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Adrenomedullin blockade improves catecholamine responsiveness and kidney function in resuscitated murine septic shock
Critical Care volume 16, Article number: P22 (2012)
The effects of adrenomedullin in circulatory shock states are controversially discussed: while its exogenous supplementation improved organ function and survival  in experimental models due to maintenance of hyperdynamic hemodynamics  in otherwise hypodynamic conditions, high blood levels were associated with increased mortality in patients with septic shock , most likely as a result of excessive vasodilatation  and/or impaired systolic heart function .
Immediately after cecal ligation and puncture to induce peritonitis, mice randomly received vehicle (n = 11) or the adrenomedullin antibody HAM1101 (n = 9; 2 μg/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).
Adrenomedullin antagonism decreased the noradrenaline requirements needed to achieve target hemodynamics (0.009 (0.009; 0.012) vs. 0.02 (0.015; 0.044) μg/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) μg/ml, P = 0.006; creatinine clearance: 400 (316; 509) vs. 197 (110; 301) μl/minute, P = 0.006).
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.
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Supported by an unrestricted grant from AdrenoMed AG.
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Wagner, K., Wachter, U., Vogt, J. et al. Adrenomedullin blockade improves catecholamine responsiveness and kidney function in resuscitated murine septic shock. Crit Care 16, P22 (2012). https://doi.org/10.1186/cc10629
- Glomerular Filtration
- Acute Kidney Injury
- Cecal Ligation
- Circulatory Shock