Debra J. Skaar

Treatment of Refractory Status Epilepticus with Propofol: Clinical and Pharmacokinetic Findings

Summary: Purpose: We compared propofol with high‐dose barbiturates in the treatment of refractory status epilepticus (RSE) and propose a protocol for the administration of propofol in RSE in adults, correlating propofols effect with plasma levels.

Effects of Patient-Directed Music Intervention on Anxiety and Sedative Exposure in Critically Ill Patients Receiving Mechanical Ventilatory Support: A Randomized Clinical Trial

IMPORTANCE Alternatives to sedative medications, such as music, may alleviate the anxiety associated with ventilatory support. OBJECTIVE To test whether listening to self-initiated patient-directed music (PDM) can reduce anxiety and sedative exposure during ventilatory support in critically ill patients. DESIGN, SETTING, AND PATIENTS Randomized clinical trial that enrolled 373 patients from 12 intensive care units (ICUs) at 5 hospitals in the Minneapolis-St Paul, Minnesota, area receiving acute mechanical ventilatory support for respiratory failure between September 2006 and March 2011. Of the patients included in the study, 86% were white, 52% were female, and the mean (SD) age was 59 (14) years. The patients had a mean (SD) Acute Physiology, Age and Chronic Health Evaluation III score of 63 (21.6) and a mean (SD) of 5.7 (6.4) study days. INTERVENTIONS Self-initiated PDM (n = 126) with preferred selections tailored by a music therapist whenever desired while receiving ventilatory support, self-initiated use of noise-canceling headphones (NCH; n = 122), or usual care (n = 125). MAIN OUTCOMES AND MEASURES Daily assessments of anxiety (on 100-mm visual analog scale) and 2 aggregate measures of sedative exposure (intensity and frequency). RESULTS Patients in the PDM group listened to music for a mean (SD) of 79.8 (126) (median [range], 12 [0-796]) minutes/day. Patients in the NCH group wore the noise-abating headphones for a mean (SD) of 34.0 (89.6) (median [range], 0 [0-916]) minutes/day. The mixed-models analysis showed that at any time point, patients in the PDM group had an anxiety score that was 19.5 points lower (95% CI, -32.2 to -6.8) than patients in the usual care group (P = .003). By the fifth study day, anxiety was reduced by 36.5% in PDM patients. The treatment × time interaction showed that PDM significantly reduced both measures of sedative exposure. Compared with usual care, the PDM group had reduced sedation intensity by -0.18 (95% CI, -0.36 to -0.004) points/day (P = .05) and had reduced frequency by -0.21 (95% CI, -0.37 to -0.05) points/day (P = .01). The PDM group had reduced sedation frequency by -0.18 (95% CI, -0.36 to -0.004) points/day vs the NCH group (P = .04). By the fifth study day, the PDM patients received 2 fewer sedative doses (reduction of 38%) and had a reduction of 36% in sedation intensity. CONCLUSIONS AND RELEVANCE Among ICU patients receiving acute ventilatory support for respiratory failure, PDM resulted in greater reduction in anxiety compared with usual care, but not compared with NCH. Concurrently, PDM resulted in greater reduction in sedation frequency compared with usual care or NCH, and greater reduction in sedation intensity compared with usual care, but not compared with NCH. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00440700.

Potential risk factors associated with thrombocytopenia in a surgical intensive care unit

