Preclinical findings predicting efficacy and side-effect profile of LY2940094, an antagonist of nociceptin receptors.

Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide whose receptor is designated ORL1 or nociceptin receptor (NOP). We utilized a potent, selective, and orally bioavailable antagonist with documented engagement with NOP receptors in vivo to assess antidepressant- and anxiolytic-related pharmacological effects of NOP receptor blockade along with measures of cognitive and motor impingement. LY2940094 ([2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol) displayed antidepressant-like behavioral effects in the forced-swim test in mice, an effect absent in NOP -/- mice. LY2940094 also augmented the behavioral effect of fluoxetine without changing target occupancies (NOP and serotonin reuptake transporter [SERT]). LY2940094 did not have effects under a differential-reinforcement of low rate schedule. Although anxiolytic-like effects were not observed in some animal models (conditioned suppression, 4-plate test, novelty-suppressed feeding), LY2940094 had effects like that of anxiolytic drugs in three assays: fear-conditioned freezing in mice, stress-induced increases in cerebellar cGMP in mice, and stress-induced hyperthermia in rats. These are the first reports of anxiolytic-like activity with a systemically viable NOP receptor antagonist. LY2940094 did not disrupt performance in either a 5-choice serial reaction time or delayed matching-to-position assay. LY2940094 was also not an activator or suppressor of locomotion in rodents nor did it induce failures of rotarod performance. These data suggest that LY2940094 has unique antidepressant- and anxiolytic-related pharmacological effects in rodents. Clinical proof of concept data on this molecule in depressed patients have been reported elsewhere.

Pharmacist leadership in ICU quality improvement: coordinating spontaneous awakening and breathing trials.

BACKGROUND: Coordinating efforts across disciplines in the intensive care unit is a key component of quality improvement (QI) efforts. Spontaneous awakening trials (SATs) and spontaneous breathing trials (SBTs) are considered key components of guidelines, yet unfortunately are often not done or coordinated properly. OBJECTIVE: To determine if a pharmacist-driven awakening and breathing coordination (ABC) QI program would improve compliance (ie, process measures) as compared with the previous protocol, which did not involve pharmacists. METHODS: The QI program included pharmacist-led education, daily discussion on rounds, and weekly performance reports to staff. Using a pre-QI versus during-QI versus post-QI intervention design, we compared data from 500 control ventilator-days (pre-QI period) versus 580 prospective ventilator-days (during-QI period). We then evaluated the sustainability of the QI program in 216 ventilator-days in the post-QI period. RESULTS: SAT safety screens were performed on only 20% pre-QI patient-days versus 97% of during-QI patient-days (P < 0.001) and 100% of post-QI patient-days (P = 0.25). The rates of passing the SAT safety screen in pre-QI and during-QI periods were 63% versus 78% (P = 0.03) and 81% in the post-QI period (P = 0.86). The rates of SATs among eligible patients on continuous infusions were only 53% in the pre-QI versus 85% in the during-QI (P = 0.0001) and 87% in the post-QI (P = 1) periods. CONCLUSIONS: In this QI initiative, a pharmacist-driven, interdisciplinary ABC protocol significantly improved process measures compliance, comparing the pre-QI versus during-QI rates of screening, performing, and coordinating SAT and SBTs, and these results were sustained in the 8-month follow-up period post-QI program.

A comparison of the effects of ketamine and phencyclidine with other antagonists of the NMDA receptor in rodent assays of attention and working memory.

RATIONALE: N-methyl-D: -Aspartate receptor (NMDAR) antagonists such as ketamine induce cognitive symptoms in man similar to those of schizophrenia and therefore might be useful as models of the disease in animals. However, it is unclear which NMDAR antagonist(s) offer the best means to produce cognitive deficits in attention and working memory and to what extent those deficits can be measured selectively in rats. OBJECTIVES: The present study systematically compared the effects of eight different NMDAR antagonists-MK-801, phencyclidine, (S)-(+)-ketamine, memantine, SDZ-220,581, Ro 25-6981, CP 101-606 and NVP-AAM077-in rats using standard tests of visual attention, the five-choice serial reaction time task (5CSRT), and working memory, the delayed matching to position task (DMTP). RESULTS: Drug-induced responses varied qualitatively and quantitatively in both a compound- and a task-dependent manner. Effects were generally confounded by concomitant motor and motivational disruption, although individual doses of phencyclidine for example appeared to impair selectively cognitive functions. Interestingly, GluN2B selective antagonists were unique in their effects; inducing potential performance benefit in the 5CSRT. CONCLUSIONS: Overall, the opportunity to induce a selective cognitive deficit in attention (5CSRT) or working memory (DMTP) in the rat is limited by both the NMDAR antagonist and the dose range used. The importance of a preclinical focus on ketamine, which is used more frequently in clinical settings, is limited by the extent to which cognitive effects can be both detected and quantified using this exposure regimen within these two operant assays.

