Mid-Regional Pro-Adrenomedullin in Combination With Pediatric Early Warning Scores for Risk Stratification of Febrile Children Presenting to the Emergency Department: Secondary Analysis of a Nonprespecified United Kingdom Cohort Study*

Abstract

OBJECTIVES: Current sepsis guidelines do not provide good risk stratification of subgroups in whom prompt IV antibiotics and fluid resuscitation might of benefit. We evaluated the utility of mid-regional pro-adrenomedullin (MR-proADM) in identification of patient subgroups at risk of requiring PICU or high-dependency unit (HDU) admission or fluid resuscitation. DESIGN: Secondary, nonprespecified analysis of prospectively collected dataset. SETTING: Pediatric Emergency Department in a United Kingdom tertiary center. PATIENTS: Children less than 16 years old presenting with fever and clinical indication for venous blood sampling ( n = 1,183). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcome measures were PICU/HDU admission or administration of fluid resuscitation, with a secondary outcome of definite or probable bacterial infection. Biomarkers were measured on stored plasma samples and children phenotyped into bacterial and viral groups using a previously published algorithm. Of the 1,183 cases, 146 children (12.3%) required fluids, 48 (4.1%) were admitted to the PICU/HDU, and 244 (20.6%) had definite or probable bacterial infection. Area under the receiver operating characteristic (AUC) was used to assess performance. MR-proADM better predicted fluid resuscitation (AUC, 0.73; 95% CI, 0.67–0.78), than both procalcitonin (AUC, 0.65; 95% CI, 0.59–0.71) and Pediatric Early Warning Score (PEWS: AUC, 0.62; 95% CI, 0.56–0.67). PEWS alone showed good accuracy for PICU/HDU admission 0.83 (0.78–0.89). Patient subgroups with high MR-proADM (≥ 0.7 nmol/L) and high procalcitonin (≥ 0.5 ng/mL) had increased association with PICU/HDU admission, fluid resuscitation, and bacterial infection compared with subgroups with low MR-proADM (< 0.7 nmol/L). For children with procalcitonin less than 0.5 ng/mL, high MR-proADM improved stratification for fluid resuscitation only. CONCLUSIONS: High MR-proADM and high procalcitonin were associated with increased likelihood of subsequent disease progression. Incorporating MR-proADM into clinical risk stratification may be useful in clinician decision-making regarding initiation of IV antibiotics, fluid resuscitation, and escalation to PICU/HDU admission.

Risk Stratifying Febrile Children in the Emergency Department: An Ongoing Challenge*

“…In one study of adults, a cutpoint of 1.54 nmol/L was found to best discriminate disease progression, whereas a cutpoint of 0.9 nmol/L was used for disposition decisions (11). In one pediatric study evaluating the use of MR-proADM to predict severe disease, a cutpoint of 0.66 nmol/L was found to be the best discriminator of disease severity (6), whereas in the present study by Lenihan et al (1), a cutpoint of 0.7 nmol/L was used. Until cutpoints are established and the assay becomes more generalizable, implementation of MR-proADM will remain difficult.…”

“…In this issue of Pediatric Critical Care Medicine , Lenihan et al (1) evaluate the utility of adding the blood biomarkers mid-regional proadrenomedullin (MR-proADM) and procalcitonin to the Pediatric Early Warning Score (PEWS) to risk stratify children who present to the emergency department (ED) with fever. They performed an unplanned secondary analysis of a study of 1,183 febrile children less than 16 years old who underwent blood sampling as part of their ED evaluation.…”

“…First, it is not widely available. Although the study by Lenihan et al (1) and others suggest possible utility of MR-proADM, it cannot be used unless it is demonstrated to be clinically acceptable and widely available. Second, unified cutpoints have not been defined, particularly for children.…”

“…The study by Lenihan et al (1) has several challenges inherent to retrospective designs evaluating risk of severe illness in children with fever. First, the study population was limited to children having blood work performed in the ED.…”

“…Another important limitation of this work (1) is around the timing of when prediction (i.e., measurement of PEWS and biomarkers) occurred and when the outcomes of fluid administration and ICU disposition decisions were made. It is important when evaluating studies attempting to stratify risk of critical illness to determine whether they are identifying risk in children who already have organ dysfunction upon ED arrival (and thus there is nothing to predict since the outcome is already present) versus predicting organ dysfunction in children who do not yet show signs.…”