Adrenomedullin blockade improves catecholamine responsiveness and kidney function in resuscitated murine septic shock

Abstract

Introduction The effects of adrenomedullin in circulatory shock states are controversially discussed: while its exogenous supplementation improved organ function and survival [1] in experimental models due to maintenance of hyperdynamic hemodynamics [2] in otherwise hypo dynamic conditions, high blood levels were associated with increased mortality in patients with septic shock [3], most likely as a result of excessive vasodilatation [4] and/or impaired systolic heart function [5]. Methods Immediately after cecal ligation and puncture to induce peritonitis, mice randomly received vehicle (n = 11) or the adrenomedullin antibody HAM1101 (n = 9; 2 mug/g to achieve antibody concentrations >4 ng/ml). Fifteen hours later animals were anesthetized, mechanically ventilated and instrumented for a consecutive 6-hour observation period. Colloid fluid resuscitation and continuous i.v. noradrenaline were titrated to maintain normotensive (mean blood pressure >60 mmHg) and hyperdynamic hemodynamics. Creatinine blood levels and clearance were assessed as surrogate for glomerular filtration [6,7]. All data are median (quartiles). Results Adrenomedullin antagonism decreased the noradrenaline requirements needed to achieve target hemodynamics (0.009 (0.009; 0.012) vs. 0.02 (0.015; 0.044) mug/g/hour, P <0.001), increased total diuresis (2.6 (2.3; 3.9) vs. 0.6 (0.5; 2.7) ml, P = 0.028) resulting in improved fluid balance (0.18 (0.14; 0.2) vs. 0.26 (0.19; 0.27), P = 0.011) and kidney function (creatinine levels at the end of the experiment: 1.3 (1.2; 1.5) vs. 2.0 (1.5; 2.9) mug/ml, P = 0.006; creatinine clearance: 400 (316; 509) vs. 197 (110; 301) mul/minute, P = 0.006). Conclusion In resuscitated murine septic shock, early modulation of excess adrenomedullin activity via antibody HAM1101 improves cardiovascular catecholamine responsiveness, ultimately associated with attenuation of acute kidney injury.