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