Status Epilepticus: An Update on Pharmacological Management.

Status epilepticus (SE) is a neurological emergency that requires timely pharmacological therapy to cease seizure activity. The treatment approach varies based on the time and the treatment stage of SE. Benzodiazepines are considered the first-line therapy during the emergent treatment phase of SE. Antiseizure medicines such as phenytoin, valproic acid, and levetiracetam are recommended during the urgent treatment phase. These drugs appear to have a similar safety and efficacy profile, and individualized therapy should be chosen based on patient characteristics. Midazolam, propofol, pentobarbital, and ketamine are continuous intravenous infusions of anesthetic medications utilized in the refractory SE (RSE) period. The most efficacious pharmacotherapeutic treatments for RSE and superrefractory status epilepticus are not clearly defined.

Sex differences in time course and diagnostic accuracy of GFAP and UCH-L1 in trauma patients with mild traumatic brain injury.

Glial Fibrillary Acidic Protein (GFAP) and Ubiquitin C-terminal hydrolase (UCH-L1) have been FDA-approved for clinical use in mild and moderate traumatic brain injury (TBI). Understanding sex differences in their diagnostic accuracy over time will help inform clinical practice. We sought to evaluate the sex differences in the temporal profile of GFAP and UCH-L1 in a large cohort of trauma patients presenting to the emergency department. To compare the biomarkers' diagnostic accuracy in male versus female patients for detecting mild TBI (MTBI), and traumatic intracranial lesions on head CT. This prospective cohort study enrolled female and male adult trauma patients presenting to a Level 1 Trauma Center. All patients underwent rigorous screening to determine whether or not they had experienced a MTBI. Of 3025 trauma patients assessed, 1030 met eligibility criteria and 446 declined. Initial blood samples were obtained in 584 patients enrolled within 4 h of injury. Repeated blood sampling was conducted at 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, and 180-h post-injury. The main outcomes included the diagnostic accuracy in detection of MTBI and traumatic intracranial lesions on head CT scan. A total of 1831 samples were drawn in 584 patients over 7 days, 362 (62%) were male and 222 (38%) were female. The pattern of elevation was similar in both sexes. Although the pattern of elevation was similar between male and female for both biomarkers, male patients had significantly higher concentrations of UCH-L1 compared to female patients at several timepoints post-injury, particularly within 24 h of injury. There were no significant differences in diagnostic accuracy for detecting MTBI or for detecting CT lesions between male and female patients at any timepoint for both GFAP and UCH-L1. Although patterns of GFAP and UCH-L1 release in trauma patients over a week post-injury was similar between the sexes, there were significantly higher concentrations of UCH-L1 in males at several timepoints post-injury. Despite this, the overall diagnostic accuracies of both GFAP and UCH-L1 over time for detecting MTBI and CT lesions were not significantly different between male and female trauma patients.

Comparison of nimodipine formulations and administration techniques via enteral feeding tubes in patients with aneurysmal subarachnoid hemorrhage: A multicenter retrospective cohort study.

