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.

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.

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.

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.

Pharmacist impact on posttraumatic seizure prophylaxis in patients with head injury.

Phenytoin is the most commonly administered antiepileptic agent for the prevention of early (< or = 7 days) posttraumatic seizures. Use of the agent, however, requires strict monitoring due to its narrow target range and nonlinear pharmacokinetics. The impact of a clinical pharmacist participating in the care of patients with head injury on posttraumatic seizure prophylaxis with regard to phenytoin dosing and monitoring, cost avoidance, and patient outcome, was measured retrospectively. Parameters from time periods before (BP) and after (AP) a clinical pharmacist participated in patient care were compared. The average number of days that phenytoin was given was 13.4 (BP) and 7.6 (AP), and the duration of phenytoin prophylaxis was 7 days or less in 35% and 65% of patients, respectively. The average number of phenytoin levels drawn from each patient was 10.3 (BP) and 3.4 (AP). Seizures occurred in 4.7% (BP) and 1.5% (AP) of patients. A cost savings of approximately $28,000 was observed for the AP group. A clinical pharmacist reduced the use of posttraumatic seizure prophylaxis and associated costs without jeopardizing patient outcomes.

Balance of academic responsibilities of clinical track pharmacy faculty in the United States: a survey of select American College of Clinical Pharmacy Practice and Research Network Members.

STUDY OBJECTIVES: To characterize the balance of clinical and academic responsibilities of clinical track pharmacy faculty in the United States and evaluate organizational structures that promote satisfactory balance between these responsibilities. DESIGN: Prospective cross-sectional survey. SETTING: A 22-item online survey was developed and distributed via Qualtrics software. PARTICIPANTS: Clinical faculty members of the American College of Clinical Pharmacy Adult Medicine, Ambulatory Care, Cardiology, Critical Care, Gastrointestinal/Liver/Nutrition, Immunology/Transplantation, Infectious Disease, and Pediatrics Practice and Research Networks (PRNs) were invited to participate via the PRN electronic mailing list. MEASUREMENTS AND MAIN RESULTS: The survey comprised questions related to demographics, organizational structure, and balance of clinical and academic responsibilities. A total of 344 participants responded to some or all of the survey questions. The demographics were relatively equally balanced between faculty at state and private academic institutions, academic rank, and practice setting. Expected and actual effort allocations were similar for each of the clinical and academic responsibilities, with direct patient care and clinical teaching representing more than 50% effort allocation cumulatively. Clinical faculty at state institutions devoted a larger proportion of time to clinical service, whereas clinical faculty at private institutions devoted a greater proportion of time to didactic teaching. When asked about time constraints, 157 (69.8%) of the 225 survey participants responding to this question did not believe they had sufficient time to fulfill their nonclinical academic needs. Clinical faculty who were provided "protected time" away from clinical service had a significantly more favorable opinion of this question. CONCLUSION: Most of the clinical track pharmacy faculty indicated that they have insufficient time to fulfill their nonclinical academic responsibilities. Provision of protected time may alleviate some of these time constraints.

Pharmacological management of seizures and status epilepticus in critically ill patients.

Seizures are serious complications seen in critically ill patients and can lead to significant morbidity and mortality if the cause is not identified and treated quickly. Uncontrolled seizures can lead to status epilepticus (SE), which is considered a medical emergency. The first-line treatment of seizures is an intravenous (IV) benzodiazepine followed by anticonvulsant therapy. Refractory SE can evolve into a nonconvulsive state requiring IV anesthetics or induction of pharmacological coma. To prevent seizures and further complications in critically ill patients with acute neurological disease or injury, short-term seizure prophylaxis should be considered in certain patients.

Outcomes associated with transdermal nicotine replacement therapy in a neurosurgery intensive care unit.

PURPOSE: The outcomes associated with transdermal nicotine replacement therapy (NRT) in a neurosurgery intensive care unit (ICU) were studied. METHODS: Data from pharmacy records, neurosurgery ICU admission logs, and computerized patient charts at the University of Illinois Medical Center at Chicago from January 2001 through August 2008 were reviewed for patients older than 18 years who were admitted to the neurosurgery ICU for neurologic insults. Patients were categorized into three groups: smokers who received transdermal NRT (n = 114), smokers who did not receive transdermal NRT (n = 113), and nonsmokers (n = 113). The primary outcome of this study was unfavorable disposition at discharge from the hospital. Secondary outcomes measured included overall mortality; lengths of hospital and neurosurgery ICU stays; and rates of subarachnoid hemorrhage (SAH) rebleeding, angiographic vasospasm, intracerebral hemorrhage rebleeding, and ischemic stroke. RESULTS: Overall, there was no difference in unfavorable discharge disposition among the three groups (p = 0.17). However, the group who received NRT had higher admission rates of SAH, smoked more cigarettes for a longer period of time, and had longer stays in the neurosurgery ICU and hospital compared with the other groups. All patients who received NRT had prolonged hospital (p = 0.014) and neurosurgery ICU (p = 0.006) stays compared with those who did not receive NRT. There were no differences in other secondary outcomes among the groups. CONCLUSION: There was no significant difference in unfavorable discharge disposition among neurosurgery ICU patients who were smokers treated with NRT, smokers not treated with NRT, and nonsmokers not treated with NRT.

The treatment of cancer pain.

Pain is probably one of the most common cancer symptoms. In addition to being a major source of suffering and disability, cancer pain is extremely frightening for patients and their families. This review discusses the current options for treating cancer pain, focusing on the pharmacological agents currently available and briefly exploring some of the surgical options for pain management. The authors propose to adjust the World Health Organization (WHO) pain management ladder from its current three-step approach to a more sophisticated five-step algorithm that includes physical and psychological modalities along the entire continuum of care and adds two more steps related to neuromodulative and neurodestructive procedures once the opioids fail.

The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients.

Sedative medications are widely used in intensive care unit (ICU) patients. Structured assessment of sedation and agitation is useful to titrate sedative medications and to evaluate agitated behavior, yet existing sedation scales have limitations. We measured inter-rater reliability and validity of a new 10-level (+4 "combative" to -5 "unarousable") scale, the Richmond Agitation-Sedation Scale (RASS), in two phases. In phase 1, we demonstrated excellent (r = 0.956, lower 90% confidence limit = 0.948; kappa = 0.73, 95% confidence interval = 0.71, 0.75) inter-rater reliability among five investigators (two physicians, two nurses, and one pharmacist) in adult ICU patient encounters (n = 192). Robust inter-rater reliability (r = 0.922-0.983) (kappa = 0.64-0.82) was demonstrated for patients from medical, surgical, cardiac surgery, coronary, and neuroscience ICUs, patients with and without mechanical ventilation, and patients with and without sedative medications. In validity testing, RASS correlated highly (r = 0.93) with a visual analog scale anchored by "combative" and "unresponsive," including all patient subgroups (r = 0.84-0.98). In the second phase, after implementation of RASS in our medical ICU, inter-rater reliability between a nurse educator and 27 RASS-trained bedside nurses in 101 patient encounters was high (r = 0.964, lower 90% confidence limit = 0.950; kappa = 0.80, 95% confidence interval = 0.69, 0.90) and very good for all subgroups (r = 0.773-0.970, kappa = 0.66-0.89). Correlations between RASS and the Ramsay sedation scale (r = -0.78) and the Sedation Agitation Scale (r = 0.78) confirmed validity. Our nurses described RASS as logical, easy to administer, and readily recalled. RASS has high reliability and validity in medical and surgical, ventilated and nonventilated, and sedated and nonsedated adult ICU patients.