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Introduction: Clopidogrel hyperresponsiveness is a timely topic, with wide ranging reports of hemorrhagic complications, using various clopidogrel dosing strategies following neuroendovascular procedures. This study serves to investigate hemorrhagic complications using standard clopidogrel doses and timing of these complications in relation to the procedure. Materials and Methods: Retrospective cohort of consecutive adult patients undergoing flow diversion with Pipeline Embolization Device (PED) at an academic medical center, receiving on-label clopidogrel doses. Patients with clopidogrel hyperresponsiveness (VerifyNow TM P2Y12 reaction unit (PRU) ≤ 70) were compared to those who were normoresponsive. The primary outcome is the rate of hemorrhagic complications between groups. Results: Of 148 included patients, 54 (36.5%) were identified as clopidogrel hyperresponsive (PRU ≤ 70) and 94 (63.5%) as clopidogrel normoresponsive (PRU 71 - 194). There were no hemorrhagic complications observed in patients who were clopidogrel hyperresponsive, with 5 occurring in patients who were normoresponsive ( P = 0.09). Three (60%) of the hemorrhages were intracranial with most occurring intra-procedure or within the first week of the procedure. Age > 60 years was the only candidate predictor for hemorrhagic complications ( P = 0.004). Conclusion: Our findings are contradictory, with lower hemorrhagic complications in clopidogrel hyperresponders than prior literature, and most occurring intra-op or in the immediate acute post-op phase., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Despite advances in endovascular techniques, mechanical thrombectomy (MT) fails to achieve successful reperfusion in approximately 20% of patients. This study aimed to identify common etiologies and predictors of failed thrombectomy in a contemporary series., Methods: A prospectively maintained database of MT patients between January 2013 and August 2021 was interrogated. Failed MT was defined as a final modified Thrombolysis in Cerebral Infarction score < 2b. Demographic data, procedural details, stroke etiology, and anatomical data in patients who underwent MT with subsequent failed reperfusion were collected., Results: Of a total 1010 MT procedures, 120 (11.9%) were unsuccessful. The mean patient age was 66.8 years; 51.5% of patients were male, and 61.1% were White. The most common failure location was intracranial (93.3%) followed by failure at the arch (3.3%) and neck (3.3%). Among patients with intracranial failure, underlying intracranial atherosclerosis (ICAS) was the cause of failure in 84 patients (70%). Compared with patients with successful MT, patients with failed MT had a longer onset to puncture time (p = 0.012) and onset to groin time (p = 0.04). Rescue stenting was performed in 45 cases: 39 patients (4.4%) with successful MT and 6 (5.0%) with MT failure (p = 0.765). Multivariate analysis demonstrated that diabetes mellitus (p = 0.009) was independently associated with unsuccessful reperfusion., Conclusions: Failed MT was encountered in approximately 12% of MT procedures. The most common cause of failed MT was underlying ICAS. Further studies to evaluate better ways of early identification and treatment of ICAS-related large-vessel occlusion are warranted.

