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Levetiracetam versus phenytoin for seizure prophylaxis in severe traumatic brain injury

OBJECT Current standard of care for patients with severe traumatic brain injury (TBI) is prophylactic treatment with phenytoin for 7 days to decrease the risk of early posttraumatic seizures. Phenytoin alters drug metabolism, induces fever, and requires therapeutic-level monitoring. Alternatively, levetiracetam (Keppra) does not require serum monitoring or have significant pharmacokinetic interactions. In the current study, the authors compare the EEG findings in patients receiving phenytoin with those receiving levetiracetam monotherapy for seizure prophylaxis following severe TBI. METHODS Data were prospectively collected in 32 cases in which patients received levetiracetam for the first 7 days after severe TBI and compared with data from a historical cohort of 41 cases in which patients received phenytoin monotherapy. Patients underwent 1-hour electroencephalographic (EEG) monitoring if they displayed persistent coma, decreased mental status, or clinical signs of seizures. The EEG results were grouped into normal and abnormal findings, with abnormal EEG findings further categorized as seizure activity or seizure tendency. RESULTS Fifteen of 32 patients in the levetiracetam group warranted EEG monitoring. In 7 of these 15 cases the results were normal and in 8 abnormal; 1 patient had seizure activity, whereas 7 had seizure tendency. Twelve of 41 patients in the phenytoin group received EEG monitoring, with all results being normal. Patients treated with levetiracetam and phenytoin had equivalent incidence of seizure activity (p = 0.556). Patients receiving levetiracetam had a higher incidence of abnormal EEG findings (p = 0.003). CONCLUSIONS Levetiracetam is as effective as phenytoin in preventing early posttraumatic seizures but is associated with an increased seizure tendency on EEG analysis.

Validation of the Effectiveness of a Vancomycin Nomogram in Achieving Target Trough Concentrations of 15–20 mg/L Suggested by the Vancomycin Consensus Guidelines

Study Objective. To assess and validate the effectiveness of a newly constructed vancomycin dosing nomogram in achieving target trough serum concentrations of 15–20 mg/L.

Grading the Severity of Drug-Drug Interactions in the Intensive Care Unit: A Comparison Between Clinician Assessment and Proprietary Database Severity Rankings

Background: Computerized provider order entry with decision support software offers an opportunity to identify and prevent medication-related errors, including drug-drug interactions (DDIs), through alerting mechanisms. However, the number of alerts generated can overwhelm and lead to “alert fatigue.” A DDI alert system based on severity rankings has been shown to reduce alert fatigue; however, the best method to populate this type of database is unclear. Objective: To compare the severity ranking of proprietary databases to clinician assessment for DDIs occurring in critically ill patients. Methods: This observational, prospective study was conducted over 8 weeks in the cardiac and cardiothoracic intensive care unit. Medication profiles of patients were screened for the presence of DDIs and a severity evaluation was conducted using rankings of proprietary databases and clinician opinion using a DDI severity assessment tool. The primary outcome measure was the number of DDIs considered severe by both evaluation methods. Results: A total of 1150 DDIs were identified after 400 patient medication profiles were evaluated. Of these, 458 were unique drug pairs. Overall, 7.4% (34/458) were considered a severe interaction based upon proprietary database ratings. The assessment by clinicians ranked 6.6% (30/458) of the unique DDIs as severe. Only 3 interactions, atazanavir–simvastatin, atazanavir–tenofovir, and aspirin–warfarin, were considered severe by both evaluation methods. Conclusions: Since proprietary databases and clinician assessment of severe DDIs do not agree, developing a knowledge base for a DDI alert system likely requires proprietary database information in conjunction with clinical opinion.

Neuroleptic malignant syndrome in traumatic brain injury patients treated with haloperidol.

BACKGROUND Haloperidol, which is commonly used to treat agitation in critically ill patients, has been associated with the development of neuroleptic malignant syndrome (NMS). The purpose of this manuscript was to review the literature describing NMS and haloperidol use in patients sustaining a traumatic brain injury (TBI) since these patients may be at greater risk for NMS. METHODS A computerized search of MEDLINE was conducted (1966-May 2008) to identify all publications in which haloperidol was related to NMS in patients with a TBI. The references of these manuscripts were reviewed for additional literature. RESULTS Nine case reports describe the development of NMS in patients with TBI treated with haloperidol for agitation. Cumulative haloperidol doses before the onset of NMS ranged from 10 mg to at least 210 mg. Most of these patients received high dose (> or =30 mg) haloperidol. Four patients received haloperidol parenterally. On diagnosis, of NMS, haloperidol was discontinued in five cases, and all were given supportive care and pharmacologic treatment. Patients were discharged with improved, but diminished functional capacity. CONCLUSION Development of NMS in TBI patients treated with haloperidol should be a concern for clinicians since these patients may be at greater risk for this adverse event; especially if the patient is receiving haloperidol at high doses parenterally. Future studies are needed to evaluate the incidence and increased risk of adverse events in patients sustaining a TBI and receiving haloperidol especially since haloperidol is being used more frequently in the critically ill patients.

Trough concentration of voriconazole and its relationship with efficacy and safety: a systematic review and meta-analysis

This meta-analysis showed trough concentrations of 0.5 mg/L to be the lower limit of voriconazole during treatment, whereas trough concentrations of 3.0 mg/L were associated with an increased risk of moderate to severe hepatotoxicity, particularly for the Asian population.

