Metabolic septic shock sub-phenotypes, stability over time and association with clinical outcome.

Summary

Across two septic shock RCT cohorts, k-means clustering of 474 serum metabolites revealed three subphenotypes driven by lipid species, notably lysophospholipids. Persistently low lysophospholipids tracked with higher cytokines and increased mortality, while no baseline subphenotype modified trial treatment effects.

Key Findings

• Three metabolic subphenotypes of septic shock were identified, driven mainly by lipid species, especially lysophospholipids.
• Persistent low-lysophospholipid subphenotypes had higher cytokines and higher mortality (e.g., LeoPARDS OR 3.66 and 2.49; VANISH OR 4.13 and 3.22 vs cluster 1).
• No heterogeneity of treatment effect by baseline metabolic subphenotype for trial interventions.

Clinical Implications

Serial metabolite profiling could flag patients with persistently low lysophospholipids at higher risk, informing monitoring intensity and trial enrichment strategies.

Limitations

• Post hoc clustering with potential overfitting and limited generalizability beyond trial populations.
• No demonstrated treatment effect modification to guide current therapy selection.

Future Directions

Prospective validation, development of parsimonious clinical/metabolite panels for bedside use, and interventional trials targeting lysophospholipid pathways.