Background/objective: Inactivated four-factor prothrombin complex concentrate (I4F-PCC, Kcentra ® ) has become an important agent for the urgent or emergent reversal of bleeding associated with vitamin K antagonists such as warfarin. There is recognized inter-institutional variability with the use of I4F-PCC, especially as it relates to dosing practices. We sought to characterize variations in I4F-PCC dosing practices and their impact on patient outcomes and describe overall real-world clinical practice surrounding I4F-PCC utilization in the context of the management of warfarin-related intracranial hemorrhage (ICH)., Methods: This is a multicenter retrospective pragmatic registry study of adult patients admitted at a participating study site between January 1, 2014, and December 31, 2015, who received I4F-PCC for reversal of warfarin-related ICH. Practices around warfarin-related ICH reversal in context of I4F-PCC utilization are described, including repeat I4F-PCC dosing, adjunctive reversal agents, and dose rounding policies (i.e., rounding doses to nearest vial size vs preparing exact/unrounded doses). All research was approved by local human investigation committees at each institution., Results: Seventeen institutions contributed data on 528 patients to this registry. These institutions were primarily urban centers (74%), located in the southeast USA (47%), with Level 1 Trauma designation (79%), and with Comprehensive Stroke Center designation (74%). Most patients included in the study had sustained a non-traumatic ICH (68%), had a median admission GCS of 14 (IQR 7-15), and were receiving warfarin for atrial fibrillation (57.4%). There was substantial time latency between baseline INR and I4F-PCC (median 2.4 h, IQR 1.4-4.5 h). Most patients received adjunctive reversal agents, including vitamin K (89.5%) and fresh frozen plasma (FFP) (31.9%). A smaller proportion (6.0%) of patients received repeat I4F-PCC dosing. The median ICU length of stay (LOS) was 3 days (IQR 2-7 days), median hospital LOS was 6 days (IQR 3-12 days), and overall mortality rate was 28.8%. For institutions rounding doses to the nearest vial size, the first post-I4F-PCC dose INR was statistically but not clinically significantly lower than for institutions without vial size dose rounding, with comparable degrees of INR reduction from baseline. No differences were observed between dose rounding cohorts in adverse effects, ICU or hospital LOS, modified Rankin score at discharge, or mortality rates., Conclusions: Most patients received single doses of I4F-PCC, with adjunctive reversal agents and rounding doses to vial size. The time difference from baseline INR to factor product administration is a potential opportunity for process improvement in the management of warfarin-related ICH., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Background: Valproic acid (VPA) is a broad-spectrum anticonvulsant drug. Under normal conditions, this drug is highly protein bound. However, in patients with hypoalbuminemia, the free fraction can increase substantially while the total VPA levels remain in therapeutic range. The neurologic activity and toxicity of the drug are directly related to free drug levels., Methods: Our in-house free VPA assay was validated using 20 patient samples obtained from a reference laboratory (RL1). It was further evaluated by parallel testing with RL1 using samples collected from our patients. Subsequently, sample handling effects were investigated by comparing free VPA levels measured in our laboratory to 3 selected RLs with different sample transportation conditions., Results: No significant bias was observed between the in-house assay (y) and RL1 (x) assay in free VPA measurement (y = 1.12x + 0.072, r = 0.994). However, patient samples collected in our institution and sent to RL1 revealed significant negative bias (y = 0.776x - 3.861, r = 0.954). A large discrepancy in free VPA levels was further observed from identical aliquots of the same samples transported to 3 RLs in different conditions., Conclusions: Our study demonstrated that sample handling has significant impact on free VPA levels. The observed magnitude of variation exceeds a clinically acceptable limit and could alter clinical decisions., (© American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: VerifyNow-directed personalized antiplatelet therapy for aneurysm embolization with a Pipeline Embolization Device (PED) remains controversial. Evaluate thrombotic complications between patients who received VerifyNow-directed personalized antiplatelet therapy versus those who did not after PED flow diversion of complex cerebral aneurysms., Methods: This was a retrospective cohort of consecutive patients undergoing flow diversion with PED at the Medical University of South Carolina between January 2012 and May 2018. Patients who received VerifyNow-directed personalized antiplatelet therapy were compared with those who received antiplatelet therapy without platelet function testing. Patients with a P2Y12 reaction unit (PRU) ≥194 were deemed to be clopidogrel hyporesponsive. The primary outcome is the rate of thrombotic complications, and the secondary outcomes are the rate of hemorrhagic and thrombotic complications stratified by PRU and high-risk clinical and procedure-related candidate predictors., Results: Thrombotic complications were not different between patients managed with (n = 159) versus without (n = 110) VerifyNow (6.9% vs. 7.3%; P = 0.911). Hemorrhagic complications were also no different (3.1% vs. 4.5%; P = 0.550). PRU stratification revealed no difference in thrombotic or hemorrhagic complications (P = 0.488 and P = 0.136, respectively). The only significant predictors for thrombotic complications were the presence of diabetes (OR 2.9; P = 0.034), obesity (OR 5.1; P ≤ 0.001), fusiform aneurysm (OR 3.3; P = 0.023), posterior circulation implantation (OR 3.4; P = 0.016), and >1 PED implanted (OR 2.4; P = 0.046)., Conclusions: The role of VerifyNow and personalized antiplatelet therapy in patients undergoing flow diversion with PED to treat complex aneurysms did not demonstrate a benefit in reducing thrombotic complications., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Central nervous system (CNS) infections are particularly prevalent in the adult neurocritical care patient population and are associated with significant morbidity and mortality. Factors relevant to the nature of CNS infections pose significant challenges to clinicians treating afflicted patients. Intraventricular (IVT) administration of antibiotics may offer several benefits over systemic therapy; however, the outcomes and current practices of such treatments are poorly described in the literature., Objective: To describe current practices and outcomes of patients receiving intraventricular antibiotic treatment for CNS infections in neurological intensive care units of academic medical centers nationwide., Methods: A retrospective cohort study was conducted on patients admitted to intensive care units who received IVT antibiotic treatment at participating centers in the USA between January 01, 2003, and December 31, 2013. Clinical and laboratory parameters, microbiology, surgical and antimicrobial management, and treatment outcomes were collected and described., Results: Of the 105 patients included, all received systemic antimicrobial therapy along with at least one dose of IVT antimicrobial agents. Intraventricular vancomycin was used in 52.4% of patients. The average dose was 12.2 mg/day for a median duration of 5 days. Intraventricular aminoglycosides were used in 47.5% of the patients, either alone or in combination with IVT vancomycin. The average dose of gentamicin/tobramycin was 6.7 mg/day with a median duration of 6 days. Overall mortality was 18.1%. Cerebrospinal fluid (CSF) culture sterilization occurred in 88.4% of the patients with a rate of recurrence or persistence of positive cultures of 9.5%., Conclusion: Intraventricular antimicrobial agents resulted in a high CSF sterilization rate. Contemporary use of this route typically results in a treatment duration of less than a week. Prospective studies are needed to establish the optimal patient population, as well as the efficacy and safety of this route of administration.

