Sepsis, September 20 edition

In mice, chronic restraint stress aggravated mortality, systemic inflammation, and immune imbalance during endotoxemia. Chemogenetic activation of the medial prefrontal cortex–dorsal motor nucleus of the vagus pathway restored splenic autonomic signaling, improved neurotransmitter balance, reduced inflammation, enhanced regulatory T-cell activity, and improved survival; these effects depended substantially on splenic sympathetic signaling and α7 nicotinic acetylcholine receptor-mediated macrophage–T-cell communication.

Impact: This study moves beyond the epidemiologic observation that psychological stress worsens sepsis by defining a specific brain–autonomic–spleen circuit and testing its causal manipulability. It provides a mechanistic basis for neuromodulatory approaches to stress-associated immune dysfunction in sepsis.

Clinical Implications: The findings support investigation of cortical, vagal, splenic sympathetic, or α7 nicotinic acetylcholine receptor-targeted neuromodulation as adjunctive strategies for stress-associated sepsis. Translation requires validation in clinically relevant polymicrobial sepsis models and human studies before clinical application.

Future Directions: Future studies should validate the circuit in polymicrobial and clinically treated sepsis models, define the timing and dose of neuromodulation, assess sex and age effects, and determine whether stress-related neural or autonomic biomarkers identify patients most likely to benefit.

In resuscitated rats with cecal ligation and puncture sepsis, hypertonic sodium lactate improved mesenteric perfusion and reduced plasma tumor necrosis factor-alpha without altering systemic arterial pressure or cardiac function measurements. Ex vivo, lactate dose-dependently restored impaired mesenteric artery vasoconstriction after lipopolysaccharide exposure or glucose deprivation, suggesting a direct vascular and metabolic mechanism.

Impact: The study addresses a major unmet need in sepsis by targeting microcirculatory dysfunction rather than only systemic hemodynamics. Its combined in vivo and ex vivo findings provide a mechanistic rationale for clinical evaluation of hypertonic sodium lactate as a resuscitation fluid.

Clinical Implications: Hypertonic sodium lactate may become a candidate resuscitation fluid for patients with sepsis-associated microcirculatory dysfunction, particularly when impaired tissue perfusion persists despite restoration of systemic pressure. Clinical trials should first establish dosing, safety, acid–base effects, and effects on organ failure and mortality.

Future Directions: The next steps are dose-finding and safety studies, comparison with balanced crystalloids and other hypertonic solutions, evaluation in both sexes and larger-animal models, and randomized clinical trials focused on microcirculatory endpoints, organ dysfunction, and mortality.

This first national Irish analysis identified 4,442 pediatric sepsis admissions from 2020 to 2025, including 1,364 hospital-onset and 3,078 community-onset episodes. Hospital-onset sepsis was associated with markedly higher critical care admission and mortality rates than community-onset sepsis, while comorbidities strongly predicted adverse outcomes among community-onset cases; severe outcomes also occurred in children without documented comorbidity.

Impact: The study provides nationally representative evidence for pediatric sepsis burden and distinguishes hospital-onset from community-onset disease, supporting targeted prevention and escalation pathways. Its finding that previously healthy children can develop severe outcomes is important for avoiding overly narrow risk-based recognition strategies.

Clinical Implications: Hospital-onset pediatric sepsis should prompt heightened surveillance and rapid critical care assessment, especially among neonates. Comorbidity-based risk stratification may help prioritize community-onset patients, but screening and escalation pathways should also include children without documented comorbidities.

Future Directions: Future work should validate coding-based findings with clinical chart review, examine pathogen and treatment-level variables, evaluate preventable hospital-onset risk factors, and develop prospective early-warning and escalation tools that do not exclude previously healthy children.