Immunosuppressive Aspects of Analgesics and Sedatives Used in Mechanically Ventilated Patients: An Underappreciated Risk Factor for the Development of Ventilator-Associated Pneumonia in Critically Ill Patients

Objective: To evaluate the evidence describing the immunosuppressive and pharmacokinetic properties of commonly used analgesic and sedation agents in critically ill patients. Data Sources: MEDLINE (January 1980-September 2013) was searched. Study Selection and Data Extraction: All in vitro and in vivo studies that evaluated the immune-modulating properties of analgesic and sedation agents commonly used in the critically ill were included. Full-text and abstract-only articles (noted) were included in this review. Inclusion criteria were met by 46 studies and were evaluated. Data Synthesis: Analgesic and sedation agents have been shown to be immunosuppressive in a variety of models. In vitro models use a variety of immune cells to demonstrate the immunosuppressive properties of opioids, benzodiazepines, and to a lesser extent, propofol. In each case, animal studies provide more robust data supporting the concept that opioids, benzodiazepines, and propofol exhibit immunosuppressive activities ranging from innate to adaptive immune alterations. Human studies, though more limited, provide further support that these agents inhibit the immune response. In contrast, data have shown that dexmedetomidine may attenuate the immune system. Clinical trial data evaluating the immunosuppressive properties of these agents is limited. Conclusions: Analgesic and sedation agents have clearly been shown to alter cellular function and other mediators of the immune system; yet the clinical impact remains to be fully elucidated. The mechanism by which sedation interruption reduces ventilator-associated pneumonia may in fact be a reduction in immunosuppressive effects. Studies linking the immune-modulating effects of analgesic and sedation agents in critically ill patients are needed.

Adverse Events Lead to Drug Discontinuation More Commonly among Patients Who Receive Nafcillin than among Those Who Receive Oxacillin

ABSTRACT Nafcillin and oxacillin are used interchangeably in clinical practice, yet few studies have evaluated the safety of these two agents. Our objective was to compare the differential tolerabilities of nafcillin and oxacillin among hospitalized patients. We conducted a retrospective cohort study of all patients who received 12 g/day of nafcillin or oxacillin for at least 24 h. Two hundred twenty-four patients were included. Baseline characteristics and comorbidities were similar among patients receiving nafcillin (n = 160) and those receiving oxacillin (n = 64). Hypokalemia, defined as a potassium level of ≤3.3 mmol/liter or ≤2.9 mmol/liter or as a ≥0.5-mmol/liter decrease from the baseline level, occurred more frequently among patients who received nafcillin (51%, 20%, and 56%, respectively) than among those who received oxacillin (17%, 3%, and 34%, respectively; P < 0.0001, P = 0.0008, and P = 0.005, respectively). By multivariate logistic regression analysis, receipt of nafcillin was an independent predictor of severe hypokalemia (odds ratio [OR] = 6.74; 95% confidence interval [CI], 1.46 to 31.2; P = 0.02). Rates of hepatotoxicity did not differ between groups; however, acute kidney injury occurred more commonly with nafcillin than with oxacillin (18% versus 6%; P = 0.03). Overall, 18% of patients who received nafcillin discontinued therapy prematurely due to adverse events, compared to 2% of patients who received oxacillin (P = 0.0004). Nafcillin treatment is associated with higher rates of adverse events and treatment discontinuation than oxacillin among hospitalized adult patients. These findings have important implications for patients in both inpatient and outpatient settings, particularly patients who require long-term therapy and cannot be monitored routinely. Future randomized controlled studies evaluating the efficacy, costs, and tolerability of nafcillin versus oxacillin are warranted.

Effects of Isavuconazole on the Plasma Concentrations of Tacrolimus among Solid Organ Transplant Patients

ABSTRACT We evaluated the interaction between isavuconazole and tacrolimus among 55 organ transplant recipients. After isavuconazole discontinuation, the tacrolimus concentration/dose ratio normalized by weight (C/D) was reduced by 16%. Liver transplant recipients experienced the largest C/D reduction. A 1.3-fold decrease in tacrolimus daily dose was required to maintain desired tacrolimus levels. There was considerable interpatient variability in the magnitude of the drug interaction. Tacrolimus doses should not be adjusted uniformly but, rather, be guided by therapeutic drug monitoring.

Predictors of resistant alcohol withdrawal (RAW): A retrospective case-control study

BACKGROUND Benzodiazepine-resistant alcohol withdrawal (RAW), defined by a requirement of ≥ 40 mg of diazepam in 1 h, represents a severe form of withdrawal without predictive parameters. This study was designed to identify risk factors associated with RAW versus withdrawal without benzodiazepine resistance (nRAW). METHODS A retrospective cohort of adults with severe alcohol withdrawal were screened. Demographic and clinical variables, collected through chart review, underwent logistic regression to select the subset that predicst RAW. RESULTS 736 patients (515 nRAW, 221 RAW) were analyzed. RAW patients were younger (P < 0.001), male (P = 0.008) Caucasians (P = 0.037) with histories of psychiatric illness (P < 0.001), higher serum ethanol concentrations (P < 0.007), and abnormal liver enzymes (P = 0.01). RAW patients had significantly lower platelets (P < 0.001), chloride (P = 0.02), and potassium (P = 0.01) levels; severity of illness (SAPSII) (P < 0.001) and comorbidity scores (P < 0.001). Caucasian race and male gender were found to be 3.6 and 2.6 times more likely to be RAW. For every 1-unit increase in comorbidity and severity of illness scores, patients were 22% [OR(95% CI) 0.78 (0.66-0.90)] and 4% [0.96 (0.93-0.98)] less likely to be RAW. Patients with a psychiatric history or thrombocytopenia were 2 times more likely [2.02 (1.24-3.30); 2.13 (1.31-3.50), respectively] to be RAW. CONCLUSION These data demonstrate the predictive ability of a history of psychiatric illness, thrombocytopenia, gender, race, baseline severity of illness and comorbidity scores for developing RAW. Considering these characteristics in early withdrawal management may prevent progression to RAW outcomes.