Elsevier

Resuscitation

Volume 84, Issue 7, July 2013, Pages 999-1003
Resuscitation

Experimental paper
A comparison of etanercept vs. infliximab for the treatment of post-arrest myocardial dysfunction in a swine model of ventricular fibrillation

https://doi.org/10.1016/j.resuscitation.2012.12.028Get rights and content

Abstract

Aims

To compare the effects of two TNF-α antagonists, etanercept and infliximab, on post-cardiac arrest hemodynamics and global left ventricular function (LV) in a swine model following ventricular fibrillation (VF).

Methods

Domestic swine (n = 30) were placed under general anesthesia and instrumented before VF was induced electrically. After 7 min of VF, standard ACLS resuscitation was performed. Animals achieving return of spontaneous circulation (ROSC) were randomized to immediately receive infliximab (5 mg/kg, n = 10) or etanercept (0.3 mg/kg [4 mg/m2], n = 10) or vehicle (250 mL normal saline [NS], n = 10) and LV function and hemodynamics were monitored for 3 h.

Results

Following ROSC, mean arterial pressure (MAP), stroke work (SW), and LV dP/dt fell from pre-arrest values in all groups. However, at the 30 min nadir, infliximab-treated animals had higher MAP than either the NS group (difference 14.4 mm Hg, 95% confidence interval [CI] 4.2–24.7) or the etanercept group (19.2 mm Hg, 95% CI 9.0–29.5), higher SW than the NS group (10.3 gm-m, 95% CI 5.1–15.5) or the etanercept group (8.9 gm-m, 95% CI 4.0–14.4) and greater LV dP/dt than the NS group (282.9 mm Hg/s, 95% CI 169.6–386.1 higher with infliximab) or the etanercep group (228.9 mm Hg/s, 95% CI 115.6–342.2 higher with infliximab).

Conclusions

Only infliximab demonstrated a beneficial effect on post cardiac arrest hemodynamics and LV function in this swine model. Etanercept was no better in this regard than saline.

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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    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.

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