Stress Markers Predict Mortality in Patients With Nonspecific Complaints Presenting to the Emergency Department and May Be a Useful Risk Stratification Tool to Support Disposition Planning

To the authors’ knowledge, no prospectively validated, biomarker-based risk stratification tools exist for elderly patients presenting to the emergency department (ED) with nonspecific complaints (NSCs), such as generalized weakness, despite the fact that an acute serious disease often underlies nonspecific disease presentation. The primary purpose for this study was to validate the retrospectively derived model for outcome prediction using copeptin and peroxiredoxin 4 (Prx4), in a different group of patients, in a prospective fashion, in a multicenter setting. The secondary goals were to evaluate the potential contribution of the midregional portion of the precursor of adrenomedullin (MR-proADM) for outcome prediction and to investigate whether disposition decisions show promise for potential improvement by using biomarker levels in addition to a clinical assessment. The Basel Nonspecific Complaints (BANC) study is a delayed-type cross-sectional diagnostic study, carried out in three EDs in Switzerland, with a prospective 30-day follow-up. Patients presenting to the ED with NSCs, as defined previously, were included if their vital signs were within predefined limits. Measurement of biomarkers was performed in serum samples with sandwich immunoluminometric assays. To examine the disposition process, the final disposition was compared with a combination of the first clinical disposition decision and the risk assessment, which included the biomarker MR-proADM in a retrospective simulation. Patients were divided into three groups according to MR-proADM concentration, defining three risk classes with three disposition possibilities (admission to tertiary care, transfer to geriatric hospital, discharge). Thirty-three 30-day nonsurvivors were observed from among 504 study patients with NSCs. Biomarker levels were significantly greater in nonsurvivors than survivors (p < 0.0001 for all three biomarkers). Univariate Cox models reveal a C-index of 0.732 for MR-proADM, 0.719 for Prx4, and 0.723 for copeptin. The incremental added value for chi-square obtained via multivariate modeling showed that models inclusive of MR-proADM, copeptin, or Prx4 are superior to and independent of models limited to sex and age. The incrementally added chi-square for MR-proADM, beyond the chi-square of a base model consisting of age and sex, was 29.79 (p < 0.00001). In a multimarker approach, only Prx4 provided additional information to MR-proADM alone (C-index = 0.77). Applying an algorithm combining physicians’ first clinical assessment plus biomarker information to derive a modified risk assessment, reassignment would lead to a potential decrease of 48 admissions to acute care, seven additional transfers to geriatric care, and 41 additional discharges (negative likelihood ratio [–LR] = 0.13). Analysis of 30-day mortality reveals that our algorithm is not inferior in terms of safety. In this study the authors confirm that these new stress biomarkers permit reliable prognostication of adverse outcomes in a heterogeneous group of patients with NSCs. A simulation showed that this prognostic information could be useful to enhance the appropriateness of disposition decisions of ED patients with NSC. The use of biomarkers for risk stratification in this patient group should be evaluated with prospective intervention studies. Según nuestro conocimiento, no existen herramientas basadas en biomarcadores, prospectivamente validadas para estratificar el riesgo de los pacientes ancianos que acuden al SU con sintomatología no específica (SNE), como por ejemplo debilidad generalizada, a pesar del hecho que una enfermedad grave aguda a menudo subyace en una presentación inespecífica. El objetivo principal de este estudio fue validar el modelo obtenido de forma retrospectiva para la predicción de resultados usando la copeptina y la peroxiredoxina 4 (Prx4), en un grupo diferente de pacientes, con un diseño prospectivo y en un escenario multicéntrico. El objetivo secundario fue evaluar la contribución potencial del precursor de la adrenomedulina (MR-ProADM) para la predicción de resultados, sí el uso de biomarcadores, en conjunción con la valoración clínica, permite mejorar las decisiones de ubicación del paciente tras su atención en el SU. El estudio Basel Nonspecific Complaints (BANC) es un estudio diagnóstico transversal tipo diferido, llevado a cabo en tres SU en Suiza, con un seguimiento prospectivo a 30 días. Los pacientes que acudieron al SU con SNE, según la definición previa, se incluyeron si sus constantes vitales estaban entre los límites predefinidos. Se