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The Fibrin-Derived Peptide Bβ15–42 (FX06) Ameliorates Vascular Leakage and Improves Survival and Neurocognitive Recovery: Implications From Two Animal Models of Cardiopulmonary Resuscitation*

Bergt, Stefan MD; Gruenewald, Matthias MD; Beltschany, Claudia MD; Grub, Andrea MD; Neumann, Tobias MD; Albrecht, Martin PhD; Vollmar, Brigitte MD; Zacharowski, Kai MD, PhD, FRCA; Roesner, Jan P. MD; Meybohm, Patrick MD

doi: 10.1097/CCM.0000000000001860
Online Laboratory Investigations

Objectives: The fibrin-derived peptide Bβ15–42 (FX06) has been proven to attenuate ischemia/reperfusion injury. We tested the hypothesis that Bβ15–42 improves survival rate and neurocognitive recovery after cardiopulmonary resuscitation.

Design: Pig and mouse model of cardiopulmonary resuscitation.

Setting: Two university hospitals.

Subjects: Pigs and mice.

Interventions: Pigs (n = 16) were subjected to 8-minute cardiac arrest. Successful resuscitated pigs (n = 12) were randomized either to 3 mg/kg Bβ15–42 followed by a continuous infusion of 1 mg/kg/hr for 5 hours (pFX06; n = 6) or the control group (pCONTROL; n = 6). Cardiac damage, function, and hemodynamics were recorded up to 8 hours. Mice (n = 52) were subjected to 4-minute cardiac arrest followed by cardiopulmonary resuscitation, and randomized either to two boli of 2.4 mg/kg Bβ15–42 (mFX06; n = 26) or the control group (mCONTROL; n = 26). Fourteen-day survival rate, neurocognitive function, and endothelial integrity (additional experiment with n = 26 mice) were evaluated.

Measurements and Main Results: 15–42 reduced cumulative fluid intake (3,500 [2,600–4,200] vs 6,800 [5,700–7,400] mL; p = 0.004) within 8 hours in pigs. In mice, Bβ15–42 improved 14-day survival rate (mFX06 vs mCONTROL; 11/26 vs 6/26; p < 0.05) and fastened neurocognitive recovery in the Water-Maze test (15/26 vs 9/26 mice with competence to perform test; p < 0.05). Bβ15–42-treated mice showed a significant higher length of intact pulmonary endothelium and reduced pulmonary leukocyte infiltration.

Conclusions: This study confirms the new concept of an important role of fibrin derivatives in global ischemia/reperfusion injury, which can be attenuated by the fibrin-derived peptide Bβ15–42.

Supplemental Digital Content is available in the text.

1Department of Anesthesiology and Critical Care Medicine, University Hospital Rostock, Rostock, Germany.

2Department of Anesthesiology and Intensive Care Medicine, Schleswig-Holstein University Hospital, Campus Kiel, Kiel, Germany.

3Department of Anesthesiology and Intensive Care Medicine, University Hospital of Cologne, North Rhine-Westphalia, Germany.

4Institute for Experimental Surgery, Rostock University, Rostock, Germany.

5Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany.

6Department of Anesthesiology and Intensive Care Medicine, Suedstadt Hospital, Rostock, Germany.

*See also p. 1956.

Drs. Bergt, Gruenewald, Roesner, and Meybohm contributed equally.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Supported, in part, by a grant of the Forschungsförderung der Medizinischen Fakultät der Rostocker Universität (FORUN)-program (number: 889034) by the Medical Faculty, Rostock University, and by departmental funding by the University Hospital Schleswig-Holstein, Department of Anesthesiology and Intensive Care Medicine, Campus Kiel, Germany.

Dr. Gruenewald disclosed other support (he reports grants and personal fees from Air Liquide Santé International, Fresenius Medical, GE Healthcare, Pulsion Medical Systems and Werfen Group outside the submitted work); and he lectured for Beltschany, GE Healthcare, and Werfen Group. Dr. Roesner received support for article research from FORUN-program (research start-up program given by the Medical Faculty of Rostock University). His institution received funding from FORUN-program (research start-up grant, given by the Medical Faculty of Rostock University). The remaining authors have disclosed that they do not have any potential conflicts of interest.

Address requests for reprints to: Patrick Meybohm, MD, Department for Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. E-mail: patrick.meybohm@kgu.de

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