAH in mice. It should be noted that the beneficial effects of VPA and the underlying mechanisms have not been fully elucidated. OBJECTIVE: To characterize the effects of VPA on BBB disruption and neural apoptosis and to determine mechanisms involved in EBI after SAH. METHODS: An endovascular perforation model was used to induce SAH in rats. VPA (300 mg/kg) was promptly administered after SAH induction, and the same dose was given 12 hours later. Quercetin (100 mg/kg), an inhibitor of heat shock protein 70 (HSP70), was injected into the peritoneum 2 hours before SAH induction. Mortality, SAH grades, neurological function, Evans Blue extravasation, brain edema, transmission electron microscopy, Western blot, double fluorescence labeling, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling staining also were used. RESULTS: VPA treatment decreased BBB disruption and brain edema, attenuated neural apoptosis, and improved neurobehavioral functions in EBI after SAH. Double fluorescence labeling indicated that matrix metallopeptidase 9 (MMP-9) was located predominately in neurons and endothelial cells. VPA upregulated the expression of HSP70, effectively decreased the expression and activity of MMP-9, and reduced claudin-5 and occludin degradation. Meanwhile, VPA also upregulated the expression of phosphorylated Akt and bcl-2. Both the anti-BBB disruption and antiapoptotic effects of VPA were abolished by quercetin. CONCLUSION: VPA prevented BBB disruption and alleviated neural apoptosis after SAH. The action of VPA appeared to be mediated though the HSP70/MMPs and HSP70/Akt pathways. ABBREVIATIONS: BBB, blood-brain barrierEBI, early brain injuryHSP, heat shock proteinMMP, matrix metalloproteinasePBS, phosphate-buffered salineSAH, subarachnoid hemorrhageTUNEL, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelingVPA, valproic acid.
Subject(s)
Blood-Brain Barrier/drug effects , HSP70 Heat-Shock Proteins/physiology , Matrix Metalloproteinases/physiology , Neuroprotective Agents/therapeutic use , Subarachnoid Hemorrhage, Traumatic/drug therapy , Valproic Acid/therapeutic use , Animals , Apoptosis/drug effects , Blood-Brain Barrier/metabolism , Disease Models, Animal , In Situ Nick-End Labeling , Male , Rats , Rats, Sprague-Dawley , Subarachnoid Hemorrhage, Traumatic/complications , Subarachnoid Hemorrhage, Traumatic/metabolismABSTRACT
El flujo sanguíneo cerebral es el parámetro más importante en el pronóstico de la lesión cerebral. Una medida regional del flujo se puede obtener usando métodos continuos como la flujometría por difusión termal, que permite detectar y cuantificar fenómenos isquémicos relacionados con el clipaje temporal arterial o malposición del clip definitivo y en pacientes que han sufrido una hemorragia subaracnoidea o un traumatismo craneoencefálico. Asimismo, la detección precoz de la isquemia podría ayudarnos a adoptar más rápidamente medidas terapéuticas y con mayor eficacia. Presentamos 2 casos durante cirugía de clipaje de aneurisma y un caso en cuidados intensivos donde valoramos: el efecto de diferentes hipnóticos sobre la flujometría por difusión termal; la relación entre esta y los potenciales evocados somatosensoriales y motores; y cambios en la flujomería y Doppler transcraneal durante el vasoespasmo. La flujometría por difusión termal mostró variaciones en tiempo real del flujo sanguíneo producidas por anestésicos endovenosos e inhalatorios. Detectó cambios del flujo sanguíneo cerebral antes que los potenciales evocados y el Doppler(AU)
No disponible
Subject(s)
Humans , Male , Adult , Regional Blood Flow , Rheology/instrumentation , Aneurysm/diagnosis , Aneurysm/drug therapy , Aneurysm/surgery , Brain Ischemia/diagnosis , Brain Ischemia/drug therapy , Brain Ischemia/surgery , Intracranial Aneurysm/diagnosis , Intracranial Aneurysm/drug therapy , Subarachnoid Hemorrhage/drug therapy , Intracranial Aneurysm/surgery , Subarachnoid Hemorrhage, Traumatic/drug therapy , Somatosensory Disorders/drug therapyABSTRACT
BACKGROUND: Physiological reactions of the stress hormone cortisol include hyperglycemia, hypertension, and endothelium dysfunction. In patients with aneurysmal subarachnoid hemorrhage (SAH), hyperglycemia, hypertension, and endothelium dysfunction are associated with the occurrence of delayed cerebral ischemia (DCI). Therefore, the purpose of the present study was to investigate whether increased serum cortisol levels after aneurysmal SAH are associated with DCI occurrence. METHODS: Blood samples were obtained at standard intervals after SAH. DCI was defined as the gradual onset of new focal neurological impairment, and/or a decreased level of consciousness of at least 2 points as recorded on the Glasgow Coma Scale. Correlation coefficients were calculated to investigate the associations between cortisol and serum glucose levels, and between cortisol and von Willebrand factor levels. RESULTS: Thirty-one patients were included. Eleven patients (35%) developed DCI. Signs of DCI started at a median of 6 days (range 4-10 days). Patients who developed DCI had significantly higher cortisol levels than patients without DCI (P = 0.006). Statistically significant, but weak, correlations were observed between cortisol and serum glucose levels (r = 0.216, P = 0.006), and cortisol and von Willebrand factor levels (r = 0.282, P < 0.001). CONCLUSIONS: Increased serum cortisol levels after SAH are associated with DCI occurrence and might be the link between the associations of hyperglycemia and endothelium dysfunction with DCI. It remains to be investigated whether the association between cortisol levels and DCI is independent from known prognostic baseline factors, such as amount of blood on admission CT scan.