BACKGROUND: Nimodipine improves outcomes following aneurysmal subarachnoid hemorrhage (aSAH) and current guidelines suggest that patients with aSAH receive nimodipine for 21 days. Patients with no difficulty swallowing will swallow the whole capsules or tablets; otherwise, nimodipine liquid must be drawn from capsules, tablets need to be crushed, or the commercially available liquid product be used to facilitate administration through an enteral feeding tube (FT). It is not clear whether these techniques are equivalent. The goal of the study was to determine if different nimodipine formulations and administration techniques were associated with the safety and effectiveness of nimodipine in aSAH. METHODS: This was a retrospective multicenter observational cohort study conducted in 21 hospitals across North America. Patients admitted with aSAH and received nimodipine by FT for ≥3 days were included. Patient demographics, disease severity, nimodipine administration, and study outcomes were collected. Safety end points included the prevalence of diarrhea and nimodipine dose reduction or discontinuation secondary to blood pressure reduction. Predictors of the study outcomes were analyzed using regression modeling. RESULTS: A total of 727 patients were included. Administration of nimodipine liquid product was independently associated with higher prevalence of diarrhea compared to other administration techniques/formulations (Odds ratio [OR] 2.28, 95% confidence interval [CI] 1.41-3.67, p-value = 0.001, OR 2.76, 95% CI 1.37-5.55, p-value = 0.005, for old and new commercially available formulations, respectively). Bedside withdrawal of liquid from nimodipine capsules prior to administration was significantly associated with higher prevalence of nimodipine dose reduction or discontinuation secondary to hypotension (OR 2.82, 95% CI 1.57-5.06, p-value = 0.001). Tablet crushing and bedside withdrawal of liquid from capsules prior to administration were associated with increased odds of delayed cerebral ischemia (OR 6.66, 95% CI 3.48-12.74, p-value <0.0001 and OR 3.92, 95% CI 2.05-7.52, p-value <0.0001, respectively). CONCLUSIONS: Our findings suggest that enteral nimodipine formulations and administration techniques might not be equivalent. This could be attributed to excipient differences, inconsistency and inaccuracy in medication administration, and altered nimodipine bioavailability. Further studies are needed.

Personalized antiseizure medication therapy in critically ill adult patients.

Precision medicine has the potential to have a significant impact on both drug development and patient care. It is crucial to not only provide prompt effective antiseizure treatment for critically ill patients after seizures start but also have a proactive mindset and concentrate on epileptogenesis and the underlying cause of the seizures or seizure disorders. Critical illness presents different treatment issues compared with the ambulatory population, which makes it challenging to choose the best antiseizure medications and to administer them at the right time and at the right dose. Since there is a paucity of information available on antiseizure medication dosing in critically ill patients, therapeutic drug monitoring is a useful tool for defining each patient's personal therapeutic range and assisting clinicians in decision-making. Use of pharmacogenomic information relating to pharmacokinetics, hepatic metabolism, and seizure etiology may improve safety and efficacy by individualizing therapy. Studies evaluating the clinical implementation of pharmacogenomic information at the point-of-care and identification of biomarkers are also needed. These studies may make it possible to avoid adverse drug reactions, maximize drug efficacy, reduce drug-drug interactions, and optimize medications for each individual patient. This review will discuss the available literature and provide future insights on precision medicine use with antiseizure therapy in critically ill adult patients.

Levetiracetam-associated behavioral adverse events in neurocritical care patients.

STUDY OBJECTIVES: The objective of this study was to identify the incidence of levetiracetam-associated BAEs in NCC patients. DESIGN: Single-center retrospective cohort analysis. DATA SOURCE: Patient charts. PATIENTS: 965 adult ICU patients with a neurological injury receiving levetiracetam that were admitted to an intensive care unit. MEASUREMENTS AND MAIN RESULTS: There were 965 patients included; 52% males with a median GCS of 13. Injury types included TBI (43.1%), ICH (21.8%), SAH (20.5%), and CI (14.6%). BAEs were identified in 46% of patients. Of these, 60% had documentation of agitation/restlessness, delirium, or anxiety while receiving levetiracetam, only 25% had a positive CAM-ICU, 13% had restraints ordered, and 42% received antipsychotics. Patients with TBI had the highest incidence of BAEs (52.4%). The median time to initiation of levetiracetam after hospital admission was 6.4 hours and BAEs occurred after 1.3 days of levetiracetam initiation. CONCLUSIONS: In this study, we found that almost half of our NCC population experienced levetiracetam associated BAEs which were mostly hyperactive in nature. We believe that the incidence of BAEs in our specific patient population cannot solely be attributed to ICU delirium given the lower risk of developing hyperactive delirium in ICU patients as compared to other subtypes. Therefore, monitoring and determination of the benefit versus risk in those experiencing BAEs is highly encouraged.

