Evaluation of Delirium in Critically Ill Patients Prescribed Melatonin or Ramelteon.

BACKGROUND: An impaired sleep-wake cycle may be one factor that affects the development of delirium in critically ill patients. Several small studies suggest that exogenous melatonin or ramelteon may decrease the incidence and/or duration of delirium. OBJECTIVE: To compare the effect of prophylactic administration of melatonin, ramelteon, or no melatonin receptor agonist on the development of delirium in the intensive care unit (ICU). METHODS: This was a single-center, retrospective, observational cohort study of nondelirious patients in the ICU who received melatonin, ramelteon, or no melatonin receptor agonist. The primary end point was the incidence of delirium. Secondary end points included assessments of daily level of sedation and daily utilization of antipsychotic, sedative, and opioid agents. RESULTS: No difference was observed in the incidence of delirium among the melatonin, ramelteon, and placebo cohorts (18.7% vs 14.3% vs 13.8%; P = 0.77). A difference was observed in the rate of agitation and sedation among the 3 groups, with the greatest observed in the melatonin cohort. Additionally, there was a difference in the use of propofol, dexmedetomidine, and opioids. Overall, there was no difference in clinical outcomes, including duration of mechanical ventilation and ICU or hospital length of stay. CONCLUSION AND RELEVANCE: Therapy with melatonin, ramelteon, and no melatonin receptor agonist resulted in similar rates of delirium in a mixed ICU population. Despite significant differences in agitation, sedation, and medication utilization, there was no differences in the clinical outcomes evaluated.

Evaluation of Dexmedetomidine Withdrawal and Management After Prolonged Infusion.

PURPOSE: Dexmedetomidine is often used for longer than its labeled indication of 24 hours, raising concerns for potential withdrawal. Data are limited regarding this syndrome in adult patients. This study aimed to further characterize dexmedetomidine withdrawal in critically ill adult patients after prolonged use. METHODS: This was an institutional review board-approved, single-center, retrospective chart review conducted at a tertiary academic medical center. Adult intensive care unit (ICU) patients on dexmedetomidine for ≥72 hours in 2019 were screened for inclusion. Exclusion criteria were interruption of dexmedetomidine for >6 hours, indications for dexmedetomidine other than sedation, or patients with neurological or burn injury. The major end point was the incidence of dexmedetomidine withdrawal, defined as meeting ≥2 of the following criteria within 24 hours of discontinuation: newly positive Confusion Assessment Method for ICU, Richmond Agitation Sedation Scale score of ≥+2, hypertension, and tachycardia. Minor end points were incidence of individual withdrawal signs as previously described, additional sedatives or antipsychotics required, dose and duration of dexmedetomidine infusion, length of ventilation, ICU and hospital length of stay, and new onset of the following: fever, vomiting, loose stools/diarrhea, diaphoresis, or seizure. FINDINGS: Of the 152 patients included, dexmedetomidine withdrawal occurred in 54 patients (35.5%). Rebound hypertension was the most common withdrawal sign (47 patients [87.0%]). In the withdrawal group, significantly more patients required additional ß-blockers (29 [53.7%] vs 10 [10.2%]; P < 0.01), were reinitiated on dexmedetomidine (16 [29.6%] vs 10 [10.2%]; P < 0.01), and required a start or increased dose of clonidine (6 [11.1%] vs 3 [3.1%]; P = 0.04). There was no significant difference in the cumulative dose or duration of dexmedetomidine between the groups. Length of ventilation was longer in the withdrawal group (171 hours [83.7-280.8 hours] vs 159 hours [149.0-335.7 hours]; P < 0.01), but there was no difference in ICU or hospital length of stay. IMPLICATIONS: Prolonged use of dexmedetomidine was associated with withdrawal syndrome in 35.5% of patients in our study. Larger trials are needed to confirm the risk factors for dexmedetomidine withdrawal and identify measures to prevent withdrawal.

The Role of Double and Triple Therapy with Direct Oral Anticoagulants in Coronary Artery Disease, Peripheral Artery Disease, and Stroke.

