The diagnostic and prognostic value of systems biology research in major traumatic and thermal injury: a review

The metabolomic response to major traumatic injury

A technique that identifies and quantifies metabolites within biological fluids, cells and tissues, metabolomics is a systems-based approach for the profiling and analysis of cellular processes. A long-standing interest of researchers in the fields of inflammatory disease and infection [62–67] metabolic profiling is an emerging area of research in the settings of critical care and trauma. In animal models of polytrauma with haemorrhagic shock [68–73], as well as in cohorts of TBI [74], burns [75] and major trauma [9, 12, 76, 77] patients, analysis of blood [9], plasma [9, 12, 72, 73, 75, 76], serum [69, 71, 74], lymph [77] and urine [70, 71] collected in the hours and days post-injury has shown severe metabolic disruption to be a consequence of trauma. For example, marked alterations, relative to healthy controls, have been reported in the concentrations of multiple metabolites such as serine, lactate, succinate, carnitine and citrate, demonstrating that trauma leads to disturbances in carbohydrate, protein and fatty acid metabolism [9, 12, 68–77].

Besides simply describing the changes that occur in the circulating “metabolome” post-injury, a handful of groups have investigated whether metabolic profiling has the potential to serve as a prognostic tool. In one of the first studies to examine the relationship between trauma-induced metabolic derangement and patient outcome, Cohen et al. found in a cohort of major trauma patients that survivors and non-survivors could be clearly discriminated by the concentrations of triacylglycerol, phospholipids and monounsaturated fatty acids in admission blood samples, with non-survivors presenting with significantly lower levels of all three lipid metabolites [9]. Similar to these observations, Lexcen and co-workers recently reported in a porcine model of polytrauma and haemorrhagic shock that when compared to survivors, concentrations of succinate and O-phosphocholine were significantly increased and decreased, respectively, in animals that succumbed to their injuries [69]. Aside from mortality, metabolic profiling in the early post-injury phase may be a useful approach for identifying patients that are at an increased risk of post traumatic complications [74, 78, 79]. For example, in a cohort of 22 severely-injured patients, a metabolomic assessment of plasma samples acquired at admission to ICU was found to identify with a reasonable degree of certainty (AUROC?=?0.778) patients that subsequently developed sepsis during their hospital stay [78]. Interestingly, in an independent cohort of ICU patients, Mickiewicz et al. recently demonstrated that a combination of metabolomic and proteomic data could accurately discriminate, with a sensitivity of 0.94 and a specificity of 1, septic shock patients from those undergoing a SIRS response in the absence of infection [79]. Shown to perform better than statistical models built on clinical scoring systems, these data highlight the improved discriminatory power that can be gained by combining system-based approaches [79].

Although in its infancy, metabolic profiling of trauma patients has potential prognostic utility for identifying individuals that are at an increased risk of poor outcome. However, given the limited number of studies and the small size of the patients cohorts analysed, further work is needed to not only validate published observations but also address whether clinical (e.g. ISS) and patient (e.g. gender, age) variables influence the metabolomic response to injury. Furthermore, in the context of tailored therapeutics, it will be interesting for future studies to examine whether the circulating “metabolome” can provide information on a patients response to treatment regimens (e.g. resuscitation) or therapeutic interventions, which if proven to be the case, could lead to the implementation of patient-specific management protocols.