Pharmacologic Therapies to Promote Recovery of Consciousness.

Pharmacologic interventions are commonly used to support rehabilitation efforts of patients with disorders of consciousness (DoC). The 2018 practice guidelines recommend amantadine in adults with traumatic DoC to promote functional recovery, though several other stimulants are used off-label in clinical practice and trials, such as methylphenidate, bromocriptine, levodopa, and zolpidem. Differences in the mechanisms of action, adverse effects, pharmacokinetics, and drug-drug interactions should be considered when selecting the best agent for each individual patient. Overall, pharmacologic stimulants may provide a safe and inexpensive pathway to increased functionality and participation in rehabilitation. This article provides a concise summary of scientific evidence supporting the use of pharmacologic therapies to stimulate recovery of consciousness in patients with DoC.

Predicting Clinical Outcomes 7-10 Years after Severe Traumatic Brain Injury: Exploring the Prognostic Utility of the IMPACT Lab Model and Cerebrospinal Fluid UCH-L1 and MAP-2.

BACKGROUND: Severe traumatic brain injury (TBI) is a major contributor to disability and mortality in the industrialized world. Outcomes of severe TBI are profoundly heterogeneous, complicating outcome prognostication. Several prognostic models have been validated for acute prediction of 6-month global outcomes following TBI (e.g., morbidity/mortality). In this preliminary observational prognostic study, we assess the utility of the International Mission on Prognosis and Analysis of Clinical Trials in TBI (IMPACT) Lab model in predicting longer term global and cognitive outcomes (7-10 years post injury) and the extent to which cerebrospinal fluid (CSF) biomarkers enhance outcome prediction. METHODS: Very long-term global outcome was assessed in a total of 59 participants (41 of whom did not survive their injuries) using the Glasgow Outcome Scale-Extended and Disability Rating Scale. More detailed outcome information regarding cognitive functioning in daily life was collected from 18 participants surviving to 7-10 years post injury using the Cognitive Subscale of the Functional Independence Measure. A subset (n = 10) of these participants also completed performance-based cognitive testing (Digit Span Test) by telephone. The IMPACT lab model was applied to determine its prognostic value in relation to very long-term outcomes as well as the additive effects of acute CSF ubiquitin C-terminal hydrolase-L1 (UCH-L1) and microtubule associated protein 2 (MAP-2) concentrations. RESULTS: The IMPACT lab model discriminated favorable versus unfavorable 7- to 10-year outcome with an area under the receiver operating characteristic curve of 0.80. Higher IMPACT lab model risk scores predicted greater extent of very long-term morbidity (ß = 0.488 p = 0.000) as well as reduced cognitive independence (ß = - 0.515, p = 0.034). Acute elevations in UCH-L1 levels were also predictive of lesser independence in cognitive activities in daily life at very long-term follow-up (ß = 0.286, p = 0.048). Addition of two CSF biomarkers significantly improved prediction of very long-term neuropsychological performance among survivors, with the overall model (including IMPACT lab score, UCH-L1, and MAP-2) explaining 89.6% of variance in cognitive performance 7-10 years post injury (p = 0.008). Higher acute UCH-L1 concentrations were predictive of poorer cognitive performance (ß = - 0.496, p = 0.029), whereas higher acute MAP-2 concentrations demonstrated a strong cognitive protective effect (ß = 0.679, p = 0.010). CONCLUSIONS: Although preliminary, results suggest that existing prognostic models, including models with incorporation of CSF markers, may be applied to predict outcome of severe TBI years after injury. Continued research is needed examining early predictors of longer-term outcomes following TBI to identify potential targets for clinical trials that could impact long-ranging functional and cognitive outcomes.

Intravenous Versus Oral Acetaminophen Use in Febrile Neurocritical Care Patients.

