Study protocol to test the efficacy of self-administration of dexmedetomidine sedative therapy on anxiety, delirium, and ventilator days in critically ill mechanically ventilated patients: an open-label randomized clinical trial.

BACKGROUND: Administration of sedative and opioid medications to patients receiving mechanical ventilatory support in the intensive care unit is a common clinical practice. METHODS: A two-site randomized open-label clinical trial will test the efficacy of self-management of sedative therapy with dexmedetomidine compared to usual care on anxiety, delirium, and duration of ventilatory support after randomization. Secondary objectives are to compare self-management of sedative therapy to usual care on level of alertness, total aggregate sedative and opioid medication exposure, and ventilator-free days up to day 28 after study enrolment. Exploratory objectives of the study are to compare self-management of sedative therapy to usual care on 3- and 6-month post-discharge physical and functional status, psychological well-being (depression, symptoms of post-traumatic stress disorder), health-related quality of life, and recollections of ICU care. ICU patients (n = 190) who are alert enough to follow commands to self-manage sedative therapy are randomly assigned to self-management of sedative therapy or usual care. Patients remain in the ICU sedative medication study phase for up to 7 days as long as mechanically ventilated. DISCUSSION: The care of critically ill mechanically ventilated patients can change significantly over the course of a 5-year clinical trial. Changes in sedation and pain interventions, oxygenation approaches, and standards related to extubation have substantially impacted consistency in the number of eligible patients over time. In addition, the COVID-19 pandemic resulted in mandated extended pauses in trial enrolment as well as alterations in recruitment methods out of concern for study personnel safety and availability of protective equipment. Patient triaging among healthcare institutions due to COVID-19 cases also has resulted in inconsistent access to the eligible study population. This has made it even more imperative for the study team to be flexible and innovative to identify and enrol all eligible participants. Patient-controlled sedation is a novel approach to the management of patient symptoms that may be able to alleviate mechanical ventilation-induced distress without serious side effects. Findings from this study will provide insight into the efficacy of this approach on short- and long-term outcomes in a subset of mechanically ventilated patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02819141. Registered on June 29, 2016.

Pharmacogenomics in kidney transplant recipients and potential for integration into practice.

WHAT IS KNOWN AND OBJECTIVE: Pharmacogenomic biomarkers are now used in many clinical care settings and represent one of the successes of precision medicine. Genetic variants are associated with pharmacokinetic and pharmacodynamic changes leading to medication adverse effects and changes in clinical response. Actionable pharmacogenomic variants are common in transplant recipients and have implications for medications used in transplant, but yet are not broadly incorporated into practice. METHODS: From the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group guidelines, and PharmGKB databases, 12 pharmacogenomic genes with 30 variants were selected and used to create diplotypes and actionable pharmacogenomic phenotypes. A total of 853 kidney allograft recipients who had genomic information available from a genome-wide association study were included. RESULTS: Each recipient had at least one actionable pharmacogenomic diplotype/phenotype, whereas the majority (58%) had three or four actionable diplotypes/phenotypes and 17.4% had five or more among the 12 genes. The participants carried actionable diplotypes/phenotypes for multiple medications, including tacrolimus, azathioprine, clopidogrel, warfarin, simvastatin, voriconazole, antidepressants and proton-pump inhibitors. WHAT IS NEW AND CONCLUSION: Pharmacogenomic variants are common in transplant recipients, and transplant recipients receive medications that have actionable variants. CLINICAL TRIAL: Genomics of Transplantation, clinicaltrials.gov (NCT01714440).

A Novel Research Method for Determining Sedative Exposure in Critically Ill Patients.

BACKGROUND: Although potent sedative and opioid drugs are some of the most commonly used medications to manage pain, anxiety, and discomfort in critically ill patients, conducting clinical trials where sedative and opioid medications are outcome variables within a longitudinal research design can be a methodological challenge. OBJECTIVES: The purpose of this article is to provide in detail a conceptual discussion of the concept and analysis of sedative exposure: A novel research analysis method for aggregating sedative and opioid medication doses from disparate drug classes commonly administered to critically ill patients and used by our team in several clinical research studies. METHODS: Comparing the dose of each sedative and opioid administered to an individual patient (within a defined time interval) to all other patients in a research study receiving the same medications allows for ranking of dosages for each medication by quartiles. Rank values for all sedatives and opioids received can be summed to a single value resulting in a Sedation Intensity Score. In addition, a simple count of how many hours at least one dose of a sedative or opioid medication has been administered can determine sedation frequency. RESULTS: This method can allow for comparison of sedative exposure with medications from disparate drug classes and for analysis of estimates of change in medication use over time. DISCUSSION: This novel research analysis method can overcome the challenges and limitations of determining changes in sedative and opioid medication regimens in cohort and clinical trial study designs.

Pharmacogenomics of Medications Commonly Used in the Intensive Care Unit.

In the intensive care unit (ICU) setting, where highly variable and insufficient drug efficacies, as well as frequent and unpredictable adverse drug reactions (ADRs) occur, pharmacogenomics (PGx) offers an opportunity to improve health outcomes. However, PGx has not been fully evaluated in the ICU, partly due to lack of knowledge of how genetic markers may affect drug therapy. To fill in this gap, we conducted a review to summarize the PGx information for the medications commonly encountered in the ICU.

