Infliximab attenuates early myocardial dysfunction after resuscitation in a swine cardiac arrest model

Abstract

Objective: Left ventricular dysfunction after successful cardiopulmonary resuscitation contributes to early death after resuscitation. Proinflammatory cytokines are known to decrease myocardial function, and tumor necrosis factor-alpha has been shown to increase after successful resuscitation. We hypothesized that blocking the effects of tumor necrosis factor-alpha with infliximab would prevent or minimize postresuscitation cardiac dysfunction.

Design: Randomized, placebo-controlled comparative study.

Setting: Large animal research laboratory.

Subjects: Twenty-eight anesthetized and instrumented domestic male swine (Yorkshire and Yorkshire/Hampshire mix; weight, 35-45 kg).

Interventions: Infusion of infliximab (5 mg/kg) or normal saline after resuscitation from ventricular fibrillation cardiac arrest.

Measurements and main results: Hemodynamic variables, indices of left ventricular function, and tumor necrosis factor-alpha were measured before and after 8 mins of cardiac arrest during the early postresuscitation period (3 hrs). Within 5 mins of restoration of spontaneous circulation, 14 animals received infliximab, 5 mg/kg, infused over 30 mins. Fourteen animals received an infusion of normal saline. Inotropes and vasopressors were not administered to either group after resuscitation. Tumor necrosis factor-alpha increased after restoration of circulation and remained elevated throughout the observation period. Differences between groups were not significant. Interleukin-1beta concentration did not change significantly during the observation period in either study group. Mean arterial pressure and stroke work were significantly greater in the infliximab group within 30 mins of resuscitation, and these differences were sustained throughout the 3-hr postresuscitation period. The effect of tumor necrosis factor-alpha blockade was evident only in animals with a significant increase (doubling) in plasma tumor necrosis factor-alpha at 30 mins after arrest.

Conclusion: Tumor necrosis factor-alpha plays a role in cardiac dysfunction after arrest and infliximab may attenuate or prevent postresuscitation myocardial dysfunction when administered immediately after resuscitation.

Figure 1. Plasma TNF-α Concentrations Following Resuscitation

Plasma TNF-α concentrations (mean ± SE) were not significantly different between control and infliximab treatment groups during the 3 hour post-arrest observation period. TNF-α levels were greater than pre-arrest values (*p < 0.02) at 30 and 60 min following resuscitation in both groups.

Figure 2. Plasma IL-1β Concentrations Following Resuscitation

Plasma IL-1β concentrations (mean ± SE) did not increase significantly from pre-arrest values following resuscitation and differences were not observed between groups.

Figure 3. Mean Arterial Pressure (MAP) and Left Ventricular Stroke Work (LV SW) Following Resuscitation

MAP and SW (mean ± SE) were significantly decreased from pre-arrest values in both groups within 30 min of reperfusion. Values were significantly higher at all time points in the infliximab group. (*p < 0.002, Dunnet-Hsu adjusted for differences between groups).

Figure 4. Plasma TNF-α Concentrations in TNF Producers and Nonproducers

A dichotomy in the TNF-α response to reperfusion was observed in animals of both treatment groups. Fifty four percent of animals (n=15) demonstrated at least a doubling of TNF-α at 30 min post-arrest. *p < 0.002 compared to pre-arrest value. Data are mean ± SE.