Daily Sepsis Research Analysis
Key advances span mechanistic neuroimmune control of inflammation, bedside evaluation of ventilatory strategies, and prognostic body composition markers. Selective vagal afferent stimulation engaged an adrenal epinephrine–dependent brain–lung anti-inflammatory circuit. Clinically, the recruitment-to-inflation ratio underperformed CT for assessing lung recruitability in ARDS, while CT-derived skeletal muscle mass strongly associated with short- and long-term ICU mortality.
Summary
Key advances span mechanistic neuroimmune control of inflammation, bedside evaluation of ventilatory strategies, and prognostic body composition markers. Selective vagal afferent stimulation engaged an adrenal epinephrine–dependent brain–lung anti-inflammatory circuit. Clinically, the recruitment-to-inflation ratio underperformed CT for assessing lung recruitability in ARDS, while CT-derived skeletal muscle mass strongly associated with short- and long-term ICU mortality.
Research Themes
- Neuroimmune modulation to suppress sepsis-related lung inflammation
- Bedside assessment of lung recruitability versus imaging standards
- Body composition by CT as a prognostic biomarker in critical illness
Selected Articles
1. Inhibition of acute lung inflammation by a neuroimmune circuit induced by vagal nerve stimulation.
Selective afferent VNS suppressed TLR7-driven macrophage activation and neutrophil lung recruitment via an adrenal epinephrine–dependent pathway. It engaged nucleus tractus solitarius and rostral ventrolateral medulla; inhibiting these sympathetic control regions abrogated protection. Findings delineate a brain–adrenal–lung anti-inflammatory circuit relevant to sepsis-related lung injury.
Impact: This work uncovers a defined neuroimmune circuit whereby afferent VNS controls lung inflammation through adrenal epinephrine and specific brainstem nuclei, advancing mechanistic understanding and neuromodulation strategies.
Clinical Implications: Supports exploration of afferent-selective VNS as an adjunct to mitigate inflammatory lung injury in sepsis and viral pneumonitis; parameter optimization and patient selection will be key.
Key Findings
- Only selective vagal afferent stimulation inhibited TLR7-driven macrophage activation and neutrophil recruitment to the lung.
- Anti-inflammatory protection required adrenal gland–derived epinephrine; adrenalectomy or epinephrine inhibition abolished VNS benefits.
- Afferent VNS activated the nucleus tractus solitarius and rostral ventrolateral medulla; inhibiting neuronal activity in this region negated VNS efficacy.
Methodological Strengths
- Selective neural pathway interrogation (afferent vs efferent VNS) with physiological readouts
- Causal validation via adrenalectomy and targeted brainstem neuronal inhibition
Limitations
- Preclinical animal study; clinical translatability and safety of afferent-selective VNS remain to be established
- Incomplete delineation of downstream β-adrenergic receptor subtype involvement
Future Directions: Test afferent-selective VNS in translational models and early-phase trials for sepsis-induced lung injury; map β-adrenergic subtype contributions and optimize stimulation parameters.
Vagus nerve stimulation (VNS) has been shown to limit immune cell activity across several pathologies ranging from sepsis to auto-immune diseases. While stimulation of vagal efferent neurons is known to reduce maladaptive host responses during endotoxemia, only selective vagal afferent neuron stimulation inhibited TLR7-induced macrophage activation and neutrophil recruitment to the lung. These anti-inflammatory actions are dependent on adrenal gland-derived epinephrine, as adrenalectomy or inhibition of epinephrine production eliminated the protection afforded by VNS. Selective afferent VNS induced activation in the nucleus tractus solitarius and the rostral ventrolateral medulla. Inhibition of neuronal activity in this brain region that controls peripheral sympathetic nervous system activity rendered VNS ineffective. Activation of the β
2. Exploring the association between computed tomography (CT)-derived skeletal muscle mass and short- and long-term mortality in critically ill patients: a systematic review and meta-analysis.
Across 35 studies (n=9366), low CT-derived lumbar skeletal muscle mass strongly associated with higher short-term mortality (OR≈2.33) and also predicted long-term mortality in critical illness cohorts including sepsis. Findings support CT muscle metrics (e.g., L3 skeletal muscle index) as pragmatic prognostic biomarkers.
Impact: Synthesizes heterogeneous ICU evidence to establish CT-derived skeletal muscle mass as a robust prognostic marker, facilitating risk stratification and potential interventional targeting.
Clinical Implications: Admission or early ICU CT can inform mortality risk via L3 muscle metrics, guiding nutrition, mobilization, and goals-of-care discussions in sepsis and other critical illnesses.
Key Findings
- Low CT-derived skeletal muscle mass (L3 area/index) was associated with increased short-term mortality (pooled OR ≈ 2.33).
- Low muscle mass also predicted long-term mortality (90 days to 1 year) across multiple cohorts.