PURPOSE: Combining antiplatelet and anticoagulant therapy is often necessary in clinical practice. However, there is limited literature on tolerability and efficacy for triple therapy with the newer direct oral anticoagulants (DOACs). The objective of this study is to characterize the discharge prescribing practice of double versus triple antithrombotic therapy with a DOAC at a large, tertiary academic medical center. METHODS: In this retrospective, cross-sectional, observational study, patients were identified if they had received any combination of a DOAC, aspirin, and a P2Y12 inhibitor during an admission at our institution from June 1, 2015, to May 31, 2016. Patients were included in the analysis if they had any indication for anticoagulation and antiplatelet therapies and were discharged from the hospital with prescriptions for a DOAC and single or dual antiplatelet agents (aspirin and/or P2Y12 inhibitor). Patients were excluded if they had an unclear indication for antiplatelet therapy. Patient characteristics and 6-month efficacy and tolerability outcomes were collected via review of the electronic medical record. FINDINGS: A total of 367 patients were included in this analysis. Most patients at our institution who required both antiplatelet and anticoagulant agents were discharged on a regimen of aspirin and a DOAC. Patients across all groups most commonly received antiplatelet therapy for coronary artery disease and acute coronary syndrome-related events, whereas they received anticoagulation for stroke prophylaxis in atrial fibrillation. Within 6 months of discharge, there were 16 bleeding-related readmissions in the DOAC-aspirin group, 1 in the DOAC-P2Y12 group, and 0 in the triple therapy group. IMPLICATIONS: This analysis found that varying combinations of antiplatelet agents and anticoagulants are used, depending on clinical indications. Further studies are needed that focus on patients with indications for dual antiplatelet therapy and anticoagulation to compare double and triple therapy strategies for efficacy and bleeding risk.

Selective inhibition of spleen tyrosine kinase (SYK) with a novel orally bioavailable small molecule inhibitor, RO9021, impinges on various innate and adaptive immune responses: implications for SYK inhibitors in autoimmune disease therapy.

INTRODUCTION: Spleen tyrosine kinase (SYK) is a key integrator of intracellular signals triggered by activated immunoreceptors, including Bcell receptors (BCR) and Fc receptors, which are important for the development and function of lymphoid cells. Given the clinical efficacy of Bcell depletion in the treatment of rheumatoid arthritis and multiple sclerosis, pharmacological modulation of Bcells using orally active small molecules that selectively target SYK presents an attractive alternative therapeutic strategy. METHODS: A SYK inhibitor was developed and assayed in various in vitro systems and in the mouse model of collagen-induced arthritis (mCIA). RESULTS: A novel ATP-competitive inhibitor of SYK, 6-[(1R,2S)-2-Amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide, designated RO9021, with an adequate kinase selectivity profile and oral bioavailability, was developed. In addition to suppression of BCR signaling in human peripheral blood mononuclear cells (PBMC) and whole blood, FcγR signaling in human monocytes, and FcϵR signaling in human mast cells, RO9021 blocked osteoclastogenesis from mouse bone marrow macrophages in vitro. Interestingly, Toll-like Receptor (TLR) 9 signaling in human Bcells was inhibited by RO9021, resulting in decreased levels of plasmablasts, immunoglobulin (Ig) M and IgG upon B-cell differentiation. RO9021 also potently inhibited type I interferon production by human plasmacytoid dendritic cells (pDC) upon TLR9 activation. This effect is specific to TLR9 as RO9021 did not inhibit TLR4- or JAK-STAT-mediated signaling. Finally, oral administration of RO9021 inhibited arthritis progression in the mCIA model, with observable pharmacokinetics (PK)-pharmacodynamic (PD) correlation. CONCLUSIONS: Inhibition of SYK kinase activity impinges on various innate and adaptive immune responses. RO9021 could serve as a starting point for the development of selective SYK inhibitors for the treatment of inflammation-related and autoimmune-related disorders.