Minocycline decreases blood-brain barrier permeability following aneurysmal subarachnoid hemorrhage: a randomized, double-blind, controlled trial.

OBJECTIVE: Aneurysmal subarachnoid hemorrhage (aSAH)-induced vasospasm is linked to increased inflammatory cell trafficking across a permeable blood-brain barrier (BBB). Elevations in serum levels of matrix metalloprotease 9 (MMP9), a BBB structural protein, have been implicated in the pathogenesis of vasospasm onset. Minocycline is a potent inhibitor of MMP9. The authors sought to detect an effect of minocycline on BBB permeability following aSAH. METHODS: Patients presenting within 24 hours of symptom onset with imaging confirmed aSAH (Fisher grade 3 or 4) were randomized to high-dose (10 mg/kg) minocycline or placebo. The primary outcome of interest was BBB permeability as quantitated by contrast signal intensity ratios in vascular regions of interest on postbleed day (PBD) 5 magnetic resonance permeability imaging. Secondary outcomes included serum MMP9 levels and radiographic and clinical evidence of vasospasm. RESULTS: A total of 11 patients were randomized to minocycline (n = 6) or control (n = 5) groups. No adverse events or complications attributable to minocycline were reported. High-dose minocycline administration was associated with significantly lower permeability indices on imaging analysis (p < 0.01). There was no significant difference with respect to serum MMP9 levels between groups, although concentrations trended upward in both cohorts. Radiographic vasospasm was noted in 6 patients (minocycline = 3, control = 3), with only 1 patient developing symptoms of clinical vasospasm in the minocycline cohort. There was no difference between cohorts with respect to Lindegaard ratios, transcranial Doppler values, or onset of vasospasm. CONCLUSIONS: Minocycline at high doses is well tolerated in the ruptured cerebral aneurysm population. Minocycline curtails breakdown of the BBB following aSAH as evidenced by lower permeability indices, though minocycline did not significantly alter serum MMP9 levels. Larger randomized clinical trials are needed to assess minocycline as a neuroprotectant against aSAH-induced vasospasm. Clinical trial registration no.: NCT04876638 (clinicaltrials.gov).

Association Between Glycemic Gap and In-hospital Outcomes in Aneurysmal Subarachnoid Hemorrhage.

Introduction: Glycemic gap (GG), as determined by the difference between glucose and the hemoglobin A1c (HbA1c)-derived estimated average glucose (eAG), is associated with poor outcomes in various clinical settings. There is a paucity of data describing GG and outcomes after aneurysmal subarachnoid hemorrhage (aSAH). Our main objectives were to evaluate the association of admission glycemic gap (aGG) with in-hospital mortality and with poor composite outcome and to compare aGG's predictive value to admission serum glucose. Secondary outcomes were the associations between aGG and neurologic complications including vasospasm and delayed cerebral ischemia following aSAH. Methods: We retrospectively reviewed 119 adult patients with aSAH admitted to a single tertiary care neuroscience ICU. Spearman method was used for correlation for non-normality of data. Area under the curve (AUC) for Receiver Operating Characteristic (ROC) curve was used to estimate prediction accuracy of aGG and admission glucose on outcome measures. Multivariable analyses were conducted to assess the value of aGG in predicting in-hospital poor composite outcome and death. Results: Elevated aGG at or above 30 mg/dL was identified in 79 (66.4%) of patients. Vasospasm was not associated with the elevated aGG. Admission GG correlated with admission serum glucose (r = 0.94, p < 0.01), lactate (r = 0.41, p < 0.01), procalcitonin (r = 0.38, p < 0.01), and Hunt and Hess score (r = 0.51, p < 0.01), but not with HbA1c (r = 0.02, p = 0.82). Compared to admission glucose, aGG had a statistically significantly improved accuracy in predicting inpatient mortality (AUC mean ± SEM: 0.77 ± 0.05 vs. 0.72 ± 0.06, p = 0.03) and trended toward statistically improved accuracy in predicting poor composite outcome (AUC: 0.69 ± 0.05 vs. 0.66 ± 0.05, p = 0.07). When controlling for aSAH severity, aGG was not independently associated with delayed cerebral ischemia, poor composite outcome, and in-hospital mortality. Conclusion: Admission GG was not independently associated with in-hospital mortality or poor outcome in a population of aSAH. An aGG ≥30 mg/dL was common in our population, and further study is needed to fully understand the clinical importance of this biomarker.