- Studies were predominantly retrospective and heterogeneous, underscoring the need for standardized measurement and thresholds.
Methodological Strengths
- PRISMA-guided systematic review with meta-analysis of 35 studies
- Large aggregated sample (n=9366) spanning diverse ICU populations
Limitations
- Predominantly retrospective single-centre studies with methodological heterogeneity
- Variable definitions and cutoffs for low skeletal muscle mass limit comparability
Future Directions: Develop and validate standardized CT muscle measurement protocols and thresholds; test whether targeted nutrition/rehabilitation modifies risk in randomized trials.
BACKGROUND: Low skeletal mass, often present at hospital admission, has been associated with poor prognoses. AIM: To explore the association between computed tomography (CT)-derived skeletal muscle mass at the lumbar level and short- and long-term mortality in critically ill patients. METHODS: Following PRISMA 2020 guidelines, we included studies on critically ill adults (≥ 18 years) hospitalized in intensive care units (ICU) that measured CT-derived skeletal muscle mass at the lumbar vertebral level within ± 7 days of ICU admission. The primary outcome was mortality, categorized as short-term (including ICU, hospital, 28- and 30-day mortality) and long-term (> 30 days) mortality. MEDLINE and Embase databases were searched without date restrictions. Study screening was performed using Rayyan, data extraction was guided by a custom-designed tool, and quality assessment was performed using the JBI Cohort Study Checklist. A meta-analysis was conducted, focusing on studies that reported short- and long-term mortality among patients with preserved and reduced skeletal muscle. A prevalence meta-analysis was also performed for studies that reported the size of subgroups with low muscle mass. RESULTS: Out of 1248 unique records, 35 studies met the inclusion criteria, involving 9366 participants. The majority were retrospective, single-centre studies conducted on four continents and included heterogeneous populations such as patients with sepsis, COVID-19 and trauma. Sample sizes ranged from 36 to 939, with a wide age range, from 40 to 70 s, and a predominance of male patients (62%). Skeletal mass was most commonly reported as skeletal muscle index at the third lumbar vertebra. Studies reported mainly short-term mortality on day 28 or 30. Long-term mortality, measured at 90 days, 6 months, and 1 year, was evaluated in 11 studies. Meta-analyses revealed that low skeletal muscle mass area and index were significantly associated with increased risks of both short (OR = 2.33, CI 1.90-2.87, I
3. Diagnostic performance of the recruitment-to-inflation ratio to assess lung recruitability by PEEP in ARDS. a computed tomography study.
In a prospective ARDS cohort, the R/I ratio showed poor overall diagnostic performance against CT-defined recruitability. However, an R/I threshold <0.57 reliably identified low recruitability except in focal ARDS, informing cautious application of PEEP strategies.
Impact: Provides CT-validated evidence on the limits and potential threshold utility of the R/I ratio, a widely discussed bedside tool for PEEP titration.
Clinical Implications: R/I ratio should not be used alone to guide PEEP in ARDS; values <0.57 may help identify low recruiters (non-focal phenotypes), but imaging or other confirmatory methods remain important.
Key Findings
- R/I ratio had poor diagnostic performance versus CT-defined recruitability in a population with low recruitment potential.
- An R/I threshold <0.57 reliably identified low recruitability provided ARDS was not focal.
- Technical limitations impacted feasibility: 14% excluded for suspected air leaks and 2% for high airway opening pressure.
Methodological Strengths
- Prospective design with CT as gold standard comparator
- Standardized ventilator-based R/I measurement at two PEEP levels
Limitations
- Single-center study with relatively small sample size after exclusions
- Predominance of low recruiters and exception for focal ARDS limit generalizability
Future Directions: Validate thresholds across ARDS phenotypes and mixed recruitability populations; integrate R/I with imaging or EIT-based metrics for multimodal PEEP titration.
BACKGROUND: The recruitment-to-inflation (R/I) ratio is a new bedside tool with potential to evaluate lung recruitability by positive end-expiratory pressure (PEEP) but was only validated using pressure-volume curves and the optimal threshold separating low and high recruiters by PEEP is not precisely known. The aim of the study is to evaluate the diagnostic performance of the R/I ratio using computed tomography (CT) as a gold standard in patients with acute respiratory distress syndrome (ARDS). METHODS: This study is a single-center prospective observational study performed on adults ARDS patients under invasive mechanical ventilation. The R/I ratio was measured with the ventilator, and low-dose CT scans were acquired at PEEP 15 and 5 cmH RESULTS: Fifty patients were included, and eight patients were secondarily excluded (7/50 [14%] for suspected air leaks, and 1/50 [2%] for airway opening pressure > 15 cmH CONCLUSIONS: In a population of ARDS patients with low recruitment potential, the R/I ratio had a poor diagnostic performance to predict lung recruitability, but R/I ratio values below 0.57 reliably identified ARDS patients with low recruitability, provided they did not present focal ARDS.