Clinical outcomes of baloxavir versus oseltamivir in patients hospitalized with influenza A.

OBJECTIVES: To date, clinical trials evaluating baloxavir have excluded patients hospitalized with influenza infection and therefore this study sought to evaluate the efficacy of baloxavir in inpatients with influenza A. METHODS: This study was a multicentre, retrospective chart review of adult patients admitted to the hospital within the Yale New Haven Health System who received oseltamivir or baloxavir for the treatment of influenza A. Patients were screened for inclusion between January 2018 and April 2018 in the oseltamivir group, while patients in the baloxavir group were screened for inclusion between January 2019 and April 2019. Influenza A diagnosis was confirmed by RT-PCR using a nasopharyngeal swab specimen. RESULTS: Of the 2392 patients assessed, 790 met the inclusion criteria. There were 359 patients who received baloxavir and 431 patients who received oseltamivir. Patients who received baloxavir were younger compared with those who received oseltamivir [median = 69 (IQR = 57-81) years versus 77 (IQR = 62-86) years; P < 0.001]. Patients who received baloxavir had no significant difference in hospital length of stay [median = 4 (IQR = 3-6) days versus 5 (IQR = 3-6) days; P = 0.45] or 30 day all-cause mortality [12 (3.3%) versus 26 (6%); P = 0.079] compared with those who received oseltamivir. However, patients who received baloxavir had a significantly faster time to hypoxia resolution [median = 51.7 (IQR = 25.3-89.3) h versus 72 (IQR = 37.5-123) h; P < 0.001]. CONCLUSIONS: The results of this study support the use of baloxavir for the treatment of influenza A in hospitalized patients with the potential benefit of a faster time to resolution of hypoxia.

Experience with integrating pharmacist documenters on cardiac arrest teams to improve quality.

OBJECTIVES: To determine if adding a clinical pharmacist to the cardiac arrest team in a documenter role improves completeness of documentation and quality of advanced cardiovascular life support (ACLS). SETTING: A 1541-bed, tertiary care, academic medical center with an integrated clinical pharmacy practice model. PRACTICE DESCRIPTION: In 2012, we identified documentation of resuscitation activities during cardiac arrest events and compliance with published ACLS guidelines as opportunities for systematic quality improvement at our tertiary care academic medical center. Although clinical pharmacists provided pharmacotherapy support through active participation on multidisciplinary patient care rounds, pharmacists were not routinely accountable for care provided during cardiac arrest events. PRACTICE INNOVATION: We integrated pharmacists on the cardiac arrest team in the unique role of documenter and pharmacotherapy consultant. The pharmacist documenter was responsible for recording all activities (e.g., medication administered, endotracheal intubation, vital signs), providing real-time quality assurance during the event, and assisting with any clinical or operational needs of the team. Participating pharmacists received didactic lectures, practical assessments, and a written examination to ensure baseline competency in ACLS and teamwork principles. EVALUATION: Using a before-and-after study design, we conducted a retrospective chart review to evaluate our pilot program. All cardiac arrest events requiring activation of the cardiac arrest team from January 2012 through December 2013 were included (n = 80). RESULTS: Pharmacists attended all cardiac arrest team events in the postintervention period during the scheduled coverage hours. The percentage of forms with all documentation components complete increased from 0% at baseline to 28% postintervention (P = 0.002). ACLS compliance also increased from 8% preintervention to 31% postintervention (P = 0.024). CONCLUSION: Implementation of a dedicated pharmacist for documentation and pharmacotherapy consultation during cardiac arrest events is associated with improved documentation completeness and ACLS compliance. This was achieved without funding or additional pharmacist resources.

Major Publications in the Critical Care Pharmacotherapy Literature: 2021.

