Ventilation With Argon Improves Survival With Good Neurological Recovery After Prolonged Untreated Cardiac Arrest in Pigs

Abstract

Background Ventilation with the noble gas argon (Ar) has shown neuroprotective and cardioprotective properties in different in vitro and in vivo models. Hence, the neuroprotective effects of Ar were investigated in a severe, preclinically relevant porcine model of cardiac arrest. Methods and Results Cardiac arrest was ischemically induced in 36 pigs and left untreated for 12 minutes before starting cardiopulmonary resuscitation. Animals were randomized to 4‐hour post‐resuscitation ventilation with: 70% nitrogen–30% oxygen (control); 50% Ar–20% nitrogen–30% oxygen (Ar 50%); and 70% Ar–30% oxygen (Ar 70%). Hemodynamic parameters and myocardial function were monitored and serial blood samples taken. Pigs were observed up to 96 hours for survival and neurological recovery. Heart and brain were harvested for histopathology. Ten animals in each group were successfully resuscitated. Ninety‐six‐hour survival was 60%, 70%, and 90%, for the control, Ar 50%, and Ar 70% groups, respectively. In the Ar 50% and Ar 70% groups, 60% and 80%, respectively, achieved good neurological recovery, in contrast to only 30% in the control group ( P <0.0001). Histology showed less neuronal degeneration in the cortex ( P <0.05) but not in the hippocampus, and less reactive microglia activation in the hippocampus ( P =0.007), after Ar compared with control treatment. A lower increase in circulating biomarkers of brain injury, together with less kynurenine pathway activation ( P <0.05), were present in Ar‐treated animals compared with controls. Ar 70% pigs also had complete left ventricular function recovery and smaller infarct and cardiac troponin release ( P <0.01). Conclusions Post‐resuscitation ventilation with Ar significantly improves neurologic recovery and ameliorates brain injury after cardiac arrest with long no‐flow duration. Benefits are greater after Ar 70% than Ar 50%.

Cardiac Arrest in Pigs With 48 hours of Post‐Resuscitation Care Induced by 2 Methods of Myocardial Infarction: A Methodological Description

“…Prior studies with a reperfusion‐reocclusion approach to myocardial infarction induction have reported infarct sizes of 6% to 10% relative to left ventricular mass. 29 , 30 , 31 The smaller infarct sizes in our model can be assigned to the lower sensitivity of a non‐contrast magnetic resonance scan relative to conventional methods for infarct size measurements.…”

“…Observation periods range between 24, 22 , 23 , 24 , 25 , 26 72, 27 , 28 or 96 hours. 29 , 30 , 31 The longest period of post‐cardiac arrest intensive care was 4 hours. 27 , 28 , 29 , 30 , 31 , 32 A consequence of awakening the animals shortly after resuscitation is that animals, which achieve initial ROSC but are cardiovascularly unstable in the early post‐resuscitation phase might die during the observation period in the pen without an exact cause of death.…”

“… 29 , 30 , 31 The longest period of post‐cardiac arrest intensive care was 4 hours. 27 , 28 , 29 , 30 , 31 , 32 A consequence of awakening the animals shortly after resuscitation is that animals, which achieve initial ROSC but are cardiovascularly unstable in the early post‐resuscitation phase might die during the observation period in the pen without an exact cause of death. In fact, 2 animals in our study (1 from each cardiac arrest group) received our maximum noradrenaline dosage (1 µg/kg per minute) and adrenaline support within the first 2 hours of ROSC, but both pigs survived until 48 hours with normal hemodynamic status, no inotropic support and in need of only low dose noradrenaline (<0.1 µg/kg per min).…”

Noble Gases Therapy in Cardiocerebrovascular Diseases: The Novel Stars?

“…The in-vivo and in-vitro studies indicated that Ar acted as a protector for cerebral ischemia injury, brain trauma, and cardiac arrest-induced neurological damage ( 97 – 110 ). The neuroprotective effects of Ar were involved in inhibiting microglia/macrophage activation and enhancing M2 microglia/macrophage polarization ( 107 , 109 , 110 ), reducing stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) activation and high mobility group protein B1 (HMGB1) expression ( 106 ), inhibiting TLR2/4-mediated activation of signal transducer and activator of transcription 3 (STAT3) and NF-κB, and subsequently decreasing IL-8 expression ( 111 ).…”

Cardiac Arrest – An interdisciplinary scoping review of preclinical literature from 2020

“…In an expansion of the use of noble gasses in the care of patients following cardiac arrest, Fumagalli et al used different concentrations of the gas argon and found that pigs resuscitated with argon gas had increased rates of neurologically intact survival in a dose-responsive relationship [23]. Pigs treated with argon gas were also noted to have lower circulating levels of biomarkers for brain injury, and a decreased concentration of neurotoxin kynurenine metabolites in comparison to controls [23].…”