Journal
CRITICAL CARE
Volume 26, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13054-022-04025-w
Keywords
Acute respiratory distress syndrome; Simvastatin; Inflammasome; Interleukin-18; Personalised medicine
Categories
Funding
- UK EME Programme, an MRC
- NIHR partnership [08/99/08, 16/33/01]
- MRC
- NIHR
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Patients with high baseline plasma IL-18 in ARDS have increased mortality rates, but simvastatin can reduce this risk and improve survival by reducing inflammasome activation.
Background Interleukin (IL)-18 is a marker of inflammasome activation, and high baseline plasma IL-18 is associated with increased mortality in patients with sepsis-induced ARDS. The aim of this analysis was to determine if simvastatin was associated with benefit in patients with ARDS and high plasma IL-18. Methods In this secondary analysis of the HARP-2 study, we compared 28-day mortality and response to simvastatin according to baseline plasma IL-18 using cox proportional hazards analysis. Separately, monocyte-derived macrophages from healthy volunteers were pre-incubated with simvastatin or rosuvastatin before stimulation with ATP and LPS, and the effect on secreted IL-18 and IL-1 beta compared. Results 511 patients from HARP-2 had available data. High baseline plasma IL-18 (>= 800 pg/ml) was associated with increased 28-day mortality (high IL-18 30.6% vs. low IL-18 17.5%; HR 1.89 [95% CI 1.30-2.73]; p = 0.001). Allocation to simvastatin in patients with high baseline plasma IL-18 was associated with a lower probability of 28-day mortality compared with placebo (24.0% vs 36.8%; p = 0.01). Finally, simvastatin, but not rosuvastatin, reduced stimulated macrophage secretion of IL-18 and IL-1 beta. Conclusion In patients with high baseline plasma IL-18, simvastatin is associated with a higher probability of survival, and this effect may be due to reduced inflammasome activation. These data suggest that baseline plasma IL-18 may allow a personalised treatment approach by identifying patients with ARDS who could benefit from simvastatin therapy.
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