To summarize the most impactful articles relevant to the pharmacotherapy of critically ill adult patients published in 2021. DATA SOURCE: PubMed/MEDLINE. STUDY SELECTION: Randomized controlled trials, prospective studies, or systematic review/meta-analyses of adult critical care patients assessing a pharmacotherapeutic intervention and reporting clinical endpoints published between January 1, 2021, and December 31, 2021. DATA EXTRACTION: Candidate articles were organized by clinical domain based on the emerging themes from all studies. A modified Delphi process was applied to obtain consensus on the most impactful publication within each clinical domain based on overall contribution to scientific knowledge and novelty to the literature. DATA SYNTHESIS: The search revealed 830 articles, of which 766 were excluded leaving 64 candidate articles for the Delphi process. These 64 articles were organized by clinical domain including: emergency/neurology, cardiopulmonary, nephrology/fluids, infectious diseases, metabolic, immunomodulation, and nutrition/gastroenterology. Each domain required the a priori defined three Delphi rounds. The resultant most impactful articles from each domain included five randomized controlled trials and two systematic review/meta-analyses. Topics studied included sedation during mechanical ventilation, anticoagulation in COVID-19, extended infusion beta-lactams, interleukin-6 antagonists in COVID-19, balanced crystalloid resuscitation, vitamin C/thiamine/hydrocortisone in sepsis, and promotility agents during enteral feeding. CONCLUSIONS: This synoptic review provides a summary and perspective of the most impactful articles relevant to the pharmacotherapy of critically ill adults published in 2021.

Corticosteroid use in ARDS and its application to evolving therapeutics for coronavirus disease 2019 (COVID-19): A systematic review.

Data regarding the use of corticosteroids for treatment of acute respiratory distress syndrome (ARDS) are conflicting. As the coronavirus disease 2019 (COVID-19) pandemic progresses, more literature supporting the use of corticosteroids for COVID-19 and non-COVID-19 ARDS have emerged. Glucocorticoids are proposed to attenuate the inflammatory response and prevent progression to the fibroproliferative phase of ARDS through their multiple mechanisms and anti-inflammatory properties. The purpose of this systematic review was to comprehensively evaluate the literature surrounding corticosteroid use in ARDS (non-COVID-19 and COVID-19) in addition to a narrative review of clinical considerations of corticosteroid use in these patient populations. OVID Medline and EMBASE were searched. Randomized controlled trials evaluating the use of corticosteroids for COVID-19 and non-COVID-19 ARDS in adult patients on mortality outcomes were included. Risk of bias was assessed with the Risk of Bias 2.0 tool. There were 388 studies identified, 15 of which met the inclusion criteria that included a total of 8877 patients. The studies included in our review reported a mortality benefit in 6/15 (40%) studies with benefit being seen at varying time points of mortality follow-up (ICU survival, hospital, and 28 and 60 days) in the COVID-19 and non-COVID-19 ARDS studies. The two non-COVID19 trials assessing lung injury score improvements found that corticosteroids led to significant improvements with corticosteroid use. The number of mechanical ventilation-free days significantly were found to be increased with the use of corticosteroids in all four studies that assessed this outcome. Corticosteroids are associated with improvements in mortality and ventilator-free days in critically ill patients with both COVID-19 and non-COVID-19 ARDS, and evidence suggests their use should be encouraged in these settings. However, due to substantial differences in the corticosteroid regimens utilized in these trials, questions still remain regarding the optimal corticosteroid agent, dose, and duration in patients with ARDS.

Analgesia and Sedation Strategies in Mechanically Ventilated Adults with COVID-19.

Evidence-based management of analgesia and sedation in COVID-19-associated acute respiratory distress syndrome remains limited. Non-guideline recommended analgesic and sedative medication regimens and deeper sedation targets have been employed for patients with COVID-19 due to exaggerated analgesia and sedation requirements with extended durations of mechanical ventilation. This, coupled with a desire to minimize nurse entry into COVID-19 patient rooms, marked obesity, altered end-organ function, and evolving medication shortages, presents numerous short- and long-term challenges. Alternative analgesic and sedative agents and regimens may pose safety risks and require judicious bedside management for appropriate use. The purpose of this commentary is to provide considerations and solutions for designing safe and effective analgesia and sedation strategies for adult patients with considerable ventilator dyssynchrony and sedation requirements, such as COVID-19.

