Bioactive adrenomedullin dynamics and microcirculatory changes in a porcine model of hemorrhagic shock.

Abstract

Background: Hemorrhagic shock is a leading cause of preventable trauma death, marked by impaired oxygen delivery and endothelial dysfunction. Bioactive adrenomedullin (bio-ADM) regulates endothelial barrier integrity, but its dynamics during hemorrhagic shock and resuscitation remain unclear. This secondary analysis of a porcine hemorrhagic shock model investigated bio-ADM and its association with macro- and microcirculatory parameters during resuscitation. All animals received crystalloid infusion (10 mL/kg/h) from anesthesia induction onward. Shock was induced by blood withdrawal to maintain MAP at 40 ± 5 mmHg for 60 min (T5), before randomization to control (n = 7), fluid (n = 6), or noradrenaline (n = 7) groups, with intervention groups titrated to MAP targets of 65 then 90 mmHg (60 min each). Macrocirculation was assessed via vital signs and pulse contour analysis; microcirculation via hyperspectral imaging (tissue oxygenation, hemoglobin, water index).

Results: Fluid resuscitation improved macrohemodynamics and microcirculatory oxygenation versus control and noradrenaline, which failed to sustain perfusion and impaired microcirculatory oxygenation. Bio-ADM increased after shock induction (p < 0.001), peaking at T9 (120 min of therapy). At T5, levels were comparable among control (16.8 [13.6-18.9] pg/ml), fluid (15.65 [15.43-16.55] pg/ml), and noradrenaline (14.3 [7.85-18.95] pg/ml). Thereafter, bio-ADM continued to rise in control (19.7 [17.4-32.6] pg/ml) and noradrenaline (21.2 [14.4-33.45] pg/ml), while stabilizing in the fluid group (12.05 [10.65-15.18] pg/ml); accordingly, the T5-T9 increase was smaller in the fluid group than in control (p = 0.022) or noradrenaline (p = 0.003). The fluid group received ~3-fold more fluid by T9. Higher bio-ADM correlated with lower MAP, higher lactate, and lower ScvO₂, but not oxygen delivery (DO₂); a higher tissue water index correlated with a smaller rise.

Conclusions: Bio-ADM increased during hemorrhagic shock, extending previous observations from cardiogenic and septic shock, and represents a comparatively non-specific marker of endothelial and microcirculatory stress rather than specific to any single shock etiology. Effective resuscitation was associated with stabilization, rather than a clear decrease, of bio-ADM levels, though this coincided with higher fluid administration, and dilution cannot be excluded. Whether bio-ADM offers therapeutic utility to guide resuscitation remains unclear, warranting further prospective evaluation in animal and human studies.