Plasma concentrations of inflammatory cytokines rise rapidly during ECMO-related SIRS due to the release of preformed stores in the intestine

Abstract

BackgroundExtracorporeal membrane oxygenation (ECMO) is a life-saving support system used in neonates and young children with severe cardiorespiratory failure. Although ECMO has reduced mortality in these critically-ill patients, almost all patients treated with ECMO develop a systemic inflammatory response syndrome (SIRS) characterized by a ‘cytokine storm’, leukocyte activation, and multisystem organ dysfunction. We used a neonatal porcine model of ECMO to investigate whether rising plasma concentrations of inflammatory cytokines during ECMO reflect de novo synthesis of these mediators in inflamed tissues, and therefore, can be used to assess the severity of ECMO-related SIRS.MethodsThree-week-old previously-healthy piglets were subjected to venoarterial ECMO for up to 8 hours. SIRS was assessed by histopathological analysis, measurement of neutrophil activation (flow cytometry), plasma cytokine concentrations (enzyme immunoassays), and tissue expression of inflammatory genes (polymerase chain reaction/western blots). Mast cell degranulation was investigated by measurement of plasma tryptase activity.ResultsPorcine neonatal ECMO was associated with systemic inflammatory changes similar to those seen in human neonates. TNF-α and interleukin-8 (IL-8) concentrations rose rapidly during the first 2 hours of ECMO, faster than the tissue expression of these cytokines. ECMO was associated with increased plasma mast cell tryptase activity, indicating that increased plasma concentrations of inflammatory cytokines during ECMO may result from mast cell degranulation and associated release of preformed cytokines stored in mast cells.ConclusionsTNF-α and IL-8 concentrations rose faster in plasma than in the peripheral tissues during ECMO, indicating that rising plasma levels of these cytokines immediately following the initiation of ECMO may not reflect increasing tissue synthesis of these cytokines. Mobilization of preformed cellular stores of inflammatory cytokines such as in mucosal mast cells may play an important pathophysiological role in ECMO-related SIRS.

Epidemiology of gastrointestinal bleeding in adult patients on extracorporeal life support

“…GI bleeding may be more frequent in ECLS patients as a result of multifactorial coagulopathy, generation of systemic inflammation, and nonpulsatile blood flow during VA ECLS, which can lead to reduced gastric perfusion and pH [2][3][4][5]. Future prospective studies would be helpful in confirming our findings.…”

Extracorporeal Membrane Oxygenation and the Kidney

“…AKI) and considerable mortality [21]. As in other extracorporeal treatments, the blood shear stress [21], the exposure to non-self surfaces and the air/blood interface may cause a hypercoagulable state [16] as well as systemic inflammation (fig. 3) [22].…”

Physiologically Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support: Fluconazole in Children on ECMO

“…However, in treating patients on ECLS, one of the challenges is understanding and appropriately compensating for the effect of the extracorporeal circuit on drug pharmacokinetics (PKs). Drug PKs can be altered in three primary ways: (i) adsorption of drug to the various components of the device;1, 2 (ii) increased volume of distribution due to hemodilution and physiologic changes associated with ECLS (e.g., inflammation);3, 4, 5 and (iii) altered clearance due to the underlying disease or direct impact of the artificial organ 6. As a result, optimal dosing in this setting likely differs compared to individuals not on ECLS.…”