Admission glycemic gap in the assessment of patients with intracerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is the most common type of hemorrhagic stroke. Glycemic gap, determined by the difference between glucose and the HbA1c-derived average glucose, predicts poor outcomes in various clinical settings. Our main objective was to evaluate association of some admission factors and outcomes in relation to admission glycemic gap (AGG) in patients with ICH. METHODS: We retrospectively analyzed 506 adult patients with ICH between 2014 and 2019. AGG was defined as A1c-derived average glucose (28.7×HbA1c-46.7) subtracted from admission glucose. Admission factors and hospital outcomes indicative of poor outcome (i.e. death, gastrostomy tube, tracheostomy, and discharge status) were compared between patients with elevated (greater than 80 mg/dL) vs. non-elevated (less than or equal-to 80 mg/dL) AGG. Pearson chi-square test was used for independence, and multivariate analysis was used for association. SPSS and excel were used for all data analysis. RESULTS: We found that 67 of 506 (13%) ICH patients had elevated AGG with a mean of 137.3 mg/dL compared to 439 (87%) non-elevated AGG with a mean of 12.6 mg/dL. While mean and standard deviation values for age, weight,and body mass index were comparable between groups, the elevated AGG group had significantly higher admission glucose (286.1 ± 84.3 vs. 140.1 ± 42.5, p < 0.001), higher lactic acid (3.26 ± 2.04 mmol/L vs. 1.99 ± 1.33 mmol/L, p < 0.001), lower Glasgow Coma Scale (GCS) scores (7.70 ± 4.28 vs. 11.24 ± 4.14, p < 0.001), and higher ICH score (median 3, IQR 2-4 vs. median 1, IQR 0-3, p < 0.001). Higher AGG was associated with an increased likelihood of mechanical ventilation, and in-hospital mortality (74.6% vs. 38.3% and 47.8% vs. 15.0% respectively, p < 0.001). Placements of tracheostomy and gastrostomy were similar between the two groups (13.4% vs. 11.8%, p = 0.69% and 1.5% and 4.6%, p = 0.34 respectively). The higher AGG group had a more common poor discharge outcome to either long-term acute care, skilled nursing facility, and/or hospice (65.7% vs. 42.6%, p < 0.001). Hospital cost and length of hospitalization did not differ significantly. Although AGG was not an independent predictor of poor outcome, multivariate analysis showed it was significantly associated with poor outcome while admission glucose was not (p < 0.001 vs. p = 0.167). CONCLUSION: Elevated AGG was associated with worse GCS and ICH scores on admission, as well as need for mechanical ventilation, in hospital mortality and poor discharge status. Elevated AGG has value in prediction of outcome, but existing understanding is limited.

CT perfusion core and ASPECT score prediction of outcomes in DEFUSE 3.

BACKGROUND: The role of Alberta Stroke Program Early CT Score (ASPECTS) for thrombectomy patient selection and prognostication in late time windows is unknown. AIMS: We compared baseline ASPECTS and core infarction determined by CT perfusion (CTP) as predictors of clinical outcome in the Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3 (DEFUSE) 3 trial. METHODS: We included all DEFUSE 3 patients with baseline non-contrast CT and CTP imaging. ASPECTS and core infarction were determined by the DEFUSE 3 core laboratory. Primary outcome was functional independence (modified Rankin Scale (mRS) ≤2). Secondary outcomes included ordinal mRS shift at 90 days and final core infarction volume. RESULTS: Of the 142 patients, 85 patients (60%) had ASPECTS 8-10 and 57 (40%) had ASPECTS 5-7. Thirty-one patients (36%) with ASPECTS 8-10 and 11 patients (19%) with ASPECTS 5-7 were functionally independent at 90 days (p = 0.03). In the primary and secondary logistic regression analysis, there was no difference in ordinal mRS shift (p = 0.98) or functional independence (mRS ≤ 2; p = 0.36) at 90 days between ASPECTS 8-10 and ASPECTS 5-7 patients. Similarly, primary and secondary logistic regression analyses found no difference in ordinal mRS shift (p = 1.0) or functional independence (mRS ≤ 2; p = 0.87) at 90 days between patients with baseline small core ( < 50 ml) versus medium core (50-70 ml). CONCLUSIONS: Higher ASPECTS (8-10) correlated with functional independence at 90 days in the DEFUSE trial. ASPECTS and core infarction volume did not modify the thrombectomy treatment effect, which indicates that patients with a target mismatch profile on perfusion imaging should undergo thrombectomy regardless of ASPECTS or core infarction volume in late time windows.

Botulinum toxin to improve vessel graft patency in cerebral revascularization surgery: report of 3 cases.

