Application of alpha1-antitrypsin in a rat model of veno-arterial extracorporeal membrane oxygenation

Fabian Edinger,Christian Koch,Christoph Schmitt,J Michael McIntosh,Winfried Padberg,Veronika Grau,Michael Sander,Melanie Markmann,Sabina Janciauskiene

doi:10.1038/s41598-021-95119-y

Abstract

Extracorporeal membrane oxygenation (ECMO) is a life-saving intervention for patients suffering from respiratory or cardiac failure. The ECMO-associated morbidity and mortality depends to a large extent on the underlying disease and is often related to systemic inflammation, consecutive immune paralysis and sepsis. Here we tested the hypothesis that human α1-antitrypsin (SERPINA1) due to its anti-protease and anti-inflammatory functions may attenuate ECMO-induced inflammation. We specifically aimed to test whether intravenous treatment with α1-antitrypsin reduces the release of cytokines in response to 2 h of experimental ECMO. Adult rats were intravenously infused with α1-antitrypsin immediately before starting veno-arterial ECMO. We measured selected pro- and anti-inflammatory cytokines and found, that systemic levels of tumor necrosis factor-α, interleukin-6 and interleukin-10 increase during experimental ECMO. As tachycardia and hypertension developed in response to α1-antitrypsin, a single additional bolus of fentanyl and midazolam was given. Treatment with α1-antitrypsin and higher sedative doses reduced all cytokine levels investigated. We suggest that α1-antitrypsin might have the potential to protect against both ECMO-induced systemic inflammation and immune paralysis. More studies are needed to corroborate our findings, to clarify the mechanisms by which α1-antitrypsin inhibits cytokine release in vivo and to explore the potential application of α1-antitrypsin in clinical ECMO.

Highlights

Extracorporeal membrane oxygenation (ECMO) is a life-saving intervention for patients suffering from respiratory or cardiac failure
ECMO often leads to the development of an initially sterile systemic inflammatory response syndrome (SIRS) that paves the way to life-threatening immune paralysis and multi organ damage
Until the end of the experiment, we found an increased native cardiac output (CO) in animals treated with veno-arterial ECMO (VA ECMO) compared to the sham group, irrespective of treatment with AAT (Fig. 3A)

Summary

Introduction

Extracorporeal membrane oxygenation (ECMO) is a life-saving intervention for patients suffering from respiratory or cardiac failure. The ECMO-associated morbidity and mortality depends to a large extent on the underlying disease and is often related to systemic inflammation, consecutive immune paralysis and sepsis. We aimed to test whether intravenous treatment with α1-antitrypsin reduces the release of cytokines in response to 2 h of experimental ECMO. ECMO often leads to the development of an initially sterile systemic inflammatory response syndrome (SIRS) that paves the way to life-threatening immune paralysis and multi organ damage. Most of these models use the right internal jugular vein for the inflow of venous blood to the ECMO (venous drainage) and the tail artery for the arterial outflow from the ECMO back to the circulation (arterial return). In contrast to Koning et al, we continue invasive ventilation of the lungs during VA ECMO to avoid pulmonary hypoxia, because we aim to investigate the inflammatory response induced by the ECMO circuit[21]

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