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.

Guidelines for Seizure Prophylaxis in Adults Hospitalized with Moderate-Severe Traumatic Brain Injury: A Clinical Practice Guideline for Health Care Professionals from the Neurocritical Care Society.

BACKGROUND: There is practice heterogeneity in the use, type, and duration of prophylactic antiseizure medications (ASMs) in patients with moderate-severe traumatic brain injury (TBI). METHODS: We conducted a systematic review and meta-analysis of articles assessing ASM prophylaxis in adults with moderate-severe TBI (acute radiographic findings and requiring hospitalization). The population, intervention, comparator, and outcome (PICO) questions were as follows: (1) Should ASM versus no ASM be used in patients with moderate-severe TBI and no history of clinical or electrographic seizures? (2) If an ASM is used, should levetiracetam (LEV) or phenytoin/fosphenytoin (PHT/fPHT) be preferentially used? (3) If an ASM is used, should a long versus short (> 7 vs. ≤ 7 days) duration of prophylaxis be used? The main outcomes were early seizure, late seizure, adverse events, mortality, and functional outcomes. We used Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to generate recommendations. RESULTS: The initial literature search yielded 1998 articles, of which 33 formed the basis of the recommendations: PICO 1: We did not detect any significant positive or negative effect of ASM compared to no ASM on the outcomes of early seizure, late seizure, adverse events, or mortality. PICO 2: We did not detect any significant positive or negative effect of PHT/fPHT compared to LEV for early seizures or mortality, though point estimates suggest fewer late seizures and fewer adverse events with LEV. PICO 3: There were no significant differences in early or late seizures with longer versus shorter ASM use, though cognitive outcomes and adverse events appear worse with protracted use. CONCLUSIONS: Based on GRADE criteria, we suggest that ASM or no ASM may be used in patients hospitalized with moderate-severe TBI (weak recommendation, low quality of evidence). If used, we suggest LEV over PHT/fPHT (weak recommendation, very low quality of evidence) for a short duration (≤ 7 days, weak recommendation, low quality of evidence).

"Intraosseous administration of tenecteplase for thrombolysis of an acute ischemic stroke".

INTRO: Current guidelines for acute ischemic stroke recommend timely administration of intravascular thrombolytic therapy to promote functional and neurologic outcomes. Tenecteplase is an emerging off-label therapy for this indication and being utilized by various institutions due to its simpler administration strategy. In emergent situations in which intravenous access cannot be obtained, intraosseous access is a viable option for medication administration. However, there has been minimal published cases to support the efficacy and safety of intraosseous administration of tenecteplase for acute ischemic stroke. CASE: We describe the case of a 51-year-old woman who developed acute ischemic stroke within our institution. Due to difficulty achieving intravenous access and time-dependent efficacy of thrombolytic therapy, the decision was made to administer tenecteplase by the intraosseous route. Stroke symptoms improved within 48 hours following administration without complication. CONCLUSION: Intraosseous administration of tenecteplase may be considered for treatment of acute ischemic stroke if intravenous access is unattainable.

Substandard and Falsified Medications: A Barrier to Global Health Equity Exemplified in Ecuador.

Medicines have been developed and have become globalized at a pace faster than traditional medical education can keep up. Physicians, pharmacists, nurses, and advanced practice providers learn the names and functions of these medications, but not how they are made and how they get to the bedside. The often economically driven intricacies behind these processes have a dramatic effect on patient care and outcomes. A staggering proportion of medications worldwide are reported to be substandard or falsified. This article explores one country's story of how medication gets to the bedside, describes how this process can go wrong, and outlines what providers can do to work toward the goal of equitable access to quality medications for all.

Hemodynamic Effects of Ketamine Compared With Propofol or Dexmedetomidine as Continuous ICU Sedation.

BACKGROUND: Ketamine has seen increased use for sedation in the intensive care unit. In contrast to propofol or dexmedetomidine, ketamine may provide a positive effect on hemodynamics. OBJECTIVE: The objective of this study was to compare the development of clinically significant hypotension or bradycardia (ie, negative hemodynamic event) between critically ill adults receiving sedation with ketamine and either propofol or dexmedetomidine. METHODS: This was a retrospective cohort study of adults admitted to an intensive care unit at an academic medical center between January 2016 and January 2021. RESULTS: Patients in the ketamine group (n = 78) had significantly less clinically significant hypotension or bradycardia compared with those receiving propofol or dexmedetomidine (n = 156) (34.6% vs 63.5%; P < 0.001). Patients receiving ketamine also experienced smaller degree of hypotension observed by percent decrease in mean arterial pressure (25.3% [17.4] vs 33.8% [14.5]; P < 0.001) and absolute reduction in systolic blood pressure (26.5 [23.8] vs 42.0 [37.8] mm Hg; P < 0.001) and bradycardia (15.5 [24.3] vs 32.0 [23.0] reduction in beats per minute; P < 0.001). In multivariate logistic regression modeling, receipt of propofol or dexmedetomidine was the only independent predictor of a negative hemodynamic event (odds ratio [OR]: 3.3, 95% confidence interval [CI], 1.7 to 6.1; P < 0.001). CONCLUSION AND RELEVANCE: Ketamine was associated with less clinically relevant hypotension or bradycardia when compared with propofol or dexmedetomidine, in addition to a smaller absolute decrease in hemodynamic parameters. The clinical significance of these findings requires further investigation.