Surgical revascularization continues to play an important role in the management of complex intracranial aneurysms and ischemic cerebrovascular disease. Graft spasm is a common complication of bypass procedures and can result in ischemia or graft thrombosis. The authors here report on the first clinical use of botulinum toxin to prevent graft spasm following extracranial-intracranial (EC-IC) bypass. This technique was used in 3 EC-IC bypass surgeries, 2 for symptomatic carotid artery occlusions and 1 for a ruptured basilar tip aneurysm. In all 3 cases, the harvested graft was treated ex vivo with botulinum toxin before the anastomosis was performed. Post-bypass vascular imaging demonstrated patency and the absence of spasm in all grafts. Histopathological analyses of treated vessels did not show any immediate endothelial or vessel wall damage. Postoperative angiograms were without graft spasm in all cases. Botulinum toxin may be a reasonable option for preventing graft spasm and maintaining patency in cerebral revascularization procedures.

Salvage of distal non-target coil embolization with stent placement and intravenous eptifibatide in a ruptured, unsecured, atypical aneurysm.

INTRODUCTION: Small aneurysms may be challenging to embolize. In cases of subarachnoid hemorrhage (SAH) where treatment is delayed, physicians may have to balance the risks of certain required therapies (antiplatelet agents) with the risk of rerupture. We describe a case of a technically challenging anterior cerebral artery aneurysm requiring eptifibatide infusion prior to definitive aneurysm treatment. CASE REPORT: A 57-year-old woman with SAH, underwent coil embolization of a small fenestrated A1-A2 junction aneurysm. The procedure was complicated by downstream coil migration which was then treated with Enterprise stent placement in the pericallosal artery. This required subsequent infusion of a glycoprotein IIb/IIIa inhibitor until the aneurysm could be repaired surgically. CONCLUSIONS: Revascularization with a stent in a distal cerebral vessel may salvage inadvertent coil migration. Although it is undesirable to administer antiplatelet agents to patients with SAH, in these circumstances short acting agents may be used.

Salvage of distal non-target coil embolization with stent placement and intravenous eptifibatide in a ruptured, unsecured, atypical aneurysm.

INTRODUCTION: Small aneurysms may be challenging to embolize. In cases of subarachnoid hemorrhage (SAH) where treatment is delayed, physicians may have to balance the risks of certain required therapies (antiplatelet agents) with the risk of rerupture. We describe a case of a technically challenging anterior cerebral artery aneurysm requiring eptifibatide infusion prior to definitive aneurysm treatment. CASE REPORT: A 57-year-old woman with SAH, underwent coil embolization of a small fenestrated A1-A2 junction aneurysm. The procedure was complicated by downstream coil migration which was then treated with Enterprise stent placement in the pericallosal artery. This required subsequent infusion of a glycoprotein IIb/IIIa inhibitor until the aneurysm could be repaired surgically. CONCLUSIONS: Revascularization with a stent in a distal cerebral vessel may salvage inadvertent coil migration. Although it is undesirable to administer antiplatelet agents to patients with SAH, in these circumstances short acting agents may be used.

Internal jugular, subclavian, and axillary deep venous thrombosis and the risk of pulmonary embolism.

The objective of this study was to investigate the risk of acute internal jugular, subclavian, and axillary deep venous thrombosis (upper torso DVT [UTDVT]) and pulmonary embolism (PE) and the role of anticoagulation in a cohort of hospitalized patients. A 2-year retrospective review of hospitalized patients who underwent upper torso vein duplex scanning was performed. Patient demographics, underlying comorbidities, indication for scanning, diagnostic tests, intensive care unit stay, length of stay, presence of a central line (current or within the last 2 weeks), malignancy (current or former), hypercoaguable condition, postoperative state, renal failure, mortality, and use of anticoagulation were recorded. Univariate and multivariate analyses were performed to investigate significant risk factors for acute UTDVT. The impact of an acute UTDVT and use of anticoagulation on hospital length of stay, survival to 30 days and 1 year, and PE rate were calculated. One hundred eighty-nine patients were scanned. Sixty-three patients (33%) were found to have an acute UTDVT. The internal jugular vein was the most common site of thrombosis. The presence of a central venous catheter was the only factor found to be a significant risk factor for an acute UTDVT (p = .03). Five patients (7.9%) with an UTDVT had a PE documented by computed tomographic angiography-pulmonary arteriography, and all had an internal jugular thrombosis (four isolated and one combined with an axillary-subclavian thrombosis). No PE was fatal. Thirty-eight (60%) patients with an acute UTDVT were treated with therapeutic anticoagulation; the remainder were observed. All patients with a PE received anticoagulation. Hospital length of stay, 30-day mortality, and 12-month survival were no different for patients with and without an UTDVT (p = .7). The use of anticoagulation had no observable effect on survival in patients with UTDVT (p = .1). An acute internal jugular, subclavian, or axillary DVT is a relatively common finding in the hospitalized patient. Patients with a central line (current or within the previous 14 days) were at greatest risk, with an internal jugular vein thrombosis being the most common source. The inconsistent use of anticoagulation therapy for UTDVT was associated with a moderate risk of PE. A survival benefit for anticoagulation could not be documented.