The use of intravenous (IV) acetaminophen (APAP) for fever has not been thoroughly studied in neurocritical care (NCC) patients, in whom a temperature of ≥38°C is associated with poor outcomes and treatment to normothermia is common practice. This retrospective study evaluated NCC patients admitted between May 1, 2012, and April 30, 2013, and received at least one dose of IV or oral (PO) APAP for a body temperature of ≥38°C. The primary aim of this study was to compare the reduction in body temperature (RIT) between IV and PO APAP, calculated as the change in temperature before and 0.5, 1, 2, 3, and 6 hours after administration. Descriptive statistics were used to assess use characteristics, and Kruskal-Wallis and Mann-Whitney U tests were used for between-group differences. There were 142 NCC patients who received a total of 405 IV APAP and 253 PO APAP doses. Seventy percent of all APAP doses resulted in a temperature of <38°C within 6 hours. The median oral body temperature before APAP was 38.8°C and 38.6°C for IV and PO APAP, respectively (p < 0.01). The median RIT at 0.5 (IV 0.25°C vs. PO 0.2°C), 1 (IV 0.4°C vs. PO 0.2°C), 2 (IV 0.7°C vs. PO 0.5°C), 3 (IV 0.9°C vs. PO 0.6°C), and 6 (IV 1°C vs. PO 0.8°C) hours was significantly greater for IV APAP than for PO APAP at all time points (p < 0.05). Patients with an acute ischemic stroke and patients with an intracerebral hemorrhage had a statistically significantly greater RIT with IV APAP therapy. IV APAP administered to febrile NCC patients was associated with a significantly greater RIT than PO, but 70% of all APAP doses resulted in a body temperature of <38°C within 6 hours. Further prospective studies are needed to determine if IV APAP improves clinical outcomes.

Time Is Brain: Acute Control of Repetitive Seizures and Status Epilepticus Using Alternative Routes of Administration of Benzodiazepines.

Time plays a major role in seizure evaluation and treatment. Acute repetitive seizures and status epilepticus are medical emergencies that require immediate assessment and treatment for optimal therapeutic response. Benzodiazepines are considered the first-line agent for rapid seizure control. Thus, various routes of administration of benzodiazepines have been studied to facilitate a quick, effective, and easy therapy administration. Choosing the right agent may vary based on the drug and route properties, patient's environment, caregiver's skills, and drug accessibility. The pharmacokinetic and pharmacodynamic aspects of benzodiazepines are essential in the decision-making process. Ultimately, agents and routes that give the highest bioavailability, fastest absorption, and a modest duration are preferred. In the outpatient setting, intranasal and buccal routes appear to be equally effective and more rapidly administered than rectal diazepam. On the other hand, in the inpatient setting, if available, the IV route is ideal for benzodiazepine administration to avoid any potential absorption delay. In this article, we will provide an overview and comparison of the various routes of benzodiazepine administration for acute control of repetitive seizures and status epilepticus.

Stress-Related Gastrointestinal Bleeding in Patients with Aneurysmal Subarachnoid Hemorrhage: A Multicenter Retrospective Observational Study.