We conducted a retrospective chart review of 193 patients admitted during a 3-month period to determine the frequency of and potential risk factors associated with thrombocytopenia, and the association of acquired thrombocytopenia with length of stay in a surgical-trauma intensive care unit (SICU) and mortality. All records were reviewed beginning 24 hours after admission. Patients were followed for the duration of SICU stay or until death. Data collected and analyzed as potential risk factors for thrombocytopenia were age, gender, admitting diagnosis, classification (trauma, surgical, medical), APACHE II score, medical history, all scheduled drugs with start and stop dates, select laboratory values, arterial or central line placement, and complications. Thrombocytopenia occurred in 25 (13%) patients. These patients were more likely (p<0.05) than those without thrombocytopenia to have the following potential risk factors: presence of a central or arterial line (76% vs 46%, p<0.025), nonsurgical diagnosis (60% vs 37%, p<0.05), diagnosis of sepsis (p<0.001), and administration of phenytoin (p<0.01), piperacillin (p<0.005), imipenem-cilastatin (p<0.001), and vancomycin (p<0.005). A longer SICU stay (mean 21 vs 4.5 days, p<0.05) and increased mortality (16% vs 4%, p<0.05) were significantly associated with thrombocytopenia. Cefazolin administration was significantly associated with nonthrombocytopenia (p<0.05). Factors not associated with thrombocytopenia were age, gender, and administration of histamine2-receptor antagonists, heparin, enoxaparin, penicillins, ceftazidime, ceftriaxone, chloramphenicol, and amphotericin B. A central or arterial line was the only factor associated with the development of thrombocytopenia in a multiple linear regression analysis (p=0.0003, multiple r=0.2580). Thrombocytopenia is not a common occurrence in the SICU, but is associated with a longer SICU stay and increased mortality.We conducted a retrospective chart review of 193 patients admitted during a 3‐month period to determine the frequency of and potential risk factors associated with thrombocytopenia, and the association of acquired thrombocytopenia with length of stay in a surgical‐trauma intensive care unit (SICU) and mortality. All records were reviewed beginning 24 hours after admission. Patients were followed for the duration of SICU stay or until death. Data collected and analyzed as potential risk factors for thrombocytopenia were age, gender, admitting diagnosis, classification (trauma, surgical, medical), APACHE II score, medical history, all scheduled drugs with start and stop dates, select laboratory values, arterial or central line placement, and complications. Thrombocytopenia occurred in 25 (13%) patients. These patients were more likely (p<0.05) than those without thrombocytopenia to have the following potential risk factors: presence of a central or arterial line (76% vs 46%, p<0.025), nonsurgical diagnosis (60% vs 37%, p<0.05), diagnosis of sepsis (p<0.001), and administration of phenytoin (p<0.01), piperacillin (p<0.005), imipenem‐cilastatin (p<0.001), and vancomycin (p<0.005). A longer SICU stay (mean 21 vs 4.5 days, p<0.05) and increased mortality (16% vs 4%, p<0.05) were significantly associated with thrombocytopenia. Cefazolin administration was significantly associated with nonthrombocytopenia (p<0.05). Factors not associated with thrombocytopenia were age, gender, and administration of histamine2‐receptor antagonists, heparin, enoxaparin, penicillins, ceftazidime, ceftriaxone, chloramphenicol, and amphotericin B. A central or arterial line was the only factor associated with the development of thrombocytopenia in a multiple linear regression analysis (p=0.0003, multiple r=0.2580). Thrombocytopenia is not a common occurrence in the SICU, but is associated with a longer SICU stay and increased mortality.

Phenytoin Protein Binding and Dosage Requirements during Acute and Convalescent Phases following Brain Injury

