Daily ReportOct 3, 2026
Sepsis, October 3 edition
We read 5 papers and selected 3.
Summary
The strongest clinical evidence comes from the TRICYCLE randomized trial, which found that early combined vasopressor therapy improved renin, lactate, and SOFA trajectories and reduced tachyarrhythmias, although mortality was unchanged in this underpowered phase II study. A registered systematic review identified major translational weaknesses in sepsis capillary-leak research, while a porcine single-nucleus transcriptomic study provided mechanistic evidence that early sepsis rapidly rewires neurovascular-unit signaling and may disrupt the blood-brain barrier.
Research Themes
- Early multimodal hemodynamic treatment in septic shock
- Translational validity and methodological quality of capillary-leak research
- Neurovascular-unit inflammation and blood-brain barrier dysfunction in sepsis
Selected Articles
1. Early multimodal vasopressor strategy in septic shock: results of the TRICYCLE randomized controlled trial.
In this phase II randomized trial of 79 patients with septic shock, early simultaneous administration of angiotensin II, vasopressin, and norepinephrine produced faster declines in plasma renin and lactate and greater SOFA-score improvement than stepwise vasopressor escalation. Tachyarrhythmias were substantially less frequent, but ICU and 28-day mortality did not differ significantly.
Impact: The study directly tests a physiologically coherent treatment strategy for the multifactorial vasoplegia of septic shock and identifies clinically measurable benefits beyond blood-pressure support. Its negative mortality result appropriately defines the need for a larger patient-centered trial rather than supporting premature practice change.
Clinical Implications: Early multimodal vasopressor therapy may be considered an investigational strategy in refractory septic shock, particularly when rapid catecholamine reduction or control of vasoplegia is desired. The findings do not establish a mortality benefit and should not replace guideline-based norepinephrine-centered resuscitation outside appropriately monitored protocols or clinical trials.
Key Findings
- The intervention group had a faster decline in plasma renin concentrations over 72 hours: 2.61% per hour versus 1.67% per hour in controls (p=0.015).
- Lactate declined faster in the multimodal group: 1.53% per hour versus 1.01% per hour (p=0.006), and SOFA score decreased by 3 versus 0 points at 72 hours (p=0.018).
- Tachyarrhythmias occurred in 15.6% versus 68.6% of patients, while ICU mortality and 28-day mortality were not significantly different.
Methodological Strengths
- Randomized controlled phase II design with prospective registration in ClinicalTrials.gov (NCT06155812).
- The trial evaluated mechanistic and clinically relevant outcomes, including plasma renin, lactate, SOFA score, vasopressor dose, arrhythmias, and mortality.
Limitations
- The sample size was small and the trial was explicitly not powered to detect mortality differences.
- The primary outcome was a physiological biomarker rather than a patient-centered outcome, and the additional norepinephrine-equivalent dose analysis was non-prespecified.
Future Directions: A larger, adequately powered, multicenter trial should test mortality, organ-support duration, renal outcomes, ischemic complications, and cost-effectiveness, with prespecified subgroup analyses based on vasoplegia severity and renin biology.
BACKGROUND: Given multifactorial mechanisms driving vasodilation in septic shock, there is a strong physiological rationale for early initiation of multiple vasopressors (angiotensin II, vasopressin and norepinephrine) with complementary mechanisms of action. Such an approach could more effectively counteract the complex pathophysiological processes characteristic of septic shock. Here we tested the physiological and clinical effects of an early multimodal vasopressor strategy in patients with septic shock. METHODS: We randomly assigned patients with septic shock receiving ≥ 0.15 µg/kg/min of norepinephrine base to either intervention (early multimodal vasopressor administration: angiotensin II, vasopressin, and norepinephrine) group or control (classic stepwise vasopressor administration: norepinephrine dose increase followed by vasopressin and then by angiotensin II or other vasopressors) group. The primary outcome was change in plasma renin concentrations. This phase II trial was not powered to detect differences in mortality. RESULTS: A total of 79 patients were included (intervention group: n = 38, control group: n = 41). We observed a faster decline in plasma renin concentrations (2.61% per hour vs. 1.67% per hour; p = 0.015) and lactate concentrations (1.53% per hour vs. 1.01% per hour; p = 0.006) during the first 72 h in the intervention group compared to the control group.
