Interventions, Barriers, and Proposed Solutions Associated With the Implementation of a Protocol That Uses Clinical Decision Support and a Stress Biomarker Test to Identify ICU Patients at High-Risk for Drug Associated Acute Kidney Injury.

BACKGROUND: Damage biomarkers are helpful in early identification of patients who are at risk of developing acute kidney injury (AKI). Investigations are ongoing to identify the optimal role of stress/damage biomarkers in clinical practice regarding AKI risk prediction, surveillance, diagnosis, and prognosis. OBJECTIVE: To determine the impact of utilizing a clinical decision support system (CDSS) to guide stress biomarker testing in intensive care unit (ICU) patients at risk for drug-induced acute kidney injury (D-AKI). METHODS: A protocol was designed utilizing a clinical decision support system (CDSS) alert to identify patients that were ordered 3 or more potentially nephrotoxic medications, suggesting risk for progressing to AKI from nephrotoxic burden. Once alerted to these high-risk patients, the pharmacist determined if action was needed by ordering a stress biomarker test, tissue inhibitor of metalloproteinase-2-insulin-like growth factor-binding protein 7 (TIMP-2•IGFBP7). If the biomarker test result was elevated, the pharmacist provided nephrotoxin stewardship recommendations to the team. Pharmacists recorded the response to the clinical decision support alert, ordering, and interpreting the TIMP-2•IGFBP7, and information regarding clinical interventions. An alert in conjunction with TIMP-2•IGFBP7 as a strategy for AKI risk prediction and stimulant for patient care management was assessed. In addition, barriers and solutions to protocol implementation were evaluated. RESULTS: There were 394 total activities recorded by pharmacists for 345 unique patients. Ninety-three (93/394; 23.6%) actionable alerts resulted in a TIMP-2•IGFBP7 test being ordered. Thirty-one TIMP-2•IGFBP7 results were >0.3 (31/81; 38.3%), suggesting a high-risk of progression to AKI, which prompted 191 pharmacist/team interventions. On average, there were 1.64 interventions per patient in the low-risk patients, 3.43 in high-risk patients, and 3.75 in the highest-risk patients. CONCLUSION AND RELEVANCE: Stress biomarkers can be used in conjunction with CDSS alerts to affect therapeutic decisions in ICU patients at high-risk for D-AKI.

Patient-Reported Outcomes Associated With Sedation and Agitation Intensity in the Critically Ill.

BACKGROUND: Patient-reported outcomes are essential to understand the relationship between patients' perception of sedation and clinicians' assessments of sedation. OBJECTIVES: To evaluate the association between sedation and agitation indexes and patient-reported outcomes of sedation and analgesia. METHODS: This prospective, single-center, observational study included adult patients who were continuously sedated for at least 24 hours in a medical or surgical/ trauma intensive care unit. Patients were interviewed after sedation was discontinued regarding their satisfaction with the quality of sedation and potentially related factors. The primary outcome was the correlation between sedation and agitation indexes and patient-reported outcomes. RESULTS: A total of 68 patients were interviewed after sedation. Of these, 29 (42.6%) described their overall feelings about their experience while receiving mechanical ventilation in the intensive care unit as "pleasant". When asked about their desires if they were to experience the situation again, 29 patients (42.6%) reported that they would want more sedation. Agitation index was statistically significantly correlated with several patient-reported outcomes. Receiving mechanical ventilation (r = 0.41, P = .002), the amount of noise (r = 0.34, P = .01), suctioning (r = 0.32, P = .02), difficulty resting or sleeping (r = 0.39, P = .003), inability to communicate by talking (r = 0.36, P = .008), anxiety (r = 0.29, P = .03), panic (r = 0.3, P = .02), and frustration (r = 0.47, P < .001) were associated with a higher agitation index. CONCLUSION: Agitation index was significantly associated with several patient-reported outcomes and thus seems to be a promising descriptor of patients' experience.

Clinical outcomes with unfractionated heparin monitored by anti-factor Xa vs. activated partial Thromboplastin time.