OBJECTIVE: TO longitudinally evaluate unbound and total serum Phenytoin concentrations during intravenous phenytoin maintenance dosage and to determine the relationship among phenytoin protein binding, serum albumin, and unbound fatty acid concentrations in patients with head injuries during intensive care unit (ICU) and convalescent care. DESIGN: Serum albumin and phenytoin unbound fraction were determined twice weekly during ICU and convalescent care in 10 patients receiving phenytoin following acute brain injury. Phenytoin protein binding was also determined in 10 healthy control subjects. MAIN OUTCOME MEASURES: Longitudinal serum phenytoin concentrations associated with dosage adjustments targeted to achieve unbound phenytoin serum concentrations between 1.0 and 2.0 mg/L were documented during ICU and convalescent care. Longitudinal phenytoin protein binding was correlated with serum albumin and unbound fatty acid concentrations in neurotrauma patients. RESULTS: ICU patients received intravenous therapy for a mean of 15.0 days. The mean ± SD initial phenytoin intravenous dosage regimen of 6.0 ± 0.7 mg/kg/d resulted in mean ± SD total and unbound phenytoin concentrations of 3.2 ± 2.3 and 0.3 ± 0.2 mg/L. Two patients had seizures associated with low phenytoin concentrations. Four patients continued to receive oral phenytoin therapy during convalescent care; phenytoin dosage requirements decreased over time in these patients. During acute and convalescent care, the phenytoin unbound fraction ranged from 6.0% to 18.3% and correlated with albumin (r2 = 0.61, p < 0.0001) but did not correlate with unbound fatty acid concentrations. The mean phenytoin unbound fraction was 10.1% and 8.9% for the ICU and convalescent patients with brain injuries, respectively, and was 7.0% for the healthy volunteers. CONCLUSIONS: Phenytoin protein binding was significantly correlated with albumin and was more variable in ICU and convalescent patients with brain injuries than in healthy volunteers. The high dosage requirements and subtherapeutic unbound phenytoin concentrations observed during acute care are best explained by increased metabolism. Phenytoin dosage requirements decreased during convalescence.

Metformin, a promising oral antihyperglycemic for the treatment of noninsulin-dependent diabetes mellitus

Noninsulin‐dependent diabetes mellitus has historically been treated with diet therapy alone or the addition of an oral hypoglycemic agent such as a sulfonylurea, or the two in combination with insulin. Although these medical interventions lower blood glucose concentrations, they may also potentiate hyperinsulinism through increased serum insulin concentrations. Insulin resistance and hyperinsulinism are associated with cardiovascular risk factors such as hypertriglyceridemia, decreased high‐density lipoprotein cholesterol levels, hypertension, and hyperglycemia, among others. Therefore, a desirable therapeutic alternative would lower blood glucose, not result in hyperinsulinism, and have beneficial effects on lipid profiles. Metformin is a biguanide antihyperglycemic agent that provides these effects. When administered to carefully selected patients and monitored appropriately, metformin may prove to be valuable in the treatment of diabetes mellitus and in altering its cardiovascular sequelae.

Interindividual and Intraindividual Variability in Labetalol Pharmacokinetics

The between‐subject and within‐subject variability in the pharmacokinetics of labetalol at steady state were determined. Sixteen nonobese normal volunteers (mean age, 27 years) received five different formulations of labetalol orally on five different occasions every 12 hours for five doses. A 7‐day washout separated each administration phase. Plasma concentration‐time data for labetalol were obtained over the 24‐hour period after the fifth dose in each phase. Labetalol concentrations in plasma were measured using high‐performance liquid chromatography (HPLC). Pharmacokinetic parameters for each subject after each study phase were estimated. The mean Vβ/F, Vdss/F, TBC/F, t1/2β, and AUC0r for each subject ranged between 18.1 and 161.9 L/kg, 7.1 and 53.9 L/kg, 1.3 and 5.72 L/hr/kg, 6.9 and 11.0 hours, and 154 and 520 μg ṁ hr/L, respectively, indicating large interindividual variability. Considerable intraindividual variability in each of the pharmacokinetic parameters was also observed. These data indicate that a larger number of subjects will be required to detect “significant” differences in the disposition of labetalol.

The Fluconazole Era: Management of Hematogenously Disseminated Candidiasis in the Nonneutropenic Patient

Hematogenously disseminated candidiasis arising from nosocomial fungal infection is a life‐threatening complication in critically ill, nonneutropenic patients. The overall nosocomial fungal infection rate in United States hospitals doubled from 1980–1990. Until recently, amphotericin B was the only agent available for the treatment of life‐threatening candidal infections, but its use is plagued by toxicities including nephrotoxicity and infusion‐related reactions such as rigors and hypotension. The availability of fluconazole, which is regarded as much less toxic than amphotericin B, prompted a surge in research to determine if it is as efficacious in the management of candidemia and hematogenously disseminated candidiasis. Complicating the interpretation of studies is the broad range of infection severity, from candidemia that may be transient and self‐limiting to life‐threatening hematogenously disseminated candidiasis. Clinical trials comparing fluconazole and amphotericin B demonstrate the efficacy of fluconazole for catheter‐associated candidemia in critically ill patients when the likely pathogen is Candida albicans. Amphotericin B should remain the first‐line agent for the management of candidemia and hematogenously disseminated candidiasis in all other patients.

