Adrenomedullin: a marker of impaired hemodynamics, organ dysfunction, and poor prognosis in cardiogenic shock

Abstract

Background: The clinical CardShock risk score, including baseline lactate levels, was recently shown to facilitate risk stratification in patients with cardiogenic shock (CS). As based on baseline parameters, however, it may not reflect the change in mortality risk in response to initial therapies. Adrenomedullin is a prognostic biomarker in several cardiovascular diseases and was recently shown to associate with hemodynamic instability in patients with septic shock. The aim of our study was to evaluate the prognostic value and association with hemodynamic parameters of bioactive adrenomedullin (bio-ADM) in patients with CS.

Methods: CardShock was a prospective, observational, European multinational cohort study of CS. In this sub-analysis, serial plasma bio-ADM and arterial blood lactate measurements were collected from 178 patients during the first 10 days after detection of CS.

Results: Both bio-ADM and lactate were higher in 90-day non-survivors compared to survivors at all time points (P < 0.05 for all). Lactate showed good prognostic value during the initial 24 h (AUC 0.78 at admission and 0.76 at 24 h). Subsequently, lactate returned normal (≤2 mmol/L) in most patients regardless of later outcome with lower prognostic value. By contrast, bio-ADM showed increasing prognostic value from 48 h and beyond (AUC 0.71 at 48 h and 0.80 at 5-10 days). Serial measurements of either bio-ADM or lactate were independent of and provided added value to CardShock risk score (P < 0.001 for both). Ninety-day mortality was more than double higher in patients with high levels of bio-ADM (>55.7 pg/mL) at 48 h compared to those with low bio-ADM levels (49.1 vs. 22.6%, P = 0.001). High levels of bio-ADM were associated with impaired cardiac index, mean arterial pressure, central venous pressure, and systolic pulmonary artery pressure during the study period. Furthermore, high levels of bio-ADM at 48 to 96 h were related to persistently impaired cardiac and end-organ function.

Conclusions: Bio-ADM is a valuable prognosticator and marker of impaired hemodynamics in CS patients. High levels of bio-ADM may show shock refractoriness and developing end-organ dysfunction and thus help to guide therapeutic approach in patients with CS. Study identifier of CardShock study NCT01374867 at clinicaltrials.gov.

Keywords: Adrenomedullin; Biomarkers; Cardiogenic shock; Hemodynamics; Lactate; Mortality.

Figures

Fig. 1

Time course of lactate (left) and bioactive adrenomedullin (bio-ADM) (right) levels in 90-day survivors (white boxes) and non-survivors (gray boxes). Box and whisker plot: central line = median, box = interquartile range, whiskers = 5th and 95th percentile, circles = outliers. Scatted line upper normal limit (2 mmol/L for lactate and 43 pg/mL for bio-ADM [8]). n = number of samples at each study time point. P values for all comparisons between survivors and non-survivors at each time point were <0.001, except for lactate at 48, 72, and 96 h, and bio-ADM at 0 h with P < 0.05

Fig. 2

Area under the curve (AUC) of lactate (gray line) and bioactive adrenomedullin, bio-ADM, (black line) to discriminate between 90-day survivors and non-survivors at each time point

Fig. 3

Ninety-day survival of patients with high (>55.7 pg/mL) or low (≤55.7 pg/mL) levels of bio-ADM at 48 h (P value = 0.001 with log-rank testing)

Fig. 4

Comparison of hemodynamics between patients with a high and low bioactive adrenomedullin (bio-ADM) and b high and low lactate levels. Data presented as median with interquartile range of hemodynamic and biomarker data collected during the initial 96 h. The number (n) of patients with each measure is indicated on top of the box plot. CI cardiac index (L/min/m2), MAP mean arterial pressure (mmHg), CVP central venous pressure (mmHg), sPAP systolic pulmonary artery pressure (mmHg). Dichotomization of biomarker values was based on median lactate (1.63 mmol/L) or bio-ADM (55.7 pg/ml) during the study period. P value based on Wilcoxon rank-sum test

Fig. 5

Association of bioactive adrenomedullin (bio-ADM) with hemodynamics and organ dysfunction at 48–96 h. Dichotomization of bio-ADM was based on 55.7 pg/ml cut-point at 48–96 h. The number (n) of patients with each measure is indicated on top of the box plot. P value based on Wilcoxon rank-sum test. CI cardiac index (L/min/m2), CVP central venous pressure (mmHg), eGRF estimated glomerular filtration rate (ml/min/1.73m2), ALAT alanine transaminase (UI/L)