Anti-factor Xa (anti-Xa) monitoring of unfractionated heparin (UFH) is associated with less time to achieve therapeutic anticoagulation compared to the activated partial thromboplastin time (aPTT). However, it is unknown whether clinical outcomes differ between these methods of monitoring. The aim of this research was to compare the rate of venous thrombosis and bleeding events in patients that received UFH monitored by anti-Xa compared to the aPTT. A retrospective review of electronic health records identified adult patients that received UFH given intravenously (IV) for ≥2 days, with either anti-Xa or aPTT monitoring at an academic tertiary care hospital. This was a pre/post study design conducted between January 1 to December 30, 2014 (aPTT), and January 1 to December 30, 2016 (anti-Xa). All UFH adjustments were based on institutional nomograms. The primary outcome was venous thrombosis and the secondary outcome was bleeding, both of which occurred between UFH administration and discharge from the index hospitalization. A total of 2500 patients were in the anti-Xa group and 2847 patients aPTT group. Venous thrombosis occurred in 10.2% vs 10.8% of patients in the anti-Xa and aPTT groups, respectively (P = .49). Bleeding occurred in 33.7% vs 33.6% of patients in the anti-Xa and aPTT groups, respectively (P = .94). Anti-Xa monitoring was not an independent predictor of either outcome in multivariate logistic regression analyses. Our study found no difference in clinical outcomes between anti-Xa and aPTT-based monitoring of UFH IV.

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.

Adjunct Ketamine Use in the Management of Severe Ethanol Withdrawal.

OBJECTIVES: Ketamine offers a plausible mechanism with favorable kinetics in treatment of severe ethanol withdrawal. The purpose of this study is to determine if a treatment guideline using an adjunctive ketamine infusion improves outcomes in patients suffering from severe ethanol withdrawal. DESIGN: Retrospective observational cohort study. SETTING: Academic tertiary care hospital. PATIENTS: Patients admitted to the ICU and diagnosed with delirium tremens by Diagnostic and Statistical Manual of Mental Disorders V criteria. INTERVENTIONS: Pre and post guideline, all patients were treated in a symptom-triggered fashion with benzodiazepines and/or phenobarbital. Postguideline, standard symptom-triggered dosing continued as preguideline, plus, the patient was initiated on an IV ketamine infusion at 0.15-0.3 mg/kg/hr continuously until delirium resolved. Based upon withdrawal severity and degree of agitation, a ketamine bolus (0.3 mg/kg) was provided prior to continuous infusion in some patients. MEASUREMENTS AND MAIN RESULTS: A total of 63 patients were included (29 preguideline; 34 postguideline). Patients treated with ketamine were less likely to be intubated (odds ratio, 0.14; p < 0.01; 95% CI, 0.04-0.49) and had a decreased ICU stay by 2.83 days (95% CI, -5.58 to -0.089; p = 0.043). For ICU days outcome, correlation coefficients were significant for alcohol level and total benzodiazepine dosing. For hospital days outcome, correlation coefficients were significant for patient age, aspartate aminotransferase, and alanine aminotransferase level. Regression revealed the use of ketamine was associated with a nonsignificant decrease in hospital stay by 3.66 days (95% CI, -8.40 to 1.08; p = 0.13). CONCLUSIONS: Mechanistically, adjunctive therapy with ketamine may attenuate the demonstrated neuroexcitatory contribution of N-methyl-D-aspartate receptor stimulation in severe ethanol withdrawal, reduce the need for excessive gamma-aminobutyric acid agonist mediated-sedation, and limit associated morbidity. A ketamine infusion in patients with delirium tremens was associated with reduced gamma-aminobutyric acid agonist requirements, shorter ICU length of stay, lower likelihood of intubation, and a trend toward a shorter hospitalization.

Evaluation of Branched-Narrative Virtual Patients for Interprofessional Education of Psychiatry Residents.

OBJECTIVE: This pilot study evaluated the utility of branched-narrative virtual patients in an interprofessional education series for psychiatry residents. METHODS: Third-year psychiatry residents attended four interprofessional education advanced psychopharmacology sessions that involved completion of a branched-narrative virtual patient and a debriefing session with a psychiatric pharmacist. Pre- and post-assessments analyzed resident learning and were administered around each virtual patient. Simulation 4 served as a comprehensive review. The primary outcome was differences in pre- and post-assessment scores. Secondary outcomes included resident satisfaction with the virtual patient format and psychiatric pharmacist involvement. RESULTS: Post-test scores for simulations 1, 2, and 3 demonstrated significant improvement (p < 0.05) from pre-test scores. Scores for simulation 4 did not retain significance. Resident satisfaction with the branched-narrative virtual patient format and psychiatric pharmacist involvement was high throughout the series (100 %; n = 18). CONCLUSIONS: Although there are important methodological limitations to this study including a small sample size and absence of a comparator group, this pilot study supports the use of branched-narrative virtual patients in an interprofessional education series for advanced learners.