Economic Evaluation of a Patient-Directed Music Intervention for ICU Patients Receiving Mechanical Ventilatory Support.

OBJECTIVES: Music intervention has been shown to reduce anxiety and sedative exposure among mechanically ventilated patients. Whether music intervention reduces ICU costs is not known. The aim of this study was to examine ICU costs for patients receiving a patient-directed music intervention compared with patients who received usual ICU care. DESIGN: A cost-effectiveness analysis from the hospital perspective was conducted to determine if patient-directed music intervention was cost-effective in improving patient-reported anxiety. Cost savings were also evaluated. One-way and probabilistic sensitivity analyses determined the influence of input variation on the cost-effectiveness. SETTING: Midwestern ICUs. PATIENTS: Adult ICU patients from a parent clinical trial receiving mechanical ventilatory support. INTERVENTIONS: Patients receiving the experimental patient-directed music intervention received a MP3 player, noise-canceling headphones, and music tailored to individual preferences by a music therapist. MEASUREMENTS AND MAIN RESULTS: The base case cost-effectiveness analysis estimated patient-directed music intervention reduced anxiety by 19 points on the Visual Analogue Scale-Anxiety with a reduction in cost of $2,322/patient compared with usual ICU care, resulting in patient-directed music dominance. The probabilistic cost-effectiveness analysis found that average patient-directed music intervention costs were $2,155 less than usual ICU care and projected that cost saving is achieved in 70% of 1,000 iterations. Based on break-even analyses, cost saving is achieved if the per-patient cost of patient-directed music intervention remains below $2,651, a value eight times the base case of $329. CONCLUSIONS: Patient-directed music intervention is cost-effective for reducing anxiety in mechanically ventilated ICU patients.

Safety and Acceptability of Patient-Administered Sedatives During Mechanical Ventilation.

BACKGROUND: Safety and acceptability of sedative self-administration by patients receiving mechanical ventilation is unknown. OBJECTIVES: To determine if self-administration of dexmedetomidine by patients is safe and acceptable for self-management of anxiety during ventilatory support. METHODS: In a pilot trial in 3 intensive care units, 17 intubated patients were randomly assigned to dexmedetomidine and 20 to usual care. Dexmedetomidine was administered via standard pumps for patient-controlled analgesia, with a basal infusion (0.1-0.7 µg/kg per hour) titrated by the number of patient-triggered doses (0.25 µg/kg per dose). Safety goals were heart rate greater than 40/min, systolic blood pressure greater than 80 mm Hg, and diastolic blood pressure greater than 50 mm Hg. Acceptability was based on patients' self-reported satisfaction and ability to administer the sedative. A 100-mm visual analog scale was used daily to assess patients' anxiety. RESULTS: The sample was 59% male and 89% white. Mean values were age, 50.6 years; score on the Acute Physiology and Chronic Health Evaluation, 60.1; and protocol duration, 3.4 days. Five dexmedetomidine patients had blood pressure and/or heart rate lower than safety parameters, necessitating short-term treatment. Nurses' adherence to reporting of safety parameters was 100%; adherence to the dexmedetomidine titration algorithm was 73%. Overall baseline anxiety score was 38.4 and did not change significantly (ßday = 2.1; SE, 2.5; P = .40). Most dexmedetomidine patients (92%) were satisfied or very satisfied with their ability to self-administer medication. CONCLUSIONS: For select patients, self-administration of dexmedetomidine is safe and acceptable.

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 one's professional development; and application of practice management, including documentation of direct patient care activities that affect drug-related outcomes.

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.

Patient-controlled sedation: a novel approach to sedation management for mechanically ventilated patients.

BACKGROUND: Patient self-administration of medications for analgesia and procedural sedation is common. However, it is not known whether mechanically ventilated ICU patients can self-administer their own sedation to manage symptoms. METHODS: This descriptive pilot study examined the safety, adequacy, and satisfaction of patient-controlled sedation (PCS) with a convenience sample of critically ill, mechanically ventilated patients (N = 17) in the ICUs at University of Minnesota Medical Center, Fairview, Minneapolis, Minnesota. Dexmedetomidine was administered via a patient-demand infusion pump system for a maximum of 24 h. Pumps were programmed with basal infusion plus patient-triggered boluses; nurses adjusted the basal infusion based on a dosing algorithm. Data were collected on sedation adequacy, additional dosing of analgesics and sedatives, hemodynamic parameters, safety of PCS, patient satisfaction with PCS, and nurse satisfaction with PCS. RESULTS: Although a majority of the hemodynamic values were within the established safety parameters for the study, 25% of patients experienced mild adverse physiologic effects. Furthermore, despite patients' perception of sedation adequacy with PCS, 70% received supplemental opiates or benzodiazepine medications while participating in the study. Patients rated dexmedetomidine PCS favorably for self-management of anxiety, level of relaxation obtained, and comfort in self-administering sedation. Nurses also were generally satisfied with PCS as a method of sedation, dexmedetomidine as the sedative, and patient response to the sedation. CONCLUSIONS: PCS warrants further investigation as a means to promote comfort in mechanically ventilated critically ill patients.