Subject(s)
Brain Ischemia/blood , Hydrocortisone/blood , Subarachnoid Hemorrhage, Traumatic/blood , Adult , Aged , Blood Glucose/metabolism , Brain Ischemia/drug therapy , Combined Modality Therapy , Double-Blind Method , Embolization, Therapeutic , Endothelium, Vascular/drug effects , Endothelium, Vascular/physiopathology , Female , Glasgow Coma Scale , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hyperglycemia/physiopathology , Hypertension/physiopathology , Male , Middle Aged , Neurologic Examination , Prognosis , Simvastatin/therapeutic use , Subarachnoid Hemorrhage, Traumatic/drug therapy , Surgical Instruments , von Willebrand Factor/metabolismABSTRACT
Magnesium has neuroprotective and antivasospastic properties in the presence of subarachnoid hemorrhage (SAH). The present study investigated the effect of intracisternal administration of magnesium on cerebral vasospasm in the experimental SAH rat model. The rat double-SAH model (0.2 mL autologous blood injected twice into the cisterna magna) was used. Normal saline (SAH group, N=8) or 10 mmol/L magnesium sulfate in normal saline (SAH + MG group, N=8) was infused into the cisterna magna at 1.5 microL/min for 30 min on day 5. Control rats without SAH also received intracisternal infusion of normal saline (control group, N=6). Local cerebral blood flow (CBF) at 24 locations and the weighted average were quantitatively measured by the autoradiographic technique using [(14)C]iodoantipyrine during infusion. The weighted average CBF was significantly reduced (P<0.01, Student's t-test) in the SAH group (0.78+/-0.16 mL g(-1) min(-1)) compared to the control group (1.0+/-0.15 mL g(-1) min(-1)) and was significantly improved (P<0.01, Student's t-test) in the SAH + MG group (0.98+/-0.18 mL g(-1) min(-1)). Local CBF was significantly reduced (P<0.05, unpaired t test) in 16 locations in the SAH group and significantly improved (P < 0.05, unpaired t test) in 12 locations in the SAH + MG group. Intracisternal infusion of magnesium sulfate significantly improved reduced CBF induced by experimental SAH in the rat.