Combination of a Flipped Classroom Format and a Virtual Patient Case to Enhance Active Learning in a Required Therapeutics Course.

Objective. To design and evaluate the integration of a virtual patient activity in a required therapeutics course already using a flipped-classroom teaching format. Design. A narrative-branched, dynamic virtual-patient case was designed to replace the static written cases that students worked through during the class, which was dedicated to teaching the complications of liver disease. Students completed pre- and posttests before and after completing the virtual patient case. Examination scores were compared to those in the previous year. Assessment. Students' posttest scores were higher compared to pretest scores (33% vs 50%). Overall median examination scores were higher compared to the historical control group (70% vs 80%), as well as scores on questions assessing higher-level learning (67% vs 83%). A majority of students (68%) felt the virtual patient helped them apply knowledge gained in the pre-class video lecture. Students preferred this strategy to usual in-class activities (33%) or indicated it was of equal value (37%). Conclusion. The combination of a pre-class video lecture with an in-class virtual patient case is an effective active-learning strategy.

Management of benzodiazepine-resistant alcohol withdrawal across a healthcare system: Benzodiazepine dose-escalation with or without propofol.

BACKGROUND: Severe cases of alcohol withdrawal syndrome (AWS) may not resolve despite escalating doses of benzodiazepines (BZDs). Benzodiazepine-resistant alcohol withdrawal (RAW) is a subset of severe alcohol withdrawal defined by the requirement of ≥40mg of diazepam administered within one hour. Use of adjunct agents, such as propofol, may be beneficial to minimize BZD adverse effects and improve symptom control. While limited evidence suggests propofol as an effective adjunct in AWS through improved sedation, evidence is currently lacking for the addition of only propofol to BZDs for management of RAW. METHODS: Retrospective review of adult patients from January, 2009 to March, 2012 with RAW. Patients were categorized into BZD dose-escalation only or BZD plus propofol. The primary endpoint was time to resolution of AWS. Secondary endpoints included safety outcomes associated with medication use. RESULTS: Of 1083 patients with severe AWS, 66 RAW patients (n=33 BZD only, n=33 BZD plus propofol) met inclusion. Median time to AWS resolution was 5.0 and 7.0 days for BZD only vs. BZD plus propofol (p=0.025). Duration of mechanical ventilation, ICU and hospital length of stay were significantly higher with propofol (p=0.017, <0.001 and <0.001, respectively). Ten patients required intervention for management of propofol-induced adverse reactions. CONCLUSIONS: The addition of propofol for RAW treatment is associated with significant increases in clinical care. While randomized, prospective evaluations are necessary to determine the cause of this association, our data suggests use of adjunctive propofol therapy in RAW is associated with longer and more complicated hospital admissions.

Multicenter evaluation of pharmacologic management and outcomes associated with severe resistant alcohol withdrawal.

INTRODUCTION: A subset of patients with alcohol withdrawal syndrome does not respond to benzodiazepine treatment despite escalating doses. Resistant alcohol withdrawal (RAW) is associated with higher incidences of mechanical ventilation and nosocomial pneumonia and longer intensive care unit (ICU) stay. The objective of this study is to characterize pharmacologic management of RAW and outcomes. METHODS: Adult patients were identified retrospectively via International Classification of Diseases, Ninth Revision codes for severe alcohol withdrawal from 2009 to 2012 at 3 hospitals. Data collected included pharmacologic management and clinical outcomes. RESULTS: A total of 184 patients met inclusion criteria. Sixteen medications and 74 combinations of medications were used for management. Propofol was the most common adjunct agent, with dexmedetomidine and antipsychotics also used. One hundred seventy-five patients (96.2%) were admitted to the ICU, with 149 patients (81.9%) requiring ventilator support. Median time to resolution of alcohol withdrawal syndrome from RAW designation was 6.0 days. Median ICU and hospital length of stay were 9.0 and 12.7 days, respectively. CONCLUSION: Diverse patterns exist in the management of patients meeting RAW criteria, indicating lack of refined approach to treatment. High doses of sedatives used for these patients may result in a high level of care, illustrating a need for evidence-based clinical guidelines to optimize outcomes.

Evaluation of adjunctive ketamine to benzodiazepines for management of alcohol withdrawal syndrome.