BACKGROUND/OBJECTIVE: Stress-related mucosal bleeding (SRMB) occurs in approximately 2-4% of critically ill patients. Patients with aneurysmal subarachnoid hemorrhage (aSAH) have a (diffuse) space-occupying lesion, are critically ill, often require mechanical ventilation, and frequently receive anticoagulation or antiplatelet therapy after aneurysm embolization, all of which may be risk factors for SRMB. However, no studies have evaluated SRMB in patients with aSAH. Aims of the study were to determine the incidence of SRMB in aSAH patients, evaluate the effect of acid suppression on SRMB, and identify specific risk factors for SRMB. METHODS: This was a multicenter, retrospective, observational study conducted across 17 centers. Each center reviewed up to 50 of the most recent cases of aSAH. Patients with length of stay (LOS) < 48 h or active GI bleeding on admission were excluded. Variables related to demographics, aSAH severity, gastrointestinal (GI) bleeding, provision of SRMB prophylaxis, adverse events, intensive care unit (ICU), and hospital LOS were collected for the first 21 days of admission or until hospital discharge, whichever came first. Descriptive statistics were used to analyze the data. A multivariate logistic regression modeling was utilized to examine the relationship between specific risk factors and the incidence of clinically important GI bleeding in patients with aSAH. RESULTS: A total of 627 patients were included. The overall incidence of clinically important GI bleeding was 4.9%. Of the patients with clinically important GI bleeding, 19 (61%) received pharmacologic prophylaxis prior to evidence of GI bleeding, while 12 (39%) were not on pharmacologic prophylaxis at the onset of GI bleeding. Patients who received an acid suppressant agent were less likely to experience GI bleeding than patients who did not receive pharmacologic prophylaxis prior to evidence of bleeding (OR 0.39, 95% CI 0.18-0.83). The multivariate regression analysis identified any instance of elevated intracranial pressure, creatinine clearance < 60 ml/min and the incidence of cerebral vasospasm as specific risk factors associated with GI bleeding. Cerebral vasospasm has not previously been described as a risk for GI bleeding (OR 2.5 95% CI 1.09-5.79). CONCLUSIONS: Clinically important GI bleeding occurred in 4.9% of patients with aSAH, similar to the general critical care population. Risk factors associated with GI bleeding were prolonged mechanical ventilation (> 48 h), creatinine clearance < 60 ml/min, presence of coagulopathy, elevation of intracranial pressure, and cerebral vasospasm. Further prospective research is needed to confirm this observation within this patient population.

Principles of Pharmacotherapy of Seizures and Status Epilepticus.

Status epilepticus is a neurological emergency with an outcome that is highly associated with the initial pharmacotherapy management that must be administered in a timely fashion. Beyond first-line therapy of status epilepticus, treatment is not guided by robust evidence. Optimal pharmacotherapy selection for individual patients is essential in the management of seizures and status epilepticus with careful evaluation of pharmacokinetic and pharmacodynamic factors. With the addition of newer antiseizure agents to the market, understanding their role in the management of status epilepticus is critical. Etiology-guided therapy should be considered in certain patients with drug-induced seizures, alcohol withdrawal, or autoimmune encephalitis. Some patient populations warrant special consideration, such as pediatric, pregnant, elderly, and the critically ill. Seizure prophylaxis is indicated in select patients with acute neurological injury and should be limited to the acute postinjury period.

Anticoagulation reversal for intracranial hemorrhage in the era of the direct oral anticoagulants.

PURPOSE OF REVIEW: This review focuses on recent relevant literature that examines the reversal of direct oral anticoagulants (DOACs) in patients with intracranial hemorrhage (ICH). The aim of this review is to provide an insightful description of available reversal agents and their clinical utility. RECENT FINDINGS: Increases in prescribing of DOACs has led to the introduction of drug-specific reversal agents. The clinical trials that evaluated these agents did not include a comparator arm making it difficult to determine if they are clinically superior to nonspecific reversal agents. SUMMARY: Numerous options for reversal of DOAC-associated ICH are currently available. Recent clinical trials have demonstrated drug-specific reversal agents are effective in this setting, but additional research is needed to determine whether these agents should be routinely preferred over nonspecific reversal agents.

High-Dose Intravenous Ascorbic Acid: Ready for Prime Time in Traumatic Brain Injury?

