Challenges in Sedation Management in Critically Ill Patients with COVID-19: a Brief Review.

Purpose of Review: To highlight the challenges associated with providing sedation and analgesia to critically ill patients with coronavirus disease 2019 (COVID-19) and also understand the pathophysiological alterations induced by the disease process as well as the logistical difficulties encountered by providers caring for these patients. We also discuss the rationale and risks associated with the use of common sedative agents specifically within the context of COVID-19 and provide evidence-based management strategies to help manage sedation and analgesia in such patients. Recent Findings: A significant proportion of patients with COVID-19 require intensive care and mechanical ventilation, thus requiring sedation and analgesia. These patients tend to require higher doses of sedative medications and often for long periods of time. Most of the commonly used sedative and analgesic agents carry unique risks that should be considered within the context of the unique pathophysiology of COVID-19, the logistical issues the disease poses, and the ongoing drug shortages. Summary: With little attention being paid to sedation practices specific to patients with COVID-19 in critical care literature and minimal mention in national guidelines, there is a significant gap in knowledge. We review the existing literature to discuss the unique challenges that providers face while providing sedation and analgesia to critically ill patients with COVID-19 and propose evidence-based management strategies.

Oncolytic HSV Therapy Modulates Vesicular Trafficking Inducing Cisplatin Sensitivity and Antitumor Immunity.

PURPOSE: Here we investigated the impact of oncolytic herpes simplex virus (HSV) treatment on cisplatin sensitivity of platinum-resistant ovarian cancer, and the impact of the combination on immunotherapy. EXPERIMENTAL DESIGN: Therapeutic efficacy of the combination was assessed in platinum-resistant human and murine ovarian cancer peritoneal metastatic mouse models (n = 9-10/group). RNA sequencing along with flow cytometry of splenocytes from treated mice was employed to examine the effect of antitumor immune response (n = 3/group). Anti-PD-1 antibody was performed to evaluate impact on checkpoint inhibition in vivo. RESULTS: Gene Ontology pathway analysis uncovered disruption of cellular extracellular vesicle (EV)-related pathways in infected cells (FDR = 2.97E-57). Mechanistically, we identified reduced expression of transporters expressed on EV implicated in cisplatin efflux. The increased cisplatin retention led to increased cisplatin-DNA adducts, which resulted in micronuclei and the subsequent activation of cGAS-STING pathway with a significant activation of innate immune cells and translated to an increase in antitumor immunity and efficacy. In mice bearing platinum-resistant ovarian cancer, we also observed a feedback induction of PD-L1 on tumor cells, which sensitized combination-treated mice to anti-PD-1 immune checkpoint therapy. CONCLUSIONS: To our knowledge, this is the first report to show HSV-induced cisplatin retention in infected cells. The consequential increased damaged DNA was then expelled from cells as micronuclei which resulted in induction of inflammatory responses and education of antitumor immunity. The combination therapy also created an environment that sensitized tumors to immune checkpoint therapy.