Background: Patient-specific factors can alter the pharmacokinetic disposition of valproic acid. Specifically, the free fraction of valproic acid can increase substantially in patients with hypoalbuminemia or as serum drug concentrations rise due to saturable protein binding. Direct measurement of free serum drug concentrations allows for accurate assessment of drug levels, but the assay may not be readily available in all institutions. The effect of hypoalbuminemia on free fraction has been quantified and serves as the basis of an equation used to "correct" measured total valproic acid concentrations. The aim of this study was to evaluate the accuracy of the equation., Methods: This retrospective study included adult patients with measurable free and total valproic acid concentrations between July 2014 and June 2017. The primary aim was to assess the relationship between measured and predicted free valproic acid concentrations. Free levels were categorized as subtherapeutic, therapeutic, or supratherapeutic based on the reference range of 7-23 mg/L. Concordance was defined as measured and predicted concentrations falling within the same category., Results: The analysis included 174 patients with a median age of 58 years and a median albumin of 3 g/dL. The majority of patients were hospitalized (88.5%). Concordance occurred in 56.9% of samples. A Spearman's correlation coefficient of 0.60 (p < 0.001) was found between the measured and predicted free valproic acid concentrations. Concordance of concentrations was 42% for ICU patients, 63% for floor patients, and 65% for outpatients. Of those with discordant concentrations, 97% of the predicted concentrations underestimated the measured concentrations., Conclusions: There is discordance between predicted and measured free serum valproic acid concentrations when using the proposed equation. Because of the potential impact of underestimation and variability of free valproic acid concentrations, a measured free level is the ideal option for therapeutic drug monitoring of valproic acid.

Novel oral anticoagulants present challenges and uncertainties in the management of hemorrhagic emergencies. An 84-year-old man taking dabigatran presented with a subdural hematoma requiring neurosurgical intervention. Routine coagulation assays were prolonged at admission and following administration of Factor VIII Inhibitor Bypassing Activity (FEIBA). Thromboelastography (TEG(®)) was utilized to assess clot dynamics prior to placement of a subdural drain, which was safely inserted despite a prolonged thrombin time (TT). Exclusive reliance on the TT may delay necessary interventions. TEG(®) may be a valuable tool to investigate hemostasis in patients on dabigatran requiring emergent procedures.