Traumatic brain injury (TBI) is one of the leading public health problems in the USA and worldwide. It is the number one cause of death and disability in children and adults between ages 1-44. Despite efforts to prevent TBIs, the incidence continues to rise. Secondary brain injury occurs in the first hours and days after the initial impact and is the most effective target for intervention. Inflammatory processes and oxidative stress play an important role in the pathomechanism of TBI and are exacerbated by impaired endogenous defense mechanisms, including depletion of antioxidants. As a reducing agent, free radical scavenger, and co-factor in numerous biosynthetic reactions, ascorbic acid (AA, vitamin C) is an essential nutrient that rapidly becomes depleted in states of critical illness. The administration of high-dose intravenous (IV) AA has demonstrated benefits in numerous preclinical models in the areas of trauma, critical care, wound healing, and hematology. A safe and inexpensive treatment, high-dose IV AA administration gained recent attention in studies demonstrating an associated mortality reduction in septic shock patients. High-quality data on the effects of high-dose IV AA on TBI are lacking. Historic data in a small number of patients demonstrate acute and profound AA deficiency in patients with central nervous system pathology, particularly TBI, and a strong correlation between low AA concentrations and poor outcomes. While replenishing deficient AA stores in TBI patients should improve the brain's ability to tolerate oxidative stress, high-dose IV AA may prove an effective strategy to prevent or mitigate secondary brain injury due to its ability to impede lipid peroxidation, scavenge reactive oxygen species, suppress inflammatory mediators, stabilize the endothelium, and reduce brain edema. The existing preclinical data and limited clinical data suggest that high-dose IV AA may be effective in lowering oxidative stress and decreasing cerebral edema. Whether this translates into improved clinical outcomes will depend on identifying the ideal target patient population and possible treatment combinations, factors that need to be evaluated in future clinical studies. With its excellent safety profile and low cost, high-dose IV AA is ready to be evaluated in the early treatment of TBI patients to mitigate secondary brain injury and improve outcomes.

Prevention, Treatment, and Monitoring of Seizures in the Intensive Care Unit.

The diagnosis and management of seizures in the critically ill patient can sometimes present a unique challenge for practitioners due to lack of exposure and complex patient comorbidities. The reported incidence varies between 8% and 34% of critically ill patients, with many patients often showing no overt clinical signs of seizures. Outcomes in patients with unidentified seizure activity tend to be poor, and mortality significantly increases in those who have seizure activity longer than 30 min. Prompt diagnosis and provision of medical therapy are crucial in order to attain successful seizure termination and prevent poor outcomes. In this article, we review the epidemiology and pathophysiology of seizures in the critically ill, various seizure monitoring modalities, and recommended medical therapy.

Common Data Elements for Unruptured Intracranial Aneurysms and Aneurysmal Subarachnoid Hemorrhage: Recommendations from the Working Group on Hospital Course and Acute Therapies-Proposal of a Multidisciplinary Research Group.

INTRODUCTION: The Common Data Elements (CDEs) initiative is a National Institute of Health/National Institute of Neurological Disorders and Stroke (NINDS) effort to standardize naming, definitions, data coding, and data collection for observational studies and clinical trials in major neurological disorders. A working group of experts was established to provide recommendations for Unruptured Aneurysms and Aneurysmal Subarachnoid Hemorrhage (SAH) CDEs. METHODS: This paper summarizes the recommendations of the Hospital Course and Acute Therapies after SAH working group. Consensus recommendations were developed by assessment of previously published CDEs for traumatic brain injury, stroke, and epilepsy. Unruptured aneurysm- and SAH-specific CDEs were also developed. CDEs were categorized into "core", "supplemental-highly recommended", "supplemental" and "exploratory". RESULTS: We identified and developed CDEs for Hospital Course and Acute Therapies after SAH, which included: surgical and procedure interventions; rescue therapy for delayed cerebral ischemia (DCI); neurological complications (i.e. DCI; hydrocephalus; rebleeding; seizures); intensive care unit therapies; prior and concomitant medications; electroencephalography; invasive brain monitoring; medical complications (cardiac dysfunction; pulmonary edema); palliative comfort care and end of life issues; discharge status. The CDEs can be found at the NINDS Web site that provides standardized naming, and definitions for each element, and also case report form templates, based on the CDEs. CONCLUSION: Most of the recommended Hospital Course and Acute Therapies CDEs have been newly developed. Adherence to these recommendations should facilitate data collection and data sharing in SAH research, which could improve the comparison of results across observational studies, clinical trials, and meta-analyses of individual patient data.