Low-dose corticosteroids in septic shock: Has the pendulum shifted?

PURPOSE: The utility of low-dose corticosteroids in septic shock is reviewed. SUMMARY: Low-dose corticosteroids are suggested as treatment for septic shock patients who remain hemodynamically unstable despite adequate fluid resuscitation and vasopressor therapy. However, the risks and benefits of corticosteroids are unclear in this patient population. Previous multicenter trials have yielded conflicting results on the survival benefits of corticosteroids. The recently published Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock (ADRENAL) and Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trials provide valuable but opposing insight into this ongoing debate. Discordant findings related to mortality in these trials are likely related to differences in study design, corticosteroid regimen, and baseline characteristics among enrolled patients. The utility of adding fludrocortisone to hydrocortisone compared with using hydrocortisone alone is unclear. There does not appear to be an advantage to administering corticosteroids as a continuous infusion to reduce the rate of hyperglycemia or providing a taper to prevent rebound hypotension. CONCLUSION: The mortality benefit of corticosteroids appears to be greatest in septic shock patients with high vasopressor requirements, evidence of multiorgan failure, and primary lung infections. Corticosteroids consistently lead to a faster reversal of shock and may shorten the duration of mechanical ventilation. Corticosteroids do not seem to increase the risk of superinfection at low doses but frequently lead to a higher frequency of hyperglycemia. We recommend the administration of corticosteroids to septic shock patients with escalating doses of vasopressors and evidence of multiorgan dysfunction.

Structure-activity relationships for vitamin D3-based aromatic a-ring analogues as hedgehog pathway inhibitors.

A structure-activity relationship study for a series of vitamin D3-based (VD3) analogues that incorporate aromatic A-ring mimics with varying functionality has provided key insight into scaffold features that result in potent, selective Hedgehog (Hh) pathway inhibition. Three analogue subclasses containing (1) a single substitution at the ortho or para position of the aromatic A-ring, (2) a heteroaryl or biaryl moiety, or (3) multiple substituents on the aromatic A-ring were prepared and evaluated. Aromatic A-ring mimics incorporating either single or multiple hydrophilic moieties on a six-membered ring inhibited the Hh pathway in both Hh-dependent mouse embryonic fibroblasts and cultured cancer cells (IC50 values 0.74-10 µM). Preliminary studies were conducted to probe the cellular mechanisms through which VD3 and 5, the most active analogue, inhibit Hh signaling. These studies suggested that the anti-Hh activity of VD3 is primarily attributed to the vitamin D receptor, whereas 5 affects Hh inhibition through a separate mechanism.

Targeting the fibroblast growth factor receptors for the treatment of cancer.

Receptor tyrosine kinases (RTKs) are transmembrane proteins that play a critical role in stimulating signal transduction cascades to influence cell proliferation, growth, and differentiation and they have also been shown to promote angiogenesis when they are up-regulated or mutated. For this reason, their dysfunction has been implicated in the development of human cancer. Over the past decade, much attention has been devoted to developing inhibitors and antibodies against several classes of RTKs, including vascular endothelial growth factor receptors (VEGFRs), epidermal growth factor receptors (EGFRs), and platelet-derived growth factor receptors (PDGFRs). More recently, interest in the fibroblast growth factor receptor (FGFR) class of RTKs as a drug target for the treatment of cancer has emerged. Signaling through FGFRs is critical for normal cellular function and their dysregulation has been linked to various malignancies such as breast and prostate cancer. This review will focus on the current state of both small molecules and antibodies as FGFR inhibitors to provide insight into their development and future potential as anti-cancer agents.