realizó la medición de biomarcadores en muestras plasmáticas con una prueba inmunoluminométrica. Para examinar el proceso de ubicación, la ubicación final se comparó con una combinación de la primera decisión de ubicación clínica y el riesgo de valoración, que incluyó el biomarcador MR-proADM en una simulación retrospectiva. Los pacientes se dividieron en tres grupos según la concentración de MR-proADM, definiendo tres clases de riesgo con tres posibilidades de ubicación (ingreso en hospital terciario, traslado al hospital geriátrico, alta). Se documentaron 33 muertos a los 30 días entre los 504 pacientes con SNE. Los niveles de biomarcadores fueron significativamente más altos en los no supervivientes que en los supervivientes (p < 0,0001 para los tres biomarcadores). Los modelos univariables de Cox revelan unos índices C de 0,732 para el MR-proADM, de 0,719 para el Prx4 y 0,723 para la copeptina. El valor incremental añadido para χ² obtenido según el modelo multivariable mostró que los modelos que incluyen MR-proADM, copeptina o Prx4, son superiores a, e independientes de, los modelos limitados al sexo y la edad. El χ² incremental añadido para MR-proADM, por encima de la χ² de un modelo que consiste en edad y sexo, era 29,79 (p < 0,00001). En una aproximación con multimarcadores, solo Prx4 proporcionó una información adicional al MR-proADM aislado (índice C 0,77). Si se aplicara un algoritmo que combinase la primera valoración clínica del urgenciólogo junto con la información del biomarcador para obtener una valoración del riesgo modificada, la reasignación permitiría un descenso potencial de 48 ingresos en unidad de agudos, 7 traslados adicionales a centro geriátricos y 41 altas adicionales (razón de verosimilitud negativa 0,13). Un análisis de mortalidad a 30 días revela que el algoritmo no es inferior en términos de seguridad. En este estudio se confirma que estos nuevos biomarcadores de estrés permiten un pronóstico fiable de resultados adversos en un grupo heterogéneo de pacientes con SNE. Una simulación mostró que esta información pronóstica podría ser de utilidad para mejorar la pertinencia de las decisiones de ubicación de pacientes del SU con SNE. El uso de biomarcadores para la estratificacion del riesgo en este grupo de pacientes debería ser evaluada con estudios de intervención prospectivos. Elderly patients presenting to the emergency department (ED) are at risk of acquired disability, admission to residential care, death, and larger health care expenditures.1-3 They have special care needs with potentially coexistent medical, functional, psychological, and social problems.4, 5 This can lead to nonspecific disease presentation requiring a different approach to care. To our knowledge, to date no biomarker-based risk stratification tools exist for elderly patients with nonspecific complaints (NSCs) such as functional decline or generalized weakness, despite the fact that nonspecific disease presentation may well be due to acute serious disease.6, 7 In patients with NSCs, the evaluation is complex, which can lead to undertriage, longer diagnostic work-ups, and adverse health outcomes.8, 9 The differential diagnosis of NSCs is extremely broad, and acute morbidity is underlying in almost 60% of cases.10, 11 Alternatively, unnecessary hospitalizations of elderly patients to acute care should be avoided, because hospitalization has been shown to carry significant risk for this population.12, 13 Therefore, a timely and safe disposition (i.e., hospital admission, transfer to a geriatric hospital, or discharge to home) of patients with NSC is crucial, given the rapid workflow of the ED. In a retrospective monocenter study we have recently shown that two novel stress biomarkers, copeptin and peroxiredoxin 4 (Prx4), might be helpful to support risk stratification in patients with NSC by predicting 30-day mortality irrespective of the final diagnosis, suggesting that they are nonspecific markers for disease severity.14 The biomarker performance of both copeptin and Prx4 in patients with NSC is encouraging, given the high heterogeneity and potential confounders, such as comorbidities and medication.14 Another new and promising biomarker, adrenomedullin (ADM), is a member of the calcitonin peptide family and is widely expressed.15, 16 It is up-regulated during severe infections and has been shown to have multiple effects, including immune modulation, vasodilation, stimulation of diuresis, increase of cardiac output, and antimicrobial activity.17, 18 The midregional portion of the precursor of ADM, proadrenomedullin (MR-proADM), is a more stable fragment that is easy to measure and stoichiometrically reflects levels of ADM.19 MR-proADM appears to be a prognostic marker in sepsis and lower respiratory tract