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.

Current Practices of Intraventricular Antibiotic Therapy in the Treatment of Meningitis and Ventriculitis: Results from a Multicenter Retrospective Cohort Study.

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.

Characterization of Free Phenytoin Concentrations in End-Stage Renal Disease Using the Winter-Tozer Equation.

BACKGROUND: The Winter-Tozer (WT) equation has been shown to reliably predict free phenytoin levels in healthy patients. In patients with end-stage renal disease (ESRD), phenytoin-albumin binding is altered and, thus, affects interpretation of total serum levels. Although an ESRD WT equation was historically proposed for this population, there is a lack of data evaluating its accuracy. OBJECTIVE: The objective of this study was to determine the accuracy of the ESRD WT equation in predicting free serum phenytoin concentration in patients with ESRD on hemodialysis (HD). METHODS: A retrospective analysis of adult patients with ESRD on HD and concurrent free and total phenytoin concentrations was conducted. Each patient's true free phenytoin concentration was compared with a calculated value using the ESRD WT equation and a revised version of the ESRD WT equation. RESULTS: A total of 21 patients were included for analysis. The ESRD WT equation produced a percentage error of 75% and a root mean square error of 1.76 µg/mL. Additionally, 67% of the samples had an error >50% when using the ESRD WT equation. A revised equation was found to have high predictive accuracy, with only 5% of the samples demonstrating >50% error. CONCLUSION: The ESRD WT equation was not accurate in predicting free phenytoin concentration in patients with ESRD on HD. A revised ESRD WT equation was found to be significantly more accurate. Given the small study sample, further studies are required to fully evaluate the clinical utility of the revised ESRD WT equation.

Treatment of Hyponatremia in Patients with Acute Neurological Injury.

BACKGROUND: Little data exist regarding the practice of sodium management in acute neurologically injured patients. This study describes the practice variations, thresholds for treatment, and effectiveness of treatment in this population. METHODS: This retrospective, multicenter, observational study identified 400 ICU patients, from 17 centers, admitted for ≥48 h with subarachnoid hemorrhage (SAH), traumatic brain injury (TBI), intraparenchymal hemorrhage, or intracranial tumors between January 1, 2011 and July 31, 2012. Data collection included demographics, APACHE II, Glascow Coma Score (GCS), serum sodium (Na+), fluid rate and tonicity, use of sodium-altering therapies, intensive care unit (ICU) and hospital length of stay, and modified Rankin score upon discharge. Data were collected for the first 21 days of ICU admission or ICU discharge, whichever came first. Sodium trigger for treatment defined as the Na+ value prior to treatment with response defined as an increase of ≥4 mEq/L at 24 h. RESULTS: Sodium-altering therapy was initiated in 34 % (137/400) of patients with 23 % (32/137) having Na+ >135 mEq/L at time of treatment initiation. The most common indications for treatment were declining serum Na+ (68/116, 59 %) and cerebral edema with mental status changes (21/116, 18 %). Median Na+ treatment trigger was 133 mEq/L (IQR 129-139) with no difference between diagnoses. Incidence and treatment of hyponatremia was more common in SAH and TBI [SAH (49/106, 46 %), TBI (39/97, 40 %), ICH (27/102, 26 %), tumor (22/95, 23 %); p = 0.001]. The most common initial treatment was hypertonic saline (85/137, 62 %), followed by oral sodium chloride tablets (42/137, 31 %) and fluid restriction (15/137, 11 %). Among treated patients, 60 % had a response at 24 h. Treated patients had lower admission GCS (12 vs. 14, p = 0.02) and higher APACHE II scores (12 vs. 10, p = 0.001). There was no statistically significant difference in outcome when comparing treated and untreated patients. CONCLUSION: Sodium-altering therapy is commonly employed among neurologically injured patients. Hypertonic saline infusions were used first line in more than half of treated patients with the majority having a positive response at 24 h. Further studies are needed to evaluate the impact of various treatments on patient outcomes.

Safety of Immediate-Release Nifedipine.

