Preclinical Optimization of Treatment with Inhaled Argon to Improve Neurological Outcome and Survival After Cardiac Arrest

Fumagalli, Francesca Maria (2018). Preclinical Optimization of Treatment with Inhaled Argon to Improve Neurological Outcome and Survival After Cardiac Arrest. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000d99e

Abstract

Introduction. Treatment of post cardiac arrest (CA) syndrome represents a clinical priority. Inhalation of the noble gas Argon may represent an attractive option. The purpose of the current thesis is to determine the efficacy, safety and mechanisms of action of Argon in different experimental models.

Methods. In order to assess the efficacy of argon treatment on post CA syndrome, a pig model of CA with underlying acute myocardial infarction and cardiopulmonary resuscitation (CPR) was used. Following resuscitation, animals were randomly assigned to receive ventilation with 70% Argon (Ar 70%) or 70% Nitrogen (N₂70%) in oxygen. Argon effects were studied in models of CA with different level of severity (i.e. short or long duration of untreated ventricular fibrillation). Furthermore, administration of low Argon concentration (i.e. 50%) was evaluated in a subset of animals. Hemodynamics, myocardial function, neurologic recovery, brain and cardiac histological injury and biomarkers together with survival were evaluated. The safety of Argon treatment was assessed in healthy pigs. In parallel, mechanisms of action were explored. Specifically, brain protection was investigated in a rat model of CA followed by CPR. After resuscitation, animals were randomized to receive Ar 70% or N₂70%. Brain glutamate, gamma-amino butyric acid, pyruvate and lactate were measured by in vivo micro-dialysis. In addition, myocardial protection by argon was explored in rats subjected to coronary artery occlusion followed by reperfusion and receiving Ar 70% or N₂70% during reperfusion. Six and 24 h after reperfusion, myocardial injury, plasma troponin T concentration and myocardial neutrophil infiltration were evaluated.

Results. Efficacy of argon on preventing post CA brain injury has been demonstrated in swine. Indeed, a faster and complete neurologic recovery following CA and CPR was achieved in Argon-treated animals compared to controls, without detrimental effects on hemodynamics and respiratory gas exchanges. Beneficial effects of Argon tended to be higher at a concentration of 70% than of 50%. Results obtained in small rodents suggest that ventilation with Argon reduces brain lactate/ pyruvate level and troponin T release. However, further studies are needed in order explain the mechanism underpining Argon protective effects.

Conclusion. The consistency of the results is highly suggestive to consider ventilation with Argon as a promising therapeutic approach after CA and CPR.

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