infections,20-22 and its plasma concentrations have been shown to be elevated in myocardial infarction, as well as to correlate with severity of congestive heart failure.23, 24 Furthermore, in a symptom-based study of patients presenting to the ED with dyspnea, it was shown that MR-proADM was a predictor for 30-day mortality, regardless of the underlying diagnosis.25 Plasma concentration of mature ADM is also increased in various types of glomerulonephritis and progressively increases in patients with chronic renal failure.26, 27 The aim of this study was to validate, in a multicenter setting, which biomarkers might be helpful for risk stratification in patients with NSCs by predicting 30-day mortality. Simultaneously, our secondary objective was to prospectively examine the value of a new biomarker, MR-proADM, as an alternative predictor of 30-day mortality in patients with NSCs, and compare the biomarkers` predictive performance. Finally, we aimed to investigate how the information derived from MR-proADM could be applied to an individual patient encounter by retrospectively studying whether disposition could be by biomarker assessment. The Basel Nonspecific Complaints study is a delayed-type cross-sectional diagnostic study with a prospective 30-day follow-up. The study was by the of all and is with It is in with the was obtained from The study was performed and at three ED with from to The study was carried out at the EDs of the the and the tertiary care In the ED of the all patients presenting to the ED with of or were for Elderly patients for of all ED in this to the admission are for the ED and for the elderly are three geriatric two for care, and with almost in the Basel support is provided for In and the was to of the study at the study from The was to all patients in of as well as patients in were not or patients for the of our elderly ED patients are to the department of acute in the care of patients evaluation in the ED. of elderly patients in our ED are to tertiary three geriatric in the and patients ED evaluation for They are in geriatric care, in which the patients care and to for of that they can be to patients can also be to if disposition (i.e., admission, transfer to geriatric are in the health The first disposition is patient including to in the acute assessment to for transfer to geriatric only during the and the of a decision for to the final disposition is often an the decision or in the three geriatric In the decision no diagnostic is disposition decisions are by of Patients were if they were age 18 or and if they for the Patients were included if they to the ED with NSCs such as or as were complaints patients with clinical of a diagnosis signs of or vital out of the < < patients from and was performed as In were to comorbidities as by the the and Furthermore, in the of in of was A of a independent and a of a 30 were obtained from the primary care using and hospital discharge for all transfer to care and were for all study patients and patient of the hospitalization were was performed in all study A was at for the of biomarker and diagnostic were not and was by the emergency MR-proADM was using an sandwich the for the MR-proADM was obtained by at for to The MR-proADM has a of to and a functional of and Prx4 were as The the were to the information and final to The primary of this study was the predictive value of the biomarkers MR-proADM, copeptin, and Prx4 for 30-day mortality in patients with NSCs. the secondary we a simulation to retrospectively whether the disposition of patients with NSC could potentially be by using the biomarker A simulation was performed to whether the disposition of patients with NSC could be by using the biomarker information for MR-proADM Patients were by the in the of the study clinical assessment, patients are to of three risk classes the of the disposition acute morbidity requiring is admission to an is for Patients not tertiary care, are to a geriatric hospital for patients not or they are for for the biomarker levels were at a the no to of biomarker the biomarkers, three risk classes were by two we evaluated a of MR-proADM with to the that would as as in the which was for tertiary care the to as patients as to a lower of care. the and for MR-proADM for the which are not from because they patients as or have been for patients with lower respiratory tract The risk assessment combining clinical assessment with biomarker information was the clinical assessment for The of the biomarker was retrospectively and as additional information to the disposition decision for the individual To examine whether it is of to use the biomarker in the disposition decision process, the final disposition was compared with the combination of the disposition and the information