This study compared the performance of a number of clinical severity scores, conventional and novel biomarkers following activation of an in-hospital sepsis code, in order to identify cases of infection and assess the severity of corresponding host response. Results found that the use of PCT to discriminate between sepsis code infected group and sepsis code non-infected group, and MR-proADM to identify disease severity irrespective of the location of infectious insult, had the greatest accuracy in fulfilling both criteria. Interestingly, MR-proADM was also the most accurate parameter in identifying patients presenting to the ED or receiving treatment on a medical ward who subsequently required immediate ICU admission.
The use of clinical or laboratory parameters which are significantly increased in the early stages of the infectious cascade may allow more appropriate treatment strategies to be initiated upon initial suspicion of infection, thus minimising the risk of patients being either under- or over-treated—both of which may result in undesirable consequences . To this extent, the use of blood biomarkers may provide an easy and rapid source of clinical information with which to inform and help develop clinical strategies. Of these biomarkers, PCT has been studied extensively in both the ED and ICU [12,13,14,15, 22,23,24], with routine use in the ICU especially widespread. Conversely, novel biomarkers such as MR-proADM remain poorly understood, despite a number of recent studies [16, 18, 19, 25]. Furthermore, biomarker performance may vary extensively depending on whether the infection had developed in the community or during hospitalisation. Hence a key aim of this study focused on the comparison of biomarker and clinical score performance according to the location of initial infection development, following activation of an in-hospital sepsis code.
Based on recent publications, the use of MR-proADM was of especial interest within our investigation, with previous studies showing elevated concentrations resulting from increased levels of microcirculatory and endothelial damage, resulting in the early stages of subsequent organ dysfunction [26,27,28,29]. The use of a biomarker to identify developing microcirculatory damage may contribute significant information following the activation of a local, in-hospital sepsis code.
Accordingly, results from this investigation potentially indicate two clinically important uses of MR-proADM following sepsis code activation. Firstly, MR-proADM may be used as a tool to aid in the early identification of disease severity, irrespective of medical setting or prior surgical history. Secondly, it may also be used to aid clinical decision-making in assessing ICU requirement within the ED or on a medical ward.
This study found that MR-proADM had a high accuracy in identifying both 28-day and 90-day mortality, compared to all other biomarkers and clinical scores, although many differences were not found to be significant. Performance was maintained irrespective of whether the infection was developed in the community, culminating in a visit to the ED, or following a surgical procedure. Conversely, the SOFA score appeared to more accurately predict mortality in patients following a hospital-acquired infection, although similarly, differences were not found to be significant. In each case, however, the small sample size and relatively low event rate result in few significant differences between biomarkers and scores, as highlighted when comparing 95% confidence intervals. Nevertheless, similar findings have been shown elsewhere. Elke et al.  previously found differences in performance depending on whether the infecting agent consisted solely of Gram positive vs. negative bacteria, as well as highlighting the influence of prior surgical procedures in patients directly admitted onto the ICU. A further ICU study by Andaluz-Ojeda et al.  in 326 patients with severe sepsis or septic shock, as well as that of Enguix-Armada  in 388 patients with septic shock, also found MR-proADM to have the highest predictive value compared to conventional biomarkers such as PCT, CRP and lactate, although interestingly, the greatest performance was found in patients with a lower degree of organ failure. Nevertheless, no subgroup analysis was performed in either study relating to location of infection development or prior surgical history. It is, however, interesting to note that similar results to these high severity, critical care investigations could be observed in our less severe cohort across three different hospital departments. Accordingly, a significant body of evidence now appears to have been formed across all hospital departments, highlighting the use of MR-proADM in identifying the patients at risk of mid- and long-term mortality.
In contrast, few studies have assessed MR-proADM performance in identifying patients requiring ICU admission. An early recognition of such patients is crucial, since it has previously been shown that inappropriate ED discharge can result in higher mortality rates in patients initially classified as suitable for outpatient treatment, but later directly admitted onto the ICU. Similar findings were also reported after initial triage onto a medical ward . The relatively high performance of MR-proADM in identifying these patients after presentation to the ED, with a modest performance during treatment on a medical ward, may provide clinicians with an additional tool in assessing suitability for ICU admission. Nevertheless, further observational and interventional studies are required to confirm these initial findings, and determine the actual clinical value compared to standard routine practice.
We note several limitations and strengths of this study that deserve greater discussion. This was a single-centre pilot study with a relatively low number of enrolled patients, resulting in many subgroups being underpowered for their respective endpoints. Results must therefore be treated with caution. Nevertheless, similar results were found in comparison to those previously discussed in the literature, despite the patient population enrolled in this study being preselected on the basis of fulfilling an in-house sepsis criteria, and can therefore be viewed as additional collaborative evidence. Similarly, the number of patients where the in-hospital sepsis code was activated, yet no infection was subsequently found, only amounted to 18 (12.2%) patients. A greater degree of confidence in the discriminatory results between infected and non-infected patients could be achieved with a larger sample size. Finally, biomarker incorporation within a sepsis code requires a short turnaround time to result, which may be achieved using point-of-care (POC) technology. At this point in time, however, no such platform exists for the measurement of MR-proADM, making routine incorporation of this biomarker in a clinical setting problematic.