BACKGROUND: Adjunctive medications to manage alcohol withdrawal syndrome (AWS) in patients not adequately responding to escalating doses of benzodiazepines (BZDs) are limited. The use of the N-methyl-d-aspartate antagonist ketamine, may serve as an effective adjunct agent; however, no published data currently exist for this practice. OBJECTIVE: To determine the safety and efficacy of adjunct ketamine for management of AWS. METHODS: The study was a retrospective review of adult patients from April 2011 to March 2014 who were administered ketamine specifically for management of AWS. Outcomes included changes in BZD requirements and ketamine-related adverse reactions. RESULTS: Of 235 patients screened, 23 patients met study eligibility. Ketamine was initiated primarily with toxicology consultation for significant BZD requirements or delirium tremens. The mean time to initiation of ketamine from first treatment of AWS, and total duration of therapy were 33.6 and 55.8 hours, respectively. Mean initial infusion dose and median total infusion rate during therapy were 0.21 and 0.20 mg/kg/h, respectively. There was no change in sedation or alcohol withdrawal scores in patients within 6 hours of ketamine initiation. The median change in BZD requirements at 12 and 24 hours post-ketamine initiation were -40.0 and -13.3 mg, respectively. The mean time to AWS resolution was 5.6 days. There was one documented adverse reaction of oversedation, requiring dose reduction. CONCLUSIONS: Ketamine appears to reduce BZD requirements and is well tolerated at low doses. Prospective dose range evaluations in the management of AWS would be helpful in determining its place as an adjunctive agent.

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.

Sitaxsentan in the management of pulmonary arterial hypertension.

PURPOSE: The pharmacology, pharmacokinetics, clinical trials, adverse effects, drug interactions, and dosing and administration of the endothelin receptor antagonist, sitaxsentan, and its role in the treatment of pulmonary arterial hypertension (PAH) are reviewed. SUMMARY: PAH is a serious and potentially devastating chronic disorder of the pulmonary circulation. Bosentan is the first and only approved endothelin receptor antagonist for the treatment of PAH. Endothelin-1, a potent endogenous vasoconstrictor and smooth-muscle mitogen, has been shown to be overexpressed in the plasma and lung tissue of patients with PAH; the reduction or blockade of entothelin-1 may aid in disease symptomatology and progression. Activation of ET(A) leads to vasoconstriction and vascular smooth-muscle-cell proliferation. Sitaxsentan is an orally active, organic nonpeptide that binds competitively to the ET(A) receptor. Sitaxsentan, unlike bosentan, has a high affinity for the ET(A) receptor. In one trial, sitaxsentan was compared with placebo, and the results suggested that sitaxsentan was more effective than placebo. A 12-week, open-label trial demonstrated the safety and efficacy of sitaxsentan in 20 patients. The Sitaxsentan to Relieve Impaired Exercise (STRIDE-1) trial randomized patients to receive placebo, sitaxsentan 100 mg orally once daily, or sitaxsentan 300 mg orally once daily. Significant improvements in exercise capacity and cardiopulmonary hemodynamics were demonstrated. The results of STRIDE-2, the second randomized sitaxsentan trial, demonstrated the efficacy and safety of 100 mg sitaxsentan and the unacceptable safety profile of 300 mg sitaxsentan. CONCLUSION: Sitaxsentan is an orally administered endothelin receptor blocker that offers the effective and safe treatment of patients with mild to moderate PAH.

Pharmacy student response to patient-simulation mannequins to teach performance-based pharmacotherapeutics.

OBJECTIVE: To design and implement a simulated patient-case assessment using a mannequin for critical care pharmacotherapeutic education of doctor of pharmacy students and to evaluate student satisfaction with the simulation. DESIGN: During the second year of the doctor of pharmacy program, all students were required to complete Introduction to Critical Care. This course consisted of didactic education, written patient-case sessions, and an interactive patient simulation session. Information on the patient case was distributed to students after completing the didactic portion of the course. Patient information was programmed into a simulation mannequin, which demonstrated characteristics of a critically ill human. Students were surveyed post-simulation to determine the effectiveness of the learning experience. ASSESSMENT: The majority of students (88%) were extremely satisfied with the experience. The facilitator was considered to be extremely useful in 75% of responses. CONCLUSION: By simulating a patient case, the facilitator was able to control students' learning environment, adapt the simulation to the level of the students' performance, and debrief students immediately. Ultimately, by involving students in actual patient cases early in the pharmacy curriculum, this type of education could produce pharmacists with a high level of expertise and confidence.