of the biomarker MR-proADM in a simulation. the final disposition and the risk assessment were by survivors and survivors in the disposition from the to the or to the were compared with the of patients The of nonsurvivors to a was compared with the of nonsurvivors to a and biomarkers are as and or and of were performed using the were compared using or the chi-square to the of the biomarkers, these were to To if biomarkers are useful for prediction of within 30 and multivariate Cox models were and the were in addition to the The was for all and all were The predictive value of model was by the model likelihood ratio chi-square The was given as an It was to the of the for The were for multivariable models to for The added by the addition of biomarkers to clinical was using the chi-square for for patients are are for been to for the multiple and were for biomarkers, and as well as for multivariate biomarkers, different including the were disposition we three risk groups and two the of the and at the we the lower two risk at the lower the two groups were for multivariate were from model to more and and the of with a or and outcome were The were in a to of the and performed using The study of patients were by the outcome because of and in patients an for of biomarker levels was not that 504 patients for final these 504 patients, MR-proADM copeptin and Prx4 levels could be Analysis was due to a of for samples for MR-proADM, samples for copeptin, and 11 samples for Prx4 and due to for for MR-proADM and samples for copeptin. of the are in The age of the was = to were The was = to 30-day were survivors and 33 The age not survivors and we observed more patients among nonsurvivors than among survivors the was in nonsurvivors than in survivors The was lower in nonsurvivors than in survivors department from the by also from primary care or and patients at study patients in were 504 patients, of the study patients were to tertiary care A of patients were to geriatric and were 30-day were in acute care, were in geriatric and were all were at patients were within the 30-day for new the 33 were patients to tertiary care were and at geriatric were to an or by clinical decision only with a of survivors were to the group of patients to be with a of of and likelihood the as information in the of this The 30-day was = to Biomarker levels were significantly in than in survivors (p < 0.0001 for all three Univariate Cox models show that MR-proADM has a C-index of than the two biomarkers, the predictive performance. the of C-index and added we MR-proADM for the A for 30-day is in as information in the of this and multivariate Cox and C-index of MR-proADM and for Prx4 and are provided in as information in the of this The added chi-square for models show that MR-proADM and the biomarkers are superior and independent of sex and age. The added chi-square of MR-proADM of a base model consisting of age and sex was 29.79 (p < 0.00001). biomarkers were also independent and superior to the added chi-square for MR-proADM was (p < 0.00001). all biomarkers were also independent and superior of the the added chi-square for MR-proADM was (p < 0.00001). In a multimarker approach, out of all only Prx4 provided additional information to MR-proADM, and the C-index of a model including sex, MR-proADM, and Prx4 increases to To the prognostic value of MR-proADM to mortality, we Patients were divided into three groups according to the MR-proADM concentration, with of and A decrease of with MR-proADM concentrations was In the MR-proADM group with the = to 30 In the group with MR-proADM the was = to and in the group with MR-proADM to = to the the two nonsurvivors were to an with a of at the lower the two survivors were to the group of patients to be with a of Applying the algorithm combining clinical and biomarker risk assessment to the with MR-proADM = patient disposition would have in our simulation as shown in A of patients would be by the reassignment with patients to a and patients to a The of the simulation can be as a potential decrease of 48 hospitalizations to acute care, seven additional geriatric and 41 additional the of for risk classes in the clinical disposition decision with the disposition three from the to the Applying the patient would be in this the disposition decision of the was to the This was by the patient and and was to The patient a MR-proADM of which would not have the risk stratification according to the this patient was The of a risk assessment for patient in to the risk assessment, can be that patients would be to or with an increase in mortality of in this more patients would be to care with a to increase in mortality of and more patients would be with a decrease in mortality of In the algorithm survivors with a of to the