Nifedipine immediate release (IR) is a short-acting dihydropyridine calcium channel blocker historically used for hypertensive crisis, but its use has decreased because of reports of adverse reactions such as myocardial infarction (MI), arrhythmias, and stroke. This was a retrospective evaluation of the safety of nifedipine IR in 122 patients at an academic medical center from January 1, 2009, to December 31, 2014. Patients were separated into high- and low-risk groups. High risk was defined as a medical history significant for arrhythmia, MI, or stroke. The primary outcome was a comparison of the composite incidence of nifedipine-associated adverse events including the following: new cardiology consultation, sentinel arrhythmia, stroke, MI, need for blood pressure support, transition to higher levels of care, or death. A per-dose incidence of 2.4% and per-patient incidence of 7.3% in this composite endpoint were found, with no differences between the groups. Patients received median doses of 10 mg and follow-up within 2.8 hours. There were no cases of death in either group. Although nifedipine IR may cause major adverse events, the incidence seems lower than previously believed. Future research is warranted to evaluate whether nifedipine IR may be an option to treat elevated blood pressure in hospitalized patients.

Characterization of unbound phenytoin concentrations in neurointensive care unit patients using a revised Winter-Tozer equation.

BACKGROUND: Prior studies examining the accuracy of the Winter-Tozer (WT) equation for correcting total phenytoin concentrations in critically ill patients have yielded conflicting results and are limited by small sample sizes and stringent exclusion criteria, which lessen external validity. OBJECTIVE: To determine whether the traditional WT equation is appropriate in correcting total phenytoin concentrations in a large sample of patients in a neurointensive care unit (NICU) and whether a new equation may be more predictive. METHODS: In a retrospective study, NICU patients with reports of a concurrent total and unbound phenytoin concentration and albumin level were analyzed. Two new predictive equations were generated using a revised WT equation and regression model of baseline and laboratory characteristics. Prediction error analysis using a 20% validation cohort was conducted on all 3 equations for comparison. RESULTS: A total of 140 adults were included for data analysis, with data on 80% used for derivation and 20% as validation of all equations. The mean unbound phenytoin concentration was 1.4 µg/mL, which represented a free fraction of 10%. Most samples were collected within 24 hours of NICU admission. Multivariate regression analysis demonstrated that albumin, total phenytoin concentration, sex, and creatinine clearance were predictive of measured unbound phenytoin concentrations. The traditional WT equation significantly underpredicted true unbound phenytoin concentrations, with 32.1% of patients having a prediction error of more than 50% in the validation cohort. CONCLUSIONS: The traditional WT equation was significantly biased in underpredicting true unbound phenytoin concentrations in neurointensive care unit patients and should not be used in this setting. Two modified equations were more accurate and precise and should be considered for use when unbound phenytoin concentrations are not readily available in an NICU population.

Neuropharmacology in the Intensive Care Unit.

Clinicians must individualize pharmacotherapy for patients with acute neurological injury based on multiple factors, including age, comorbidities, and chronic medication use. Many pharmacokinetic and pharmacodynamic properties are altered during acute illness, particularly absorption, distribution, metabolism, and elimination, which may result in loss of drug effect or toxicity. This article provides clinicians with general pharmacologic knowledge of the following drug regimens commonly prescribed to neurocritically ill adults: sedatives, analgesics, osmotherapy, antiseizure medications, antishivering agents, vasoactive agents, and antithrombotic reversal agents.

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.

Treatment outcomes of heparin-induced thrombocytopenia in subarachnoid hemorrhage patients: a 4-year, retrospective single-center review.

INTRODUCTION: The treatment and outcomes of heparin-induced thrombocytopenia (HIT) are not well described in neurosurgery patients. This study reviewed the treatment for HIT in subarachnoid hemorrhage (SAH) patients, and compared outcomes in patients with isolated HIT (iHIT) and HIT with thrombotic syndrome (HITTS). METHODS: Adult patients with SAH discharged from the University of Illinois Hospital & Health Sciences System from 2006 to 2009 were included if they had at least one positive HIT antibody test. Patients were categorized with either iHIT or HITTS based on documented evidence of thrombosis. The primary outcome was the incidence of new thromboses prior to discharge. Secondary outcomes included the incidence of major bleeding, new thromboses up to 3 months after discharge, or hospice/death. Patients having any secondary outcome were defined as having a "poor treatment-related effect". RESULTS: A total of 176 patients were screened and 30 patients met inclusion criteria. Eighteen patients (60 %) were categorized with iHIT and 12 (40 %) with HITTS. Twelve patients (67 %) with iHIT received prophylaxis with fondaparinux and nine patients (75 %) with HITTS were treated with argatroban. There were no differences in the primary (11 vs. 25 %, p = 0.364) or secondary outcomes in the iHIT group versus the HITTS group. Patients with iHIT had a 5.5 % incidence of "poor treatment-related effects" compared to a 33.3 % incidence in patients with HITTS (p = 0.024). CONCLUSIONS: SAH patients with iHIT and HITTS did not differ in the incidence of new thromboses, incidence of hemorrhage, or hospice/death. Patients with iHIT had fewer "poor treatment-related effects" than HITTS patients.

