Major Publications in the Critical Care Pharmacotherapy Literature: 2022.

OBJECTIVES: A number of trials related to critical care pharmacotherapy were published in 2022. We aimed to summarize the most influential publications related to the pharmacotherapeutic care of critically ill patients in 2022. DATA SOURCES: PubMed/Medical Literature Analysis and Retrieval System Online and the Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update. STUDY SELECTION: Randomized controlled trials, prospective studies, or systematic review/meta-analyses of adult critically ill patients assessing a pharmacotherapeutic intervention and reporting clinical endpoints published between January 1, 2022, and December 31, 2022, were included in this article. DATA EXTRACTION: Articles from a systematic search and the Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update were included and stratified into clinical domains based upon consistent themes. Consensus was obtained on the most influential publication within each clinical domain utilizing an a priori defined three-round modified Delphi process with the following considerations: 1) overall contribution to scientific knowledge and 2) novelty to the literature. DATA SYNTHESIS: The systematic search and Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update yielded a total of 704 articles, of which 660 were excluded. The remaining 44 articles were stratified into the following clinical domains: emergency/neurology, cardiovascular, gastroenterology/fluids/nutrition, hematology, infectious diseases/immunomodulation, and endocrine/metabolic. The final article selected from each clinical domain was summarized following a three-round modified Delphi process and included three randomized controlled trials and three systematic review/meta-analyses. Article topics summarized included dexmedetomidine versus other sedatives during mechanical ventilation, beta-blocker treatment in the critically ill, restriction of IV fluids in septic shock, venous thromboembolism prophylaxis in critically ill adults, duration of antibiotic therapy for Pseudomonas aeruginosa ventilator-associated pneumonia, and low-dose methylprednisolone treatment in severe community-acquired pneumonia. CONCLUSIONS: This concise review provides a perspective on articles published in 2022 that are relevant to the pharmacotherapeutic care of critically ill patients and their potential impact on clinical practice.

Toll-like receptor 1/2 stimulation induces elevated interleukin-8 secretion in polymorphonuclear leukocytes isolated from preterm and term newborn infants.

BACKGROUND: Neonatal neutrophil dysfunction contributes to inflammatory tissue damage in newborn infants. Toll-like receptors (TLRs) activate the innate immune response through recognition of pathogen-associated molecular patterns. Expression and function of TLRs by neonatal neutrophils has not well been characterized. OBJECTIVE: We hypothesized that, compared to polymorphonuclear leukocytes (PMNs) isolated from adults, neonatal PMNs isolated from either term or preterm infants express and release different levels of inflammatory cytokines and chemokines in response to stimulation with TLR1-9 agonists. METHODS: We stimulated PMNs isolated from preterm (n = 12) and term (n = 10) infants as well as adults (n = 10) with agonists recognized by TLRs1-9 and quantified chemokine and cytokine expression and secretion by ELISA and Luminex® multiplex quantification assay. RESULTS: Neonatal and adult PMNs stimulated with agonists recognized by TLRs1-9 differentially secrete inflammatory products. Signaling via TLR2 heterodimers is a potent mechanism for release of interleukin-8, a critical proinflammatory chemokine, by neonatal PMNs--a previously unrecognized facet of neonatal inflammation. Following TLR1/2 (PAM3CSK4) stimulation, interleukin-8 secretion by neonatal PMNs, whether term or preterm, substantially exceeds that of adult PMNs assayed in parallel. CONCLUSIONS: These studies provide new insights relevant to the inflammatory biology of neonates, both term and preterm, and implicate exaggerated PMN recruitment in neonatal syndromes of dysregulated inflammation such as necrotizing enterocolitis or neonatal chronic lung disease.

Impaired neutrophil extracellular trap (NET) formation: a novel innate immune deficiency of human neonates.

Neutrophils are highly specialized innate effector cells that have evolved for killing of pathogens. Human neonates have a common multifactorial syndrome of neutrophil dysfunction that is incompletely characterized and contributes to sepsis and other severe infectious complications. We identified a novel defect in the antibacterial defenses of neonates: inability to form neutrophil extracellular traps (NETs). NETs are lattices of extracellular DNA, chromatin, and antibacterial proteins that mediate extracellular killing of microorganisms and are thought to form via a unique death pathway signaled by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-generated reactive oxygen species (ROS). We found that neutrophils from term and preterm infants fail to form NETs when activated by inflammatory agonists-in contrast to leukocytes from healthy adults. The deficiency in NET formation is paralleled by a previously unrecognized deficit in extracellular bacterial killing. Generation of ROSs did not complement the defect in NET formation by neonatal neutrophils, as it did in adult cells with inactivated NADPH oxidase, demonstrating that ROSs are necessary but not sufficient signaling intermediaries and identifying a deficiency in linked or downstream pathways in neonatal leukocytes. Impaired NET formation may be a critical facet of a common developmental immunodeficiency that predisposes newborn infants to infection.