group of patients to be and nonsurvivors with a of to an or In this prospective study, the primary objective was were to prospectively validate, in a multicenter with a new group of patients, our that copeptin and Prx4 are useful prognostic markers for elderly patients with NSCs. In the secondary objective of the of MR-proADM showed that this additional marker has in predicting outcomes for patients with NSCs. In it appears that the addition of MR-proADM to age and sex the two In a simulation we that the prognostic information provided by the biomarker could potentially be useful for disposition decisions in patients with NSC. new prospective into The of patients with NSCs is a fact well for a in both emergency and geriatric have a for in this Furthermore, geriatric that an differential diagnosis for patients presenting to the ED with or should be among the of care of elderly tools are to support clinical The of biomarkers appears in this patient and risk stratification tools are is an almost is up-regulated by such as and and the of ADM were to be and 41 this peptide appears to be a with and and ADM has an in the of a of clinical such as lower respiratory tract acute heart and renal plasma ADM levels may prognostic information in these elevated Prx4 have been shown to be with and markers of in sepsis patients and are with elevated morbidity and mortality in this patient have that the or plasma levels of Prx4 various such as and It has been that Prx4 into the could lead to a of or Prx4, in to which in could lead to an increased of adverse outcome and the of the precursor has been shown to be a marker for the of the It is in to a that the and is a marker of the individual stress It has been shown to be a predictor of mortality in a of clinical such as acute chronic lower respiratory tract and acute and heart the heterogeneity of underlying in patients with the predictive of stress biomarkers may be helpful to the disposition in the safe discharge = if clinical risk assessment is with and disposition to acute tertiary care of for mortality at of the first our simulation showed that an additional 41 patients could have been This for a potential of discharge the our simulation showed that 48 patients would have been to tertiary care, for of In the to the final decision for disposition we a to more patients to the of care The to more patients than at risk for adverse outcomes may be to a health care algorithm may in disposition potentially admissions and safe Furthermore, stress biomarkers could a as a patients at high risk for mortality. Therefore, to a lower of care or discharge could be using Finally, the algorithm has the potential to in the as it is the first disposition decision A final disposition decision could be in a more timely using biomarkers, of if prospective our retrospectively derived This would limited to be to patients at risk of adverse Analysis of 30-day mortality reveals that our algorithm is not inferior in terms of safety. intervention are to whether this derived algorithm to in risk stratification of patients with NSCs. The disposition (i.e., the from to of our patients may be to our setting. In hospital EDs that not have patients are and to The secondary of of the hospital, might not exist in these this to study the disposition of patients with NSC in a to more patients to a of care, not to discharge patients at risk of adverse health no were that might have this are that are patients are to the hospital, including family underlying physicians’ and of In our retrospective these were not into the In no geriatric assessment in our ED. The patients were (i.e., discharge to home) in the simulation may well have support due to their social or due to functional in our support is and might be an for this group of The in our study that the of the biomarkers Prx4, and in predicting 30-day mortality is these biomarkers not significantly the the of underlying in patients with NSCs should be into study included patients from It to of the study was not to not for all patients a assessment of could be In this prospective study we confirm in a multicenter that new stress markers are reliable in the heterogeneous group of patients with nonspecific this group of biomarkers, MR-proADM a performance predicting 30-day mortality. In a simulation we that the prognostic information provided by MR-proADM may be useful for disposition decisions of ED patients with nonspecific the biomarker information be in the of a clinical assessment and the individual Therefore, the use of biomarkers for risk stratification in patients with nonspecific complaints prospective in into are to the emergency and patients in the The authors and for helpful The is not for the or of information by the than should be to the for the