2. Targeting capillary leak in experimental sepsis and endotoxemia: a systematic review of therapeutic agents, methods and models in animal studies.
This registered systematic review of 303 preclinical studies found substantial heterogeneity in models and capillary-leak measurements, with rodent models and lipopolysaccharide endotoxemia predominating. Although 93.1% of studies reported benefit for at least one leak outcome, few interventions had reached recent randomized clinical testing and none achieved high translational priority.
Impact: Rather than simply cataloguing positive preclinical interventions, this review exposes why capillary-leak therapies may repeatedly fail in clinical translation. Its emphasis on publication bias, model choice, treatment timing, and standardized read-outs provides a practical framework for improving sepsis research reproducibility.
Clinical Implications: No capillary-leak-specific therapy can currently be recommended on the basis of this evidence. Future clinical trials should enrich enrollment for endothelial dysfunction, use clinically relevant post-treatment dosing, and select interventions supported by reproducible live-pathogen and large-animal models.
Key Findings
- Among 303 included preclinical studies, rodent models accounted for 81.2% and lipopolysaccharide-induced endotoxemia for 59.7%.
- Dye-based assays were the dominant capillary-leak read-out in rodents at 81.7%, while endothelial activation, intercellular junctions, and nitric oxide pathways were the most frequent targets.
- A beneficial effect on at least one capillary-leak outcome was reported in 93.1% of studies, suggesting substantial publication bias; no intervention reached high translational priority.
Methodological Strengths
- Systematic searches across PubMed, Embase, and Web of Science with prospective PROSPERO registration (CRD42024522372).
- Risk-of-bias assessment using SYRCLE and complementary cross-referencing with recent randomized or prospective clinical studies using explicit translational criteria.
Limitations
- The included animal studies were highly heterogeneous in species, sepsis induction, dosing, timing, and outcome measurement, limiting quantitative synthesis and direct comparison.
- The review identifies publication-bias concerns but cannot fully correct for unreported negative or unpublished studies.
Future Directions: The field should adopt standardized, multimodal capillary-leak measurements; expand live-pathogen and large-animal models; prioritize clinically relevant post-treatment designs; preregister experiments; and prospectively test endothelial-dysfunction-enriched patient populations.
BACKGROUND: Sepsis-induced capillary leak is a major contributor to circulatory dysfunction and tissue edema, yet remains therapeutically unaddressed: numerous interventions showing promise in preclinical models have failed to demonstrate clinical efficacy. This systematic review aimed to characterise preclinical studies evaluating therapeutic interventions specifically targeting capillary leak and to identify candidates with the highest potential for clinical translation. METHODS: A systematic search of PubMed, Embase, and Web of Science identified in vivo studies in experimental sepsis and endotoxemia evaluating interventions targeting capillary leak. Data on animal models, sepsis induction methods, capillary leak assessment, therapeutic targets, and intervention timing were extracted. Risk of bias was assessed using the SYRCLE tool. As a complementary step, all retained interventions were cross-referenced against randomized or prospective clinical studies in sepsis published since January 2015 and appraised using a four-criterion translational quality score (reproducibility, quality of the model, clinically relevant timing, and multimodal read-out). RESULTS: Three hundred and three preclinical studies were included, exhibiting substantial heterogeneity in both models and outcomes. Rodent models predominated (81.2%), and lipopolysaccharide-induced endotoxemia was the most common induction method (59.7%). Dye-based assays constituted the most frequent capillary leak read-out in rodents (81.7%), whereas fluid balance and lymph-to-plasma ratios predominated in large-animal studies.
