Background
Risk stratification with triage of patients admitted to the emergency department (ED) plays a pivotal role in ensuring that the most acutely sick patients are cared for first [
1]. Existing triage algorithms are all based on a combination of the patients’ vital signs and primary symptoms [
1,
2]. Several retrospective studies have identified biomarkers that provide prognostic information which goes beyond the current triage utilized in the EDs [
3‐
10].
Whether the implementation of a prognostic biomarker in initial risk stratification of acutely admitted patients translates into better management and treatment of high risk patients and actually decreases mortality, morbidity, admissions or readmissions has yet to be shown.
Soluble urokinase plasminogen activator receptor (suPAR) is a prognostic biomarker with potential use in the EDs. The suPAR blood level reflects immune activation and it is strongly associated with mortality and presence, prognosis and severity of a broad variety of acute and chronic diseases [
8,
11‐
18], and it is also a predictor of disease development in the general population ([
19]; Rasmussen et al.: suPAR in Acute Care: Associated with Disease Severity, Readmission, and Mortality, in review). As an unspecific biomarker with strong prognostic value across morbidities, suPAR might be a useful biomarker for risk stratification in an ED, as the staff can target intervention, resources, and clinical focus where most beneficial.
The primary aim of the study is to evaluate whether the availability of an unspecific biomarker (suPAR) as a supplement to risk stratification of unselected acutely admitted patients can reduce all-cause mortality.
Discussion
Rapid and safe risk stratification is necessary and an important task in emergency medicine. Identifying patients at high and low risk shortly after admission can guide clinical decision-making towards the patients in need, regarding treatment, observation and allocation of resources. Several studies have suggested biomarkers as a supplement to enhance risk stratification; however they have only been studied retrospectively [
3‐
7,
9,
10], why an interventional study is both warranted and required, in order to quantify the effects of implementing a prognostic biomarker in emergency medicine. The current study is to our knowledge the first of its kind, and focuses on whether the availability of a prognostic biomarker influences the treatment strategy and overall prognosis of patients admitted to the ED.
SuPAR has been evaluated as a potential biomarker in the general population by 5 large studies with more than 4500 randomly selected healthy participants which showed that elevated suPAR is associated with an increased risk of cardiovascular morbidity and mortality [
13,
14,
23‐
25]. The TRIAGE I study along with others found suPAR independently associated with short-term mortality [
12,
18,
19], and when analyzing prospective data of the TRIAGE I study, the supplementary prognostic information of suPAR was evident (Rasmussen et al.: suPAR in Acute Care: Associated with Disease Severity, Readmission, and Mortality, in review). Receiver operational characteristic (ROC) analysis in relation to 30-day mortality showed an AUC of 0.85 (95 % CI 0.82-0.87) when triaging with suPAR and 0.62 (0.58-0.66) when triaging with the usual triage algorithm based on vital signs and symptoms [
19,
26]. Several biomarkers have shown to carry prognostic value, for example C-reactive protein, YKL-40, Pentraxin-3, and Copeptin [
26]. SuPAR was chosen in our current interventional study based on its superiority in the TRIAGE I study, which indicated that suPAR might be a very good candidate for risk stratification in the emergency setting [
19].
SuPAR as a biomarker is reflective of low-grade inflammation, a key component of disease development in e.g. cancer, cardiovascular, renal, and infectious disease and it is also strongly associated with the Charlson Comorbidity Index [
11‐
17,
27‐
34]. Plasma levels of suPAR are associated with factors such as smoking, alcohol consumption, and a passive lifestyle [
14]. Previous studies have shown that the urokinase system is deeply integrated in the pathogenesis of atherosclerotic remodeling and plays a role in fibrinolysis, angiogenesis and immunologic function [
29,
35‐
37]. The suPAR level reflects immune activation and the inflammatory state of the individual. The protein uPAR is primarily expressed on immunological cells like monocytes, leukocytes, endothelial cells and is thought to reflect subclinical organ damage and endothelial dysfunction [
13,
25,
38]. SuPAR meets many basic biochemical criteria of an ideal biomarkers because it is stable in plasma and is not significantly affected by the circadian cycle [
39].
A biomarker reflecting the level of urgency or comorbidity burden could potentially be very useful, but the value of a biomarker with a strong negative predictive value must not be underestimated [
12]. The availability of a biomarker reflecting healthiness or non-urgency (e.g. low plasma suPAR level) is particularly interesting in the setting of emergency departments where crowding is a serious concern. High bed occupancy rates are associated with an increased mortality rate, delays in initiation of time-critical care and diagnosis, increased costs and an overall poor quality of care and concerns of patient safety [
40‐
42]. Furthermore, hospitalization is associated with a number of adverse outcomes such as falls, medication errors, infections, and delirium [
43,
44]. Early discharge is associated with decreased mortality and increased patient outcome, illustrated by an American and a British study that found 26 % respectively one fifth of all hospitalizations were potentially avoidable [
45‐
47], why a more efficient selection of patients without need of admission is desirable.
Strengths and limitations
The strength of this trial is the large size of the cohort, multicenter nature and inclusion of a heterogeneous cohort under a wide variety of medical and surgical settings. Due to the unselective cohort, the trial brings generalizability whereby results will be applicable to nearly all patients admitted to EDs. A learning curve for physicians must be expected when implementing a prognostic biomarker in terms of suPAR level interpretation and intervention, why physicians might refrain from discharging patients on the basis of low suPAR levels because they do not fully trust the prognostic abilities of suPAR.
In the planned data analysis of the primary outcome, readmitted patients remain in the group to which they are primarily allocated (control vs. suPAR intervention). This increases the risk of a type 2 error as patients primarily included in the control group might have one or more following admissions where they have suPAR measured and vice versa. A possibility would be to exclude all patients that were admitted more than once during the inclusion. If this method was chosen, we would risk excluding the sickest patients, where suPAR might have the greatest value.
Acknowledgements
The authors would like to extend our gratitude to the Departments of Clinical Biochemistry at Herlev and Bispebjerg Hospital for professional assistance and support, and to Line Jee Hartmann Rasmussen for assistance with figure and pocket card creation.
Participating clusters: Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730 Herlev, Denmark. Bispebjerg Hospital, University of Copenhagen, Bispebjerg Bakke 23, 2400 Copenhagen, Denmark.