Practice variations in the management of status epilepticus.

BACKGROUND: Numerous anticonvulsant agents are now available for treating status epilepticus (SE). However, a paucity of data is available to guide clinicians in the initial treatment of seizures or SE. This study describes the current strategies being employed to treat SE in the U.S.A. METHODS: Fifteen American academic medical centers completed a retrospective, multicenter, observational study by reviewing 10-20 of the most recent cases of SE at their institution prior to December 31, 2009. A multivariate analysis was performed to determine factors associated with cessation of seizures. RESULTS: A total of 150 patients were included. Most patients with SE had a seizure disorder (58%). SE patients required a median of 3 AEDs for treatment. Three quarters of patients received a benzodiazepine as first-line therapy (74.7%). Phenytoin (33.3%) and levetiracetam (10%) were commonly used as the second AED. Continuous infusions of propofol, barbiturate, or benzodiazepine were used in 36% of patients. Median time to resolution of SE was 1 day and was positively associated with presence of a complex partial seizure, AED non-compliance prior to admission, and lorazepam plus another AED as initial therapy. Prolonged ICU length of stay and topiramate therapy prior to admission were negatively associated with SE resolution. Mortality was higher in patients without a history of seizure (22.2 vs. 6.9%, p = 0.006). CONCLUSIONS: The use of a benzodiazepine followed by an AED, such as phenytoin or levetiracetam, is common as first and second-line therapy for SE and appears to be associated with a shorter time to SE resolution. AED selection thereafter is highly variable. Patients without a history of seizure who develop SE had a higher mortality rate.

Use of Newer Anticonvulsants for the Treatment of Status Epilepticus.

Status epilepticus (SE) has a high mortality rate and is one of the most common neurologic emergencies. Fast progression of this neurologic emergency and lack of response to traditional antiepileptic drugs (AEDs) in most cases has challenged clinicians to use new agents. This article evaluates the efficacy and safety of AEDs released to the market after 2000 for SE, refractory status epilepticus (RSE), and super-refractory status epilepticus (SRSE). The PubMed database was searched for clinical trials published between January 2000 and July 2018 using the search terms status epilepticus, refractory status epilepticus, super refractory status epilepticus, brivaracetam, clobazam, cannabidiol, eslicarbazepine, lacosamide, perampanel, rufinamide, stiripentol, and zonisamide. Trials that evaluated these agents in adults with SE, RSE, and SRSE were included. Brivaracetam use was identified in two retrospective reviews with success rates of 27% and 57%. One unsuccessful case report of cannabidiol use in SE was found. Four clobazam studies were identified in SE and RSE with success rates ranging from 25-100%. No evidence for the use of eslicarbazepine and zonisamide was found. Using the search terms for lacosamide identified 38 articles: 1 systematic review, 5 prospective studies, 15 retrospective reviews, and 17 case reports. Success rates and dosing varied, but studies that included focal or partial types of SE showed higher success rates. Five articles were identified regarding perampanel use in this setting. Three were retrospective reviews with success rates ranging from 17-60%, and two were case reports. Only one case report regarding the use of rufinamide was found; rufinamide titrated up to 4.4 mg/day allowed discontinuation of barbiturate and clobazam. One case report and two case series of stiripentol were found with reported efficacy between 60% and 100% in SRSE. Evidence is currently insufficient to support the use of these agents in this setting.

Periprocedural Neuroendovascular Antiplatelet Strategies for Thrombosis Prevention in Clopidogrel-Hyporesponsive Patients.

Patients undergoing neuroendovascular procedures such as cerebral aneurysm coiling and intracranial stent deployment are frequently treated with antiplatelet agents to prevent thrombotic complications. The combination of aspirin and a P2Y12 inhibitor such as clopidogrel is often initiated days before elective procedures or as loading doses for emergent procedures; however, some patients may still experience thrombotic complications. Patients identified as clopidogrel hyporesponders are more likely to experience poor outcomes and may require changes to their regimens. Historically, high-dose clopidogrel regimens were used in response to subtherapeutic results of platelet function assays and point-of-care testing despite limited supporting data. Recently, more data have emerged using alternative P2Y12 inhibitors such as prasugrel and ticagrelor. Dosing for neuroendovascular conditions is often extrapolated from the cardiac literature, although outcomes in cardiac patients may not be relevant to neurologic patients, making prophylactic treatment recommendations challenging for these patients. This review summarizes the literature for antiplatelet prophylaxis in patients undergoing neuroendovascular device placement, focusing on alternative regimens for clopidogrel hyporesponders.