Background and Purpose: Intracranial hypertension and cerebral edema are known contributors to secondary brain injury and to poor neurologic outcomes. Small volume solutions of exceedingly high osmolarity, such as 23.4% saline, have been used for the management of intracranial hypertension crises and as a measure to prevent or reverse acute brain tissue shifts. We conducted a systematic literature review on the use of 23.4% saline in neurocritically ill patients and a meta-analysis of the effect of 23.4% saline on intracranial pressure reduction., Design: We searched computerized databases, reference lists, and personal files to identify all clinical studies in which 23.4% saline has been used for the treatment of neurocritical care patients. Studies that did not directly involve either effects on cerebral hemodynamics or the treatment of patients with clinical or radiographic evidence of intracranial hypertension and/or cerebral swelling were eliminated., Measurements and Main Results: We identified 11 clinical studies meeting eligibility criteria. A meta-analysis was performed to evaluate the percent decrease in intracranial pressure and the 95% confidence intervals, from baseline to 60 minutes or nadir from the six studies from which this information could be extracted. A fixed effects meta-analysis estimated that the percent decrease in intracranial pressure from baseline to either 60 minutes or nadir after administration of 23.4% saline was 55.6% (se 5.90; 95% confidence interval, 43.99-67.12; p < 0.0001)., Conclusions: Highly concentrated hypertonic saline such as 23.4% provides a small volume solution with low cost and an over 50% reduction effect on raised intracranial pressure. Side effects reported are minor overall in view of the potentially catastrophic event that is being treated. High quality data are still needed to define the most appropriate osmotherapeutic agent, the optimal dose, the safest and most effective mode of administration and to further elucidate the mechanism of action of 23.4% saline and of osmotherapy in general.

Background: Manganese encephalopathy is a potential complication of parenteral nutrition. Lack of early recognition leads to unnecessary testing and to continued exposure to manganese., Methods: Case report and review of the literature., Results: We describe the clinical and imaging findings of a patient with manganese encephalopathy in whom the diagnosis was delayed due to lack of recognition of the characteristic imaging findings., Conclusion: Manganese encephalopathy has protean clinical and imaging findings that can easily be overlooked.

Background: Cerebral edema and raised intracranial pressure are common problems in neurological intensive care. Osmotherapy, typically using mannitol or hypertonic saline (HTS), has become one of the first-line interventions. However, the literature on the use of these agents is heterogeneous and lacking in class I studies. The authors hypothesized that clinical practice would reflect this heterogeneity with respect to choice of agent, dosing strategy, and methods for monitoring therapy., Methods: An on-line survey was administered by e-mail to members of the Neurocritical Care Society. Multiple-choice questions regarding use of mannitol and HTS were employed to gain insight into clinician practices., Results: A total of 295 responses were received, 79.7% of which were from physicians. The majority (89.9%) reported using osmotherapy as needed for intracranial hypertension, though a minority reported initiating treatment prophylactically. Practitioners were fairly evenly split between those who preferred HTS (54.9%) and those who preferred mannitol (45.1%), with some respondents reserving HTS for patients with refractory intracranial hypertension. Respondents who preferred HTS were more likely to endorse prophylactic administration. Preferred dosing regimens for both agents varied considerably, as did monitoring parameters., Conclusions: Treatment of cerebral edema using osmotically active substances varies considerably between practitioners. This variation could hamper efforts to design and implement multicenter trials in neurocritical care.

Methylnaltrexone and alvimopan are two new and potentially useful agents in the management of opioid-induced bowel dysfunction and prevention of postoperative ileus. Both agents have promising prokinetic properties and appear to be capable of reversing the effects of opioids on delayed gastrointestinal transit. This article reviews currently available published literature to provide an overview of the clinical trials and to provide insight for the potential use of these agents for patients requiring opioid based analgesia. These compounds represent a new class of compounds that may impact the therapeutics for opioid induced bowel dysfunction as well as postoperative ileus.