Subject(s)
Cerebrovascular Circulation/drug effects , Cisterna Magna/physiology , Magnesium Sulfate/administration & dosage , Magnesium Sulfate/therapeutic use , Subarachnoid Hemorrhage, Traumatic/drug therapy , Subarachnoid Hemorrhage, Traumatic/physiopathology , Animals , Autoradiography , Blood Gas Analysis , Blood Pressure/drug effects , Hematocrit , Injections , Male , Pharmaceutical Solutions , Radiopharmaceuticals , Rats , Rats, Sprague-Dawley , Vasospasm, Intracranial/drug therapy , Vasospasm, Intracranial/etiology , Vasospasm, Intracranial/physiopathologyABSTRACT
BACKGROUND: Despite several randomised controlled trials, there is still much debate whether nimodipine improves outcome in patients with traumatic subarachnoid haemorrhage. A 2003 Cochrane review reported improved outcome with nimodipine in these patients; however, because the results of Head Injury Trial (HIT) 4 were only partly presented there is still discussion whether patients with traumatic subarachnoid haemorrhage should be treated with this drug. Here, we present data from all head-injury trials, including previously unpublished results from HIT 4. METHODS: We systematically searched PubMed and EMBASE databases using the following combinations of variables: "nimodipine" or "calcium antagonist" with "traumatic subarachnoid haemorrhage", "head injury", "head trauma", "brain injury", or "brain trauma". Bayer AG and all principal investigators or corresponding authors of the identified studies were contacted for additional information. FINDINGS: Five manuscripts were identified, describing the results of four trials. We obtained additional data from HIT 1, 2, and 4. In total, 1074 patients with traumatic subarachnoid haemorrhage were included. The occurrence of poor outcome was similar in patients treated with nimodipine (39%) and those treated with placebo (40%); odds ratio was 0.88 (95% CI 0.51-1.54). Mortality rates did not differ between nimodipine (26%) and placebo (27%) treated patients (odds ratio 0.95; 95% CI 0.71-1.26). INTERPRETATION: Our results do not lend support to the finding of a beneficial effect of nimodipine on outcome in patients with traumatic subarachnoid haemorrhage as reported in an earlier Cochrane review.
Subject(s)
Calcium Channel Blockers/therapeutic use , Nimodipine/therapeutic use , Subarachnoid Hemorrhage, Traumatic/drug therapy , Humans , Randomized Controlled Trials as Topic , Subarachnoid Hemorrhage, Traumatic/mortality , Treatment OutcomeABSTRACT
BACKGROUND: Recombinant activated factor VII (rFVIIa) is being tested to improve hemostasis in a variety of bleeding disorders. Clinical indications and efficacy are still being evaluated for this product. CASE REPORT: Over a 17-month period, rFVIIa was used to treat central nervous system hemorrhage in three patients who were found to have isolated FVII deficiency (21%, 40%, 27%). Patient A fell 30 feet, Patient B suffered a motor vehicle accident, and Patient C had a spinal cord hematoma. None of the patients had a history of bleeding diathesis. All three patients received rFVIIa after failing initial treatment with fresh-frozen plasma. RESULTS: Patient A was treated with 11 doses (initial dose 95 microg/kg; subsequent doses 8-38 microg/kg) over 10 days; Patient B received 13 doses (45-60 microg/kg) over 13 days; and Patient C received 5 doses (12-24 microg/kg) over 4 days. The prothrombin time corrected from 16.2 +/- 1.8 (mean +/- SD) to 11.2 +/- 1.6 seconds after infusion of rFVIIa, but returned to pretreatment level in 14 +/- 4 hours. At the cessation of therapy, all patients showed neurologic improvement. No complications related to the infusion of rFVIIa occurred. CONCLUSION: The use of rFVIIa may be of value both for its general effect on hemostasis, and specifically in the setting where there is a documented reduction in FVII. Doses lower than those used in patients with FVIII inhibitors appear to be effective in the setting of central nervous system hemorrhage.
Subject(s)
Factor VII Deficiency/drug therapy , Factor VIIa/therapeutic use , Hematoma, Epidural, Cranial/drug therapy , Intracranial Hemorrhage, Traumatic/drug therapy , Recombinant Proteins/therapeutic use , Adolescent , Adult , Central Nervous System Diseases , Factor VII Deficiency/complications , Factor VIIa/administration & dosage , Hematoma, Epidural, Cranial/surgery , Hematoma, Subdural/drug therapy , Humans , Laminectomy/adverse effects , Male , Postoperative Complications/drug therapy , Prothrombin Time , Recombinant Proteins/administration & dosage , Subarachnoid Hemorrhage, Traumatic/drug therapyABSTRACT
Efficiency of recombinant activated factor VII (rFVIIa) (NovoSeven) in treatment of patients with idiopathic thrombocytopenic purpura (ITP) complicated with subarachnoid and parenchimatous hemorrhage was shown in the article. The action of NovoSeven in patients with an affected megakaryocytic system depends on the binding of rFVIIa with activated thrombocites and on their surface rFVIIa provides the activation of X factor and thrombin formation. NovoSeven proved to be called a universal hemostatic medication for the idiopathic thrombocytopenic purpura treatment. Taking into account that transfusion of thrombocites concentrate is not recommended for patients with thrombocytopenia of immune origin and after immunoglobulin infusion we need time to see thrombocites number grow so in urgent NovoSeven is a medication of choice to stop bleeding in patients with ITP.