3. Coordinated response of vascular and glial cells in a pig model of sepsis.
Using a Yorkshire pig model of bacterial sepsis, the investigators combined bulk RNA sequencing and single-nucleus RNA sequencing of cortical tissue to characterize early sepsis-associated encephalopathy. Sepsis produced strong inflammatory and cytokine signaling across the neurovascular unit, altered vascular-cell populations, activated astrocytes and microglia, and reduced expression of genes related to blood-brain barrier maintenance, whereas neuronal transcriptional changes were minimal.
Impact: This study addresses a major translational gap in sepsis-associated encephalopathy by using a large-animal model with greater neuroanatomical and immunological relevance than rodents. It identifies vascular–glial inflammatory crosstalk and blood-brain barrier instability as early, potentially actionable mechanisms before prominent neuronal injury appears.
Clinical Implications: The findings support development of therapies aimed at preserving the neurovascular unit and stabilizing the blood-brain barrier during early sepsis. They do not yet justify a specific clinical treatment, but provide mechanistic targets and a translational platform for testing endothelial-, astrocyte-, or microglia-directed interventions.
Key Findings
- Bulk cortical RNA sequencing showed broad shifts in immune and inflammatory pathways, cytokine signaling, vascular dysfunction, and homeostatic regulation.
- Single-nucleus RNA sequencing demonstrated marked changes in vascular-cell populations and activation of astrocytes and microglia, with upregulation of TNF and cytokine-response pathways.
- Genes involved in blood-brain barrier maintenance and metabolic or structural functions were downregulated, while cell-cell communication increased and shifted toward inflammatory signaling; neuronal changes were minimal at this early time point.
Methodological Strengths
- Use of a live-pathogen Yorkshire pig model, which may better reflect human neuroanatomy and immune biology than standard rodent models.
- Integration of bulk and single-nucleus transcriptomics with cell-type-specific and cell-cell communication analyses from the same cortical tissue.
Limitations
- The provided abstract does not report the number of pigs, sex distribution, randomization, blinding, or detailed experimental timing, limiting assessment of statistical robustness and reproducibility.
- The study captures an early transcriptional state and does not establish whether the observed vascular-glial changes cause persistent cognitive impairment or respond to targeted therapy.
Future Directions: Future work should report adequately powered and sex-balanced animal cohorts, validate key pathways at protein and functional levels, follow animals longitudinally for neurological outcomes, and test interventions that stabilize the blood-brain barrier or interrupt vascular–glial inflammatory communication.
Sepsis is a deadly syndrome arising from overactivation of the immune system in response to a pathogen. Severe sepsis can result in sepsis-associated encephalopathy (SAE) that significantly contributes to morbidity and long-term cognitive impairment. Studying the molecular underpinnings of SAE in the human brain is challenging, and rodent models have limited translational applicability due to significant neuroanatomical and immune differences. To bridge this gap, we employed a Yorkshire pig model to investigate changes in the brain cortex during the early stages of SAE using a uropathogenic strain of E. coli to model bacterial sepsis. Bulk RNAseq of cortical brain demonstrated profound global shifts in immune and inflammatory pathways, cytokine signaling, vascular dysfunction, and homeostatic dysregulation. To gain a more granular understanding of the changes in this model, we performed single-nucleus RNA sequencing (snRNAseq) on the same cortical brain tissue. This snRNAseq analysis revealed dramatic alterations in vascular cell populations, accompanied by concomitant glial cell activation. Surprisingly minimal changes were noted in neurons, likely due to the very early nature of this insult. The neurovascular unit, including vascular leptomeningeal cells (VLMCs), mural cells, endothelial cells, astrocytes, and microglia, showed strong upregulation of genes involved in TNF signaling, cellular responses to cytokine stimuli, and cytokine signaling in the immune system.