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Transthoracic Echocardiography to Assess Post-Resuscitation Left Ventricular Dysfunction After Acute Myocardial Infarction and Cardiac Arrest in Pigs

One of the main causes of out-of-hospital cardiac arrest is acute myocardial infarction (AMI). After successful resuscitation from cardiac arrest, ...

Istituto di Ricerche Farmacologiche Mario Negri IRCCS

Quantitative electrocardiographic (ECG) waveform analysis provides a noninvasive reflection of the metabolic milieu of the myocardium during resuscitation and is a potentially useful tool to optimize the defibrillation strategy. However, whether combining multiple ECG features can improve the capability of defibrillation outcome prediction in comparison to single feature analysis is still uncertain.

Combining multiple ECG features does not improve prediction of defibrillation outcome compared to single features in a large population of out-of-hospital cardiac arrests.

Pauses in chest compressions (CCs) have a negative association with survival from cardiac arrest. Electrocardiographic (ECG) rhythm analysis and defibrillator charging are significant contributors to CC pauses.

Cardiac rhythm analysis during ongoing cardiopulmonary resuscitation using the Analysis During Compressions with Fast Reconfirmation technology.

The noble gas argon (Ar) is a "biologically" active element and has been extensively studied preclinically for its organ protection properties. This work reviews all preclinical studies employing Ar and describes the clinical uses reported in literature, analyzing 55 pertinent articles found by means of a search on PubMed and Embase. Ventilation with Ar has been tested in different models of acute disease at concentrations ranging from 20% to 80% and for durations between a few minutes up to days. Overall, lesser cell death, smaller infarct size, and better functional recovery after ischemia have been repeatedly observed. Modulation of the molecular pathways involved in cell survival, with resulting anti-apoptotic and pro-survival effects, appeared as the determinant mechanism by which Ar fulfills its protective role. These beneficial effects have been reported regardless of onset and duration of Ar exposure, especially after cardiac arrest. In addition, ventilation with Ar was safe both in animals and humans. Thus, preclinical and clinical data support future clinical studies on the role of inhalatory Ar as an organ protector.

A complete review of preclinical and clinical uses of the noble gas argon: Evidence of safety and protection.

Identifying the optimum chest compression point during cardiopulmonary resuscitation.

Novel pharmacological approaches are needed to improve outcomes of patients with idiopathic pulmonary hypertension. Rho-associated protein kinase (ROCK) inhibitors have shown beneficial effects in preclinical models of pulmonary arterial hypertension (PAH), because of their role in the regulation of pulmonary artery vasoconstrictor tone and remodeling. We compared a ROCK inhibitor, Y-27632, for the first time with the dual endothelin receptor antagonist, macitentan, in a monocrotaline-induced rat pulmonary hypertension model. Different methods (echocardiography, hemodynamics, histology of right ventricle and pulmonary vessels, and circulating biomarkers) showed consistently that 100 mg/kg daily of Y-27632 and 10 mg/kg daily of macitentan slowed the progression of PAH both at the functional and structural levels. Treatments started on day 14 after monocrotaline injection and lasted 14 days. The findings of all experimental methods show that the selective ROCK inhibitor Y-27632 has more pronounced effects than macitentan, but a major limitation to its use is its marked peripheral vasodilating action.

Monocrotaline-induced pulmonary arterial hypertension: Time-course of injury and comparative evaluation of macitentan and Y-27632, a Rho kinase inhibitor.

The identification of new treatments for primary pulmonary arterial hypertension (PAH) is a critical unmet need since there is no a definitive cure for this disease yet. Due to the complexity of PAH, a wide set of methods are necessary to assess the response to a pharmacological intervention. Thus, a rigorous protocol is crucial when experimental studies are designed. In the present experimental protocol, a stepwise approach was followed in a monocrotaline-induced PAH model in the rat, moving from the dose finding study of treatment compounds to the recognition of the onset of disease manifestation, in order to identify when to start a curative treatment. A complete multidimensional evaluation of treatment effects represented the last step. The primary study endpoint was the change in right ventricular systolic pressure after 14 days of treatment; echocardiographic and biohumoral markers together with heart and pulmonary arterial morphometric parameters were considered as secondary efficacy and/or safety endpoints and for the evaluation of the biologic coherence in the different results.

Primary pulmonary arterial hypertension: Protocol to assess comprehensively in the rat the response to pharmacologic treatments.

Whilst there has been progress in supportive treatment for traumatic brain injury (TBI), specific neuroprotective interventions are lacking. Models of ischaemic heart and brain injury show the therapeutic potential of argon gas, but it is still not known whether inhaled argon (iAr) is protective in TBI. We tested the effects of acute administration of iAr on brain oedema, tissue micro-environmental changes, neurological functions, and structural outcome in a mouse model of TBI.

Efficacy of acute administration of inhaled argon on traumatic brain injury in mice.

Available animal models of acute heart failure (AHF) and their limitations are discussed herein. A novel and preclinically relevant porcine model of decompensated AHF (ADHF) is then presented.

Searching for Preclinical Models of Acute Decompensated Heart Failure: a Concise Narrative Overview and a Novel Swine Model.

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 (<0.0001). Histology showed less neuronal degeneration in the cortex (<0.05) but not in the hippocampus, and less reactive microglia activation in the hippocampus (=0.007), after Ar compared with control treatment. A lower increase in circulating biomarkers of brain injury, together with less kynurenine pathway activation (<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 (<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%.

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

Ventilation with the noble gas argon in an  model of idiopathic pulmonary arterial hypertension in rats.