Large-scale implementation of sedation and delirium monitoring in the intensive care unit: a report from two medical centers.

OBJECTIVE: To implement sedation and delirium monitoring via a process-improvement project in accordance with Society of Critical Care Medicine guidelines and to evaluate the challenges of modifying intensive care unit (ICU) organizational practice styles. DESIGN: Prospective observational cohort study. SETTING: The medical ICUs at two institutions: the Vanderbilt University Medical Center (VUMC) and a community Veterans Affairs hospital (York-VA). SUBJECTS: Seven hundred eleven patients admitted to the medical ICUs for >24 hrs and followed over 4,163 days during a 21-month study period. INTERVENTIONS: Unit-wide nursing documentation was changed to accommodate a sedation scale (Richmond Agitation-Sedation Scale) and delirium instrument (Confusion Assessment Method for the ICU). A 20-min introductory in-service was performed for all ICU nurses, followed by graded, staged educational interventions at regular intervals. Data were collected daily for compliance, and randomly 40% of nurses each day were chosen for accuracy spot-checks by reference raters. An implementation survey questionnaire was distributed at 6 months. MEASUREMENTS AND MAIN RESULTS: The implementation project involved 64 nurses (40 at VUMC and 24 at York-VA). Sedation and delirium monitoring data were recorded for 711 patients (614 at VUMC and 97 at York-VA). Compliance with the Richmond Agitation-Sedation Scale was 94.4% (21,931 of 23,220) at VUMC and 99.7% (5,387 of 5,403) at York-VA. Compliance with the Confusion Assessment Method for the ICU was 90% (7,323 of 8,166) at VUMC and 84% (1,571 of 1,871) at York-VA. The Confusion Assessment Method for the ICU was performed more often than requested on 63% of shifts (5,146 of 8,166) at VUMC and on 8% (151 of 1871) of shifts at York-VA. Overall weighted-kappa between bedside nurses and references raters for the Richmond Agitation-Sedation Scale were 0.89 (95% confidence interval, 0.88 to 0.92) at VUMC and 0.77 (95% confidence interval, 0.72 to 0.83) at York-VA. Overall agreement (kappa) between bedside nurses and reference raters using the Confusion Assessment Method for the ICU was 0.92 (95% confidence interval, 0.90-0.94) at VUMC and 0.75 (95% confidence interval, 0.68-0.81) at York-VA. The two most-often-cited barriers to implementation were physician buy-in and time. CONCLUSIONS: With minimal training, the compliance of bedside nurses using sedation and delirium instruments was excellent. Agreement of data from bedside nurses and a reference-standard rater was very high for both the sedation scale and the delirium assessment over the duration of this process-improvement project.

The Vanderbilt Professional Nursing Practice Program, part 2: Integrating a professional advancement and performance evaluation system.

Developing a performance-based advancement system requires evaluation tools that capture essential behaviors and outcomes reflective of key nursing functions. To ensure relevance to clinical practice and enhance buy-in from nursing staff, the behaviors and outcomes were defined by a broad cross-section of nursing staff and administrators. The first article (September 2003) in this 3-part series described the foundation for and the philosophical background of the Vanderbilt Professional Nursing Practice Program (VPNPP), the career advancement program under way at Vanderbilt University Medical Center. This second article describes the development of the evaluation tools used in the VPNPP, the implementation and management of this new system, program evaluation, and improvements since the inception of the program. Additionally, the authors present the challenges and lessons we learned in development and implementation of a dynamic evaluation system that supports our career advancement program. The process of advancing within the program will be described in part 3.