Educational Outcomes Necessary to Enter Pharmacy Residency Training

It is the position of the American College of Clinical Pharmacy (ACCP) that formal postgraduate residency training, or equivalent experience, is required to enter direct patient care practice. Therefore, it is important to align professional degree educational outcomes with the knowledge, skills, and attitudes needed to enter residency training. This position statement addresses the outcomes necessary in the professional degree program curriculum to ensure the ability of pharmacy graduates to transition effectively into postgraduate year one residency training. Five key outcome areas are identified: communication, direct patient care, professionalism, research, and practice management. The position statement examines how performance in each of the five outcome areas should be addressed by professional degree programs. The ACCP believes that for the student to achieve the clinical proficiency necessary to enter residency training, the professional degree program should emphasize, assess, and provide adequate opportunities for students to practice: communication with patients, caregivers, and members of the health care team in direct patient care environments; provision of direct patient care in a wide variety of practice settings, especially those involving patient‐centered, team‐based care; professionalism under the supervision and guidance of faculty and preceptors who model and teach the traits of a health care professional; application of principles of research that engender an appreciation for the role of research and scholarship in ones professional development; and application of practice management, including documentation of direct patient care activities that affect drug‐related outcomes.

Perceived Motivating Factors and Barriers for the Completion of Postgraduate Training Among American Pharmacy Students Prior to Beginning Advanced Pharmacy Practice Experiences

Objective. To examine perceived motivating factors and barriers (MFB) to postgraduate training (PGT) pursuit among pharmacy students. Methods. Third-year pharmacy students at 13 schools of pharmacy provided demographics and their plan and perceived MFBs for pursuing PGT. Responses were characterized using descriptive statistics. Kruskal-Wallis equality-of-proportions rank tests determined if differences in perceived MFBs existed between students based on plan to pursue PGT. Results. Among 1218 (69.5%) respondents, 37.1% planned to pursue PGT (32.9% did not, 30% were undecided). Students introduced to PGT prior to beginning pharmacy school more frequently planned to pursue PGT. More students who planned to pursue PGT had hospital work experience. The primary PGT rationale was, “I desire to gain more knowledge and experience.” Student debt was the most commonly cited barrier. Conclusion. Introducing pharmacy students early to PGT options and establishing work experiences in the hospital setting may increase students’ desire to pursue PGT.

Mechanical Ventilation and Pharmacologic Strategies for Acute Respiratory Distress Syndrome

Acute or adult respiratory distress syndrome (ARDS) contributes to mortality and morbidity in the intensive care environment. Appropriate application of microprocessor‐controlled mechanical ventilatory support, pathophysiology of the disease, and new pharmacologic modalities are currently being investigated. Mechanical ventilation is usually begun when respiratory failure is caused by alveolar hypoventilation or hypoxia. Primary choices for this therapy are control‐mode ventilation, assist‐control ventilation, pressure‐control ventilation, intermittent mandatory ventilation, and synchronized intermittent mandatory ventilation with the addition of positive end‐expiratory pressure. Patients who deteriorate despite these interventions may require alternative modes of ventilation. Pharmacologic agents in ARDS is important due to the multifactorial pathophysiologic and pharmacodynamic processes that are part of the disease. Clinical studies will continue to determine advantageous agents. Unfortunately, no convincing data exist that any pharmacologic or nonpharmacologic strategy is superior for the support of these patients or results in a better outcome than others.