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Intensive Care Medicine

, Volume 33, Issue 4, pp 703–710 | Cite as

Adrenomedullin reduces vascular hyperpermeability and improves survival in rat septic shock

  • Bettina Temmesfeld-Wollbrück
  • Bernhard Brell
  • István Dávid
  • Martin Dorenberg
  • Jörn Adolphs
  • Bernd Schmeck
  • Norbert Suttorp
  • Stefan HippenstielEmail author
Experimental

Abstract

Objective

Current therapies of sepsis and septic shock require administration of a large volume of fluid to maintain hemodynamic stability. The vasoregulatory peptide adrenomedullin has been shown to prevent the transition to the fatal hypocirculatory septic state by poorly understood mechanisms. We tested the hypothesis that therapeutic administration of adrenomedullin would reduce vascular hyperpermeability, thereby contributing to improved hemodynamics and survival.

Design

Prospective randomized controlled animal study.

Subjects

Male Sprague–Dawley rats (270 g).

Interventions

We used 4.8 × 103 U/kg of Staphylococcus aureus α-toxin, a pore-forming exotoxin, to induce vascular leakage and circulatory shock in rats. The infusion rate was 24 μg/kg per hour. Adrenomedullin was started 1 h after α-toxin administration.

Measurement and results

Infusion of α-toxin in rats induced cardiocirculatory failure resulting in a 6-h mortality of 53%. α-Toxin provoked massive vascular hyperpermeability, which was indicated by an enrichment of Evans blue dye albumin in the tissues of lung, liver, ileum and kidney. Plasma fluid loss led to a significant hemoconcentration. Hemodynamic impairment observed after α-toxin infusion was closely correlated to vascular hyperpermeability. Therapeutic administration of 24 μg/kg per hour adrenomedullin reduced 6-h mortality from 53% to 7%. Stabilization of the endothelial barrier by adrenomedullin was indicated by reduced extravasation of albumin and plasma fluid and may have contributed to hemodynamic improvement.

Conclusions

These data suggest that adrenomedullin-related reduction of vascular hyperpermeability might represent a novel and important mechanism contributing to the beneficial effects of this endogenous vasoregulatory peptide in sepsis and septic shock.

Keywords

Adrenomedullin Staphylococcus aureus Vascular permeability Sepsis Cardiac output Organ failure 

Notes

Acknowledgements

The authors thank Prof. Dr. med. Sucharit Bhakdi from Johannes Gutenberg University, Mainz, Germany who generously provided purified S. aureus α-toxin. This work was supported by grants from the Deutsche Forschungsgemeinschaft to N.S. (SSP 1130) and S.H. (HI 789/5–1), the Bundesministerium für Bildung und Forschung to S.H. (BMBF-Competence Network CAPNETZ C15), and the Charité to B.T.-W. (Rahel Hirsch award).

Supplementary material

134_2007_561_MOESM1_ESM.doc (155 kb)
Electronic Supplementary Material (DOC 155K)

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Bettina Temmesfeld-Wollbrück
    • 1
  • Bernhard Brell
    • 1
  • István Dávid
    • 1
  • Martin Dorenberg
    • 1
  • Jörn Adolphs
    • 2
  • Bernd Schmeck
    • 1
  • Norbert Suttorp
    • 1
  • Stefan Hippenstiel
    • 1
    Email author
  1. 1.Department of Internal Medicine/Infectious Diseases and Respiratory MedicineCharité–University Medicine BerlinBerlinGermany
  2. 2.Department of Anaesthesiology and Critical Care MedicineCharité–Universitätsmedizin BerlinBerlinGermany

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