Third-line antiepileptic therapy and outcome in status epilepticus: the impact of vasopressor use and prolonged mechanical ventilation.

OBJECTIVES: To characterize associations between antiepileptic drugs with sedating or anesthetic effects (third-line antiepileptic drugs) vs. other antiepileptic agents, and short-term outcomes, in status epilepticus. Furthermore, to evaluate the role of adverse hemodynamic and respiratory effects of these agents in status epilepticus treatment. DESIGN: Retrospective comparative analysis. SETTING: Tertiary academic medical center with two emergency departments and two neurologic intensive care units. PATIENTS: Adults admitted with a diagnosis of status epilepticus defined as seizures lasting continuously >5 mins, or for discrete periods in succession. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 126 patients with 144 separate status epilepticus admissions, 57 were female (45%) with mean age 54.7 ± 15.7 yrs. Status epilepticus was convulsive in 132 cases (92%). Status epilepticus etiologies included subtherapeutic antiepileptic drugs (43%), alcohol or other nonantiepileptic drug (13%), and acute central nervous system disease (12%). Third-line antiepileptic drugs were administered in 47 cases (33%). Seventy-eight status epilepticus episodes (54%) had good outcomes (Glasgow Outcome Score = 1, 2) at the time of hospital discharge. On univariate analysis, poor outcome (Glasgow Outcome Score > 2) was associated with older age (mean 59.8 ± 15.5 vs. 50.5 ± 13.8 yrs, p < .001), acute central nervous system disease (21% vs. 4%, p = .001), mechanical ventilation (76% vs. 53%, p = .004), longer duration of ventilation (median 10 days [range 1-56] vs. 2 days [range 1-10], p < .001), treatment with vasopressors (35% vs. 5%, p < .001), and treatment with third-line antiepileptic drugs (51% vs. 17%, p < .001). Death was associated with acute central nervous system disease, prolonged ventilation, treatment with vasopressors, and treatment with third-line antiepileptic drugs. Predictors of poor outcome among all status epilepticus episodes were older age (odds ratio 1.06; 95% confidence interval 1.03-1.09; p < .001), treatment with third-line antiepileptic therapy (odds ratio 5.64; 95% confidence interval 2.31-13.75; p < .001), and first episode of status epilepticus (odds ratio 3.73; 95% confidence interval 1.38-10.10; p = .010). Among status epilepticus episodes treated by third-line antiepileptic drugs, predictors of poor outcome were older age (odds ratio, 1.09; 95% confidence interval 1.01-1.18; p = .038) and longer ventilation (odds ratio, 1.47; 95% confidence interval 1.08-2.00; p = .015). Predictors of mortality among all status epilepticus episodes were treatment with third-line antiepileptic drugs (odds ratio, 12.08; 95% confidence interval 2.30-63.39; p = .003) and older age (odds ratio, 1.06; 95% confidence interval 1.00-1.12; p = .045). CONCLUSIONS: Third-line antiepileptic drug therapies with sedating or anesthetic effects predicted poor outcome and death in status epilepticus. Hypotension requiring vasopressor therapy and duration of mechanical ventilation induced by these agents may be contributing factors, especially when pentobarbital is used. These findings may inform decision making on drug therapy in status epilepticus and help develop safer and more effective treatment strategies to improve outcome.

Validity and reliability of The Johns Hopkins Adapted Cognitive Exam for critically ill patients.

OBJECTIVE: To validate The Johns Hopkins Adapted Cognitive Exam designed to assess and quantify cognition in critically ill patients. DESIGN: Prospective cohort study. SETTING: Neurosciences, surgical, and medical intensive care units at The Johns Hopkins Hospital. PATIENTS: One hundred six adult critically ill patients. INTERVENTIONS: One expert neurologic assessment and four measurements of the Adapted Cognitive Exam (all patients). Four measurements of the Folstein Mini-Mental State Examination in nonintubated patients only. Adapted Cognitive Exam and Mini-Mental State Examination were performed by 76 different raters. MEASUREMENTS AND MAIN RESULTS: One hundred six patients were assessed, 46 intubated and 60 nonintubated, resulting in 424 Adapted Cognitive Exam and 240 Mini-Mental State Examination measurements. Criterion validity was assessed by comparing Adapted Cognitive Exam with a neurointensivist's assessment of cognitive status (ρ = 0.83, p < .001). Ordinal logistic regression established optimal predicted cut points for cognitive status classification (≤ 28 = severely impaired, 29-55 = moderately impaired, ≥ 56 = mildly impaired or normal). Using these cut points, the Adapted Cognitive Exam appropriately classified cognitive status 90% of the time. Construct validity was assessed by comparing Adapted Cognitive Exam with Mini-Mental State Examination in nonintubated patients (ρ = 0.81, p < .001). Face validity was assessed by surveying raters who used both the Adapted Cognitive Exam and Mini-Mental State Examination and indicated the Adapted Cognitive Exam was an accurate reflection of the patient's cognitive status, more sensitive a marker of cognition than the Mini-Mental State Examination, and easy to use. The Adapted Cognitive Exam demonstrated excellent interrater reliability (intraclass correlation coefficient = 0.997; 95% confidence interval 0.997-0.998) and interitem reliability of each of the five subscales of the Adapted Cognitive Exam and Mini-Mental State Examination (Cronbach's α: range for Adapted Cognitive Exam = 0.83-0.88; range for Mini-Mental State Examination = 0.72-0.81). CONCLUSION: The Adapted Cognitive Exam is the first valid and reliable examination for the assessment and quantification of cognition in critically ill patients. It provides a useful, objective tool that can be used by any member of the interdisciplinary critical care team to support clinical assessment and research efforts.