Primary vasopressor efficacy of epinephrine during cardiopulmonary resuscitation (CPR) is due to its α-adrenergic effects. However, epinephrine plays β1-adrenergic actions, which increasing myocardial oxygen consumption may lead to refractory ventricular fibrillation (VF) and poor outcome. Effects of a single dose of esmolol in addition to epinephrine during CPR were investigated in a porcine model of VF with an underlying acute myocardial infarction. VF was ischemically induced in 16 pigs and left untreated for 12 min. During CPR, animals were randomized to receive epinephrine (30 µg/kg) with either esmolol (0.5 mg/kg) or saline (control). Pigs were then observed up to 96 h. Coronary perfusion pressure increased during CPR in the esmolol group compared to control (47 ± 21 vs. 24 ± 10 mmHg at min 5, p < 0.05). In both groups, 7 animals were successfully resuscitated and 4 survived up to 96 h. No significant differences were observed between groups in the total number of defibrillations delivered prior to final resuscitation. Brain histology demonstrated reductions in cortical neuronal degeneration/necrosis (score 0.3 ± 0.5 vs. 1.3 ± 0.5, p < 0.05) and hippocampal microglial activation (6 ± 3 vs. 22 ± 4%, p < 0.01) in the esmolol group compared to control. Lower circulating levels of neuron specific enolase were measured in esmolol animals compared to controls (2[1-3] vs. 21[16-52] ng/mL, p < 0.01). In this preclinical model, β1-blockade during CPR did not facilitate VF termination but provided neuroprotection.

Esmolol during cardiopulmonary resuscitation reduces neurological injury in a porcine model of cardiac arrest.

Perioperative cardiac arrest is a rare complication with an incidence of around 1 in 1400 cases, but it carries a high burden of mortality reaching up to 70% at 30 days. Despite its specificities, guidelines for treatment of perioperative cardiac arrest are lacking. Gathering the available literature may improve quality of care and outcome of patients.

Clinical practice recommendations on the management of perioperative cardiac arrest: A report from the PERIOPCA Consortium.

Background Brain injury and neurological deficit are consequences of cardiac arrest (CA), leading to high morbidity and mortality. Peripheral activation of the kynurenine pathway (KP), the main catabolic route of tryptophan metabolized at first into kynurenine, predicts poor neurological outcome in patients resuscitated after out-of-hospital CA. Here, we investigated KP activation in hippocampus and plasma of rats resuscitated from CA, evaluating the effect of KP modulation in preventing CA-induced neurological deficit. Methods and Results Early KP activation was first demonstrated in 28 rats subjected to electrically induced CA followed by cardiopulmonary resuscitation. Hippocampal levels of the neuroactive metabolites kynurenine, 3-hydroxy-anthranilic acid, and kynurenic acid were higher 2 hours after CA, as in plasma. Further, 36 rats were randomized to receive the inhibitor of the first step of KP, 1-methyl-DL-tryptophan, or vehicle, before CA. No differences were observed in hemodynamics and myocardial function. The CA-induced KP activation, sustained up to 96 hours in hippocampus (and plasma) of vehicle-treated rats, was counteracted by the inhibitor as indicated by lower hippocampal (and plasmatic) kynurenine/tryptophan ratio and kynurenine levels. 1-Methyl-DL-tryptophan reduced the CA-induced neurological deficits, with a significant correlation between the neurological score and the individual kynurenine levels, as well as the kynurenine/tryptophan ratio, in plasma and hippocampus. Conclusions These data demonstrate the CA-induced lasting activation of the first step of the KP in hippocampus, showing that this activation was involved in the evolving neurological deficit. The degree of peripheral activation of KP may predict neurological function after CA.

Article	Year
Combining multiple ECG features does not improve prediction of defibrillation outcome compared to single features in a large population of out-of-hospital cardiac arrests. Critical care (London, England)\| PubMed ID: 26652159	2015
Cardiac rhythm analysis during ongoing cardiopulmonary resuscitation using the Analysis During Compressions with Fast Reconfirmation technology. Heart rhythm\| PubMed ID: 28917561	2018
A complete review of preclinical and clinical uses of the noble gas argon: Evidence of safety and protection. Annals of cardiac anaesthesia\| PubMed ID: 30971592	2019
Identifying the optimum chest compression point during cardiopulmonary resuscitation. Heart & lung : the journal of critical care\| PubMed ID: 31676063	2020
Monocrotaline-induced pulmonary arterial hypertension: Time-course of injury and comparative evaluation of macitentan and Y-27632, a Rho kinase inhibitor. European journal of pharmacology\| PubMed ID: 31697933	2019
Primary pulmonary arterial hypertension: Protocol to assess comprehensively in the rat the response to pharmacologic treatments. MethodsX\| PubMed ID: 31993338	2020
Efficacy of acute administration of inhaled argon on traumatic brain injury in mice. British journal of anaesthesia\| PubMed ID: 32977957	2021
Searching for Preclinical Models of Acute Decompensated Heart Failure: a Concise Narrative Overview and a Novel Swine Model. Cardiovascular drugs and therapy\| PubMed ID: 33098053	2022
Ventilation With Argon Improves Survival With Good Neurological Recovery After Prolonged Untreated Cardiac Arrest in Pigs. Journal of the American Heart Association\| PubMed ID: 33289464	2020
Ventilation with the noble gas argon in an model of idiopathic pulmonary arterial hypertension in rats. Medical gas research\| PubMed ID: 33942784	2021
Esmolol during cardiopulmonary resuscitation reduces neurological injury in a porcine model of cardiac arrest. Scientific reports\| PubMed ID: 34017043	2021
Clinical practice recommendations on the management of perioperative cardiac arrest: A report from the PERIOPCA Consortium. Critical care (London, England)\| PubMed ID: 34325723	2021
Brain Kynurenine Pathway and Functional Outcome of Rats Resuscitated From Cardiac Arrest. Journal of the American Heart Association\| PubMed ID: 34816736	2021

Francesca Fumagalli

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