Metabolic pathways, immune regulation and clinically relevant biomarkers impacted by Landiolol therapy in sepsis

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Thomas, Jarrod Lee (2023). Metabolic pathways, immune regulation and clinically relevant biomarkers impacted by Landiolol therapy in sepsis. University of Birmingham. M.Sc.

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Abstract

Background: Sepsis affects 245,000 people annually in the UK with up to 48,000 deaths. Globally sepsis is involved with the death of 11 million people. It has been hypothesised that β-blockade provides protection to patients during septic shock through reducing inflammation, regulating metabolism, reducing vasopressor requirements and subsequently reducing cardiac dysfunction. A previous clinical trial conducted in Rome by Morelli and colleagues in 2013, showed remarkable improvements in mortality but were criticised for the high mortality in the group who did not receive beta-blockade. STRESS-L, a multi-centre randomised trial of patients with established and severe septic shock (as measured by treatment with high dose noradrenaline >24 hours at recruitment) and a tachycardia with heart rate >95 bpm used Landiolol and aimed to perform the largest study of beta-blockade in septic shock so far performed, and to provide mechanistic insight to β-blockade in septic shock. STRESS-L stopped recruitment early following recommendation from the Data Monitoring Committee due to concerns surrounding mortality.

Methods: 100 patients (419 plasma samples) taken at time points: Day 0, 1, 2, 4, 6 and end of noradrenaline therapy following randomisation into STRESS-L were analysed by flow infusion electrospray ionisation high-resolution mass spectrometry (FIE-HRMS)-based metabolomics. Luminex multiplex analysis was further used to identify metabolic and immune changes respectively. Commercially-sourced ELISAs were used to measure CK-MB and Pro-BNP concentrations as indicators of cardiac damage. Metabolomic data were analysed by several chemometric statistical tests, including PCA, PLS-DA and data-visualisation cluster analysis. Enrichment and AUC/ROC analysis was run using MetaboAnalyst. Other statistics analysed used IBM® SPSS version 28 software package.

Results: STRESS-L enrolled 126 patients, 63 of whom received Landiolol. 58% of patients were male in both treatment arms, with the control arm seeing a 28-day mortality of 25% and the interventional arm saw 36%. Landiolol did not influence the trial primary outcome, SOFA score, sub-analysis did show improvement in survivor category. Noradrenaline requirement was minimally greater in the interventional arm (+0.05 mcg/kg/min) compared to control; no clinically relevant difference of mean arterial pressure was observed. Landiolol provided excellent heart rate management. Cytokine analysis showed IFNγ and IL-2 were both higher in standard care. IL-1Ra was higher in Landiolol treated patients. Analysis by mortality status showed non-survivors more hyper-inflamed with increases in TNFα, IL-6 and IL-8. In survivors, Landiolol treated patients had reductions in cardiac troponins and CK-MB not observed in standard care. AUC analysis showed cTnI was a good predictor of mortality along with IL-10 in early timepoints. Landiolol treated survivors also had a consistently lower cTn level despite higher of noradrenaline dosage (at the time point) not replicated in standard care. Metabolomic analysis showed poor separation by treatment allocation and generally patient mortality.

Conclusion: STRESS-L was stopped before achieving its full patient recruitment. Mortality was not significantly higher in the clinical study. Landiolol offered cardiac protection not observed to the same degree in standard care, particularly regarding noradrenaline dosage and tachycardia effects on cardiac stress (as a measure of cTnI and CK-MB). The study also showed Landiolol feasibly acting as an anti-inflammatory. Metabolomic analysis provided inconclusive outcomes but presented insight into SOFA score separations between survivors and non-survivors.

Type of Work:

Thesis (Masters by Research > M.Sc.)

Award Type:

Masters by Research > M.Sc.

Supervisor(s):