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.

The use of lacosamide in refractory status epilepticus.

BACKGROUND: Case reports suggest lacosamide may have a role in status epilepticus (SE). The purpose of this case series is to describe the use of lacosamide in refractory SE (RSE) at our institution. METHODS: Observational study of all patients admitted to the neurosciences intensive care unit with RSE who received at least one dose of lacosamide from October 2009 to September 2010. RESULTS: Nine patients received lacosamide after failure of at least two other agents. Lacosamide was started a median of 2 days (range: 0-14 days) after the onset of SE. The most frequently used dosing regimen was an initial intravenous dose of 200 mg followed by 200 mg every 12 h. Most patients had received 3 (range: 2-5) AEDs prior to lacosamide. Levetiracetam was used prior to lacosamide in all cases. No patients evaluated responded to lacosamide according to our predefined criteria. One patient developed angioedema after receiving two doses; another patient developed angioedema where timing in relation to the lacosamide was unclear. Care was withdrawn in three of the nine patients for reasons unrelated to lacosamide. Lacosamide was continued at discharge on all surviving patients except in one case of angioedema. CONCLUSIONS: This is the largest case series to date describing the use of lacosamide in patients with RSE. Despite the novel mechanism of action, we observed no evidence that lacosamide is effective in RSE; however, our sample size was small. Further study is needed to determine the role of lacosamide in SE, especially early in the treatment course.

Seizure prophylaxis in neurocritical care: a review of evidence-based support.

Seizures are a well-described complication of acute brain injury and neurosurgery. Antiepileptic drugs (AEDs) are frequently utilized for seizure prophylaxis in neurocritical care patients. In this review, the Neurocritical Care Society Pharmacy Section describes the evidence associated with the use of AEDs for seizure prophylaxis in patients with intracerebral tumors, traumatic brain injury, aneurysmal subarachnoid hemorrhage, craniotomy, ischemic stroke, and intracerebral hemorrhage. Clear evidence indicates that the short-term use of AEDs for seizure prophylaxis in patients with traumatic brain injury and aneurysmal subarachnoid hemorrhage may be beneficial; however, evidence to support the use of AEDs in other disease states is less clear.

Changing trends in the use of seizure prophylaxis after traumatic brain injury: a shift from phenytoin to levetiracetam.

PURPOSE: Current guidelines for traumatic brain injury (TBI) recommend antiepileptic drugs (AEDs) for 7 days after injury to decrease posttraumatic seizure risk. Phenytoin decreases seizure risk 73% vs placebo during this time. Levetiracetam (LEV) is an alternative; however, no published data validate comparable efficacy. Our objective was to evaluate seizure incidence 7 days after TBI in patients treated with phenytoin (PHT) vs LEV and to characterize practice of AED selection. METHODS: A retrospective observational study was conducted using a Trauma Registry (Collector Trauma Registry; Digital Innovation, Inc, Forrest Hill, Md) to evaluate patients with TBI. Patients with an initial Head/Neck Abbreviated Injury Scale score of 3 or higher and a Glasgow Coma Scale of 8 or less were included. RESULTS: Of 109 patients, 89 received PHT, and 20, LEV. Two patients experienced posttraumatic seizure, 1 in each group. Sixty-eight patients survived to hospital discharge; 65% received prophylactic AED greater than 7 days. Ninety-eight percent of 81 patients admitted between 2000 and 2007 received PHT, whereas 64% of 28 patients admitted between 2008 and 2010 received LEV. CONCLUSION: Only 2 patients experienced posttraumatic seizure after receiving AED, indicating low incidence. Most surviving to hospital discharge received AED prophylaxis greater than 7 days despite guideline recommendations. After approval of intravenous LEV, a trend favoring LEV was observed.

Dexmedetomidine preserves attention/calculation when used for cooperative and short-term intensive care unit sedation.

PURPOSE: Differential effects on cognition were recently demonstrated between dexmedetomidine (DEX) and propofol (PRO) when used for cooperative sedation. Propofol was found to reduce cognition, whereas DEX improved cognition. To further discriminate these effects, we evaluated the effect of PRO vs DEX in selected areas of cognition. METHODS: This is a post hoc analysis of the Acute Neurologic Intensive Care Unit Sedation Trial and an investigator-initiated, prospective, randomized, double-blinded, crossover study, comparing the effect of PRO and DEX on cognition measure by the Johns Hopkins Adapted Cognitive Exam (ACE). A linear model analysis accounting for within-patient correlation of measures was used to estimate differences in ACE subscales between drugs. RESULTS: Propofol diminished adjusted scores on all ACE subscales (P < .05), whereas DEX improved adjusted scores selectively for attention/calculation (3.55; 95% confidence interval, 1.49-5.61; P < .01). The positive and significant difference in ACE scores between agents was present across subscales. CONCLUSIONS: Our findings indicate that DEX improved ACE attention/calculation subscale in awake patients receiving cooperative sedation. This is in contrast to the deterioration in all mean ACE subscale scores observed using PRO, suggesting DEX preserved cognitive function with specific preservation of focus and attention and allows for greater cognition compared with PRO across all cognitive domains.