Investigating cytokine biomarkers as early predictors of poor clinical outcome following major trauma

Apreutesei, RG 2019, Investigating cytokine biomarkers as early predictors of poor clinical outcome following major trauma , MSc by research thesis, University Of Salford.

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Abstract

Despite recent advances in critical care, trauma still continues to be the leading cause of morbidity and mortality among individuals under 40 years of age and the third main cause of death throughout the world, carrying a substantial economic burden. Globally, the most common traumatic injuries are acquired through penetrating wounds, blunt injuries or burn mechanisms. Recent reports from the UK suggest a significant change in the demographics of major trauma. The typical major trauma patient is older, with a slight predominance of males, and with traumatic injuries resulted from falls from less than 2m in height. Mortality due to major trauma follows a biphasic pattern. Early fatalities occur due to haemorrhagic shock or brain injuries, whereas the late deaths (>5 days post-trauma) are attributed to progressive multiple organ failure (MOF) and sepsis postulated to result from dysfunctions of the immune system. Depending on the severity of trauma, the immune response can be over-active with uncontrolled release of pro and anti-inflammatory mediators causing multiple organ failure. This study focusses on the second-phase mortality induced due to major trauma. The hypothesis tested is that the late mortality and morbidity results from an imbalance of the pro and anti-inflammatory immune responses (SIRS and CARS) triggered after major trauma. While a balanced response of these two arms of the immune system result in homeostasis, the hyperactivity of the compensatory anti-inflammatory response (CARS) results in immunosuppression and increased risk of nosocomial infections and late onset MOF. The study is designed to investigate the role of IL-6, IL-10, IL-12 and IL-4 in the development of the late onset MOF with a view to evaluating their use as a predictive biomarker of poor clinical outcome. The data from the analysis of 80 major trauma patients show averaged IL-6 7 and IL-10 levels to decrease in major trauma patients from Day 1 to Day 5 post-admission (IL-6 p=0.000; IL-10 p=0.000), while the trends for IL-4 and IL-12 increased over the same period for the cohort (IL-4 p=0.031; IL-12 p<0.001). When patients were clustered on the basis of Sequential organ failure assessment scores (SOFA) on Day 5 (cut off >3), statistically significant differences were observed in the Day 1 IL-10 and IL-6 levels at the cut off >3 for the respective SOFA score (IL-10 p=0.023, IL -6 p=0.015) indicating a strong potential for their use as early biomarkers of poor clinical outcomes. The trends in Day 1IL - 10 and IL- 6 concentration were maintained when the SOFA cluster cut offs were increased to > 6 (IL-10 p=0.037; IL-6 p<0.001). When similar analyses were carried out with IL-12 data, a reverse trend was observed with higher Day 1 IL-12 levels being observed in the <3 Day 5 SOFA cluster, suggesting that high levels of IL-12 on Day 1 post-trauma is associated with good clinical outcomes downstream. Although the IL-12 data failed to show statistical significance at a SOFA cut off of 3 (p=0.268), when the data was clustered more stringently on a SOFA cut off of 6, the differences were statistically significant (p= 0.023). Similar trends were maintained for SOFA outcomes on Day 8. Similar to IL-6 and IL-10 patterns, high IL-4 levels on Day 1 post admission showed a significant association with poor outcome patient clusters on Day 5 (SOFA cut off 6; p=0.025) When cytokine levels were defined using Day 5 serum C-reactive protein concentration as a measure of poor outcome (rather than SOFA scores), similar trends were observed. However, the data was not statistically significant, possibly due to confounding factors resulting from a lower cohort size (n =30) where CRP records were available. In conclusion, a multiplex panel of these 4 cytokines may be of good predictive value for the early stratification of major trauma patients for focussed clinical intervention and improvement of clinical outcome.

Item Type: Thesis (MSc by research)
Schools: Schools > School of Environment and Life Sciences
Depositing User: Renata Georgeta Apreutesei
Date Deposited: 18 Dec 2019 11:34
Last Modified: 18 Jan 2020 02:30
URI: http://usir.salford.ac.uk/id/eprint/53409

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