Experimental paperA comparison of etanercept vs. infliximab for the treatment of post-arrest myocardial dysfunction in a swine model of ventricular fibrillation☆
Introduction
The post cardiac arrest syndrome is a frequently observed pathophysiological state following the return of spontaneous circulation from cardiac arrest and is characterized by brain injury, myocardial dysfunction, a systemic ischemia/reperfusion response, and the presence of persistent precipitating pathology, such as coronary ischemia.1 Inpatient mortality rates following return of spontaneous circulation are as high as 70–80%. The early post cardiac period shares characteristics with the sepsis syndrome.2, 3, 4
Inflammatory cytokines appear to play an important role in the pathophysiology of the post cardiac arrest syndrome and have been implicated in the myocardial dysfunction and brain injury observed in the early post arrest period.5, 6, 7, 8 The pro-inflammatory cytokine, TNF-α, a master regulator of the inflammatory response, is synthesized and released both locally and systemically following cardiac arrest in response to ischemia, α-adrenergic stimulation, and lactic acidosis.9 We have previously demonstrated that infliximab, a monoclonal antibody directed against both soluble and transmembrane bound forms of TNF-α, reduces myocardial dysfunction in the early post cardiac arrest period in a swine model of ventricular fibrillation (VF) when administered immediately following the return of spontaneous circulation.10
The purpose of this study was to compare the effects of infliximab on post cardiac arrest myocardial function with those of etanercept, a soluble TNF-α antagonist that acts as a decoy receptor for the cytokine, in a swine model of VF. We hypothesized that etanercept would demonstrate comparable effects to infliximab.
Section snippets
Materials and methods
This study conforms to the American Physiologic Society's Guiding Principals in the Care and Use of Animals and was approved by the LABioMed Institutional Animal Care and Use Committee.
Thirty male, mixed breed domestic swine (Yorkshire and Yorkshire/Hampshire crossbreed) weighing 39 ± 3 kg were used for this study. Animals were fasted the night before the experiment with ad libitum access to water. Animals were premedicated with intramuscular ketamine (20 mg/kg) and xylazine (2 mg/kg) after which
Results
Ten animals were assigned to each group (saline, infliximab, etanercept). Pre-arrest hemodynamic variables were similar between groups (Table 1). No statistically significant differences in important resuscitation variables were found between groups (Table 2).
TNF-α levels rose in all groups in the post-ROSC period (Fig. 1). There was no statistically significant difference in TNF-α levels between groups at any time point.
In the post-ROSC period, MAP fell from pre-arrest values in all groups (
Discussion
The results of this study suggest that infliximab is superior to etanercept in ameliorating post cardiac arrest myocardial dysfunction during the early post-ROSC period. The effects observed in swine treated with infliximab were consistent with our prior published experience.10 However, we found no evidence of a significant effect of etanercept on post cardiac arrest hemodynamics or indices of LV function. This suggests that as immune modulators for the treatment of post cardiac arrest
Conflict of interest statement
The authors report no conflicts of interest.
Funding source
Funded, in part, by a grant from the NIH NHLBI R01 HL076671.
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Gene-selective transcription promotes the inhibition of tissue reparative macrophages by TNF
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A Spanish translated version of the summary of this article appears as Appendix in the final online version at http://dx.doi.org/10.1016/j.resuscitation.2012.12.028.