Skip to main content

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

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 hypodynamic 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 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).

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) 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).

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.

References

  1. 1.

    Wu R, et al.: Mol Med. 2009, 15: 28-33.

    PubMed Central  CAS  PubMed  Google Scholar 

  2. 2.

    Ertmer C, et al.: Br J Anaesth. 2007, 99: 830-836. 10.1093/bja/aem295

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Guignant C, et al.: Intensive Care Med. 2009, 35: 1859-1867. 10.1007/s00134-009-1610-5

    Article  PubMed  Google Scholar 

  4. 4.

    Mazzocchi G, et al.: Life Sci. 2000, 66: 1445-1450. 10.1016/S0024-3205(00)00455-0

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Hyvelin JM, et al.: J Card Surg. 2002, 17: 328-335.

    Article  PubMed  Google Scholar 

  6. 6.

    Wagner F, et al.: Shock. 2011, 35: 396-402. 10.1097/SHK.0b013e3181ffff0e

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Wagner F, et al.: J Trauma. 2011, in press.

    Google Scholar 

Download references

Acknowledgements

Supported by an unrestricted grant from AdrenoMed AG.

Author information

Affiliations

Authors

Corresponding author

Correspondence to K Wagner.

Rights and permissions

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Cite this article

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

Download citation

Keywords

  • Peritonitis
  • Glomerular Filtration
  • Acute Kidney Injury
  • Cecal Ligation
  • Circulatory Shock