Treatment with inhaled Argon: a systematic review of pre-clinical and clinical studies with meta-analysis on neuroprotective effect.

BACKGROUND: Argon (Ar) has been proposed as a potential therapeutic agent in multiple clinical conditions, specifically in organ protection. However, conflicting data on pre-clinical models, together with a great variability in Ar administration protocols and outcome assessments, have been reported. The aim of this study was to review evidence on treatment with Ar, with an extensive investigation on its neuroprotective effect, and to summarise all tested administration protocols. METHODS: Using the PubMed database, all existing pre-clinical and clinical studies on the treatment with Ar were systematically reviewed (registration: https://doi.org/10.17605/OSF.IO/7983D). Study titles and abstracts were screened, extracting data from relevant studies post full-text review. Exclusion criteria included absence of full text and non-English language. Furthermore, meta-analysis was also performed to assess Ar potential as neuroprotectant agent in different clinical conditions: cardiac arrest, traumatic brain injury, ischemic stroke, perinatal hypoxic-ischemic encephalopathy, subarachnoid haemorrhage. Standardised mean differences for neurological, cognitive and locomotor, histological, and physiological measures were evaluated, through appropriate tests, clinical, and laboratory variables. In vivo studies were evaluated for risk of bias using the Systematic Review Center for Laboratory Animal Experimentation tool, while in vitro studies underwent assessment with a tool developed by the Office of Health Assessment and Translation. FINDINGS: The systematic review detected 60 experimental studies (16 in vitro, 7 ex vivo, 31 in vivo, 6 with both in vitro and in vivo) investigating the role of Ar. Only one clinical study was found. Data from six in vitro and nineteen in vivo studies were included in the meta-analyses. In pre-clinical models, Ar administration resulted in improved neurological, cognitive and locomotor, and histological outcomes without any change in physiological parameters (i.e., absence of adverse events). INTERPRETATION: This systematic review and meta-analysis based on experimental studies supports the neuroprotective effect of Ar, thus providing a rationale for potential translation of Ar treatment in humans. Despite adherence to established guidelines and methodologies, limitations in data availability prevented further analyses to investigate potential sources of heterogeneity due to study design. FUNDING: This study was funded in part by Italian Ministry of Health-Current researchIRCCS and by Ministero della Salute Italiano, Ricerca Finalizzata, project no. RF 2019-12371416.

Wolf Creek XVII Part 8: Neuroprotection.

Introduction: Post-cardiac arrest brain injury (PCABI) is the primary determinant of clinical outcomes for patients who achieve return of spontaneous circulation after cardiac arrest (CA). There are limited neuroprotective therapies available to mitigate the acute pathophysiology of PCABI. Methods: Neuroprotection was one of six focus topics for the Wolf Creek XVII Conference held on June 14-17, 2023 in Ann Arbor, Michigan, USA. Conference invitees included international thought leaders and scientists in the field of CA resuscitation from academia and industry. Participants submitted via online survey knowledge gaps, barriers to translation, and research priorities for each focus topic. Expert panels used the survey results and their own perspectives and insights to create and present a preliminary unranked list for each category that was debated, revised and ranked by all attendees to identify the top 5 for each category. Results: Top 5 knowledge gaps included developing therapies for neuroprotection; improving understanding of the pathophysiology, mechanisms, and natural history of PCABI; deploying precision medicine approaches; optimizing resuscitation and CPR quality; and determining optimal timing for and duration of interventions. Top 5 barriers to translation included patient heterogeneity; nihilism & lack of knowledge about cardiac arrest; challenges with the translational pipeline; absence of mechanistic biomarkers; and inaccurate neuro-triage and neuroprognostication. Top 5 research priorities focused on translational research and trial optimization; addressing patient heterogeneity and individualized interventions; improving understanding of pathophysiology and mechanisms; developing mechanistic and outcome biomarkers across post-CA time course; and improving implementation of science and technology. Conclusion: This overview can serve as a guide to transform the care and outcome of patients with PCABI. Addressing these topics has the potential to improve both research and clinical care in the field of neuroprotection for PCABI.

The design of the PRINCESS 2 trial: A randomized trial to study the impact of ultrafast hypothermia on complete neurologic recovery after out-of-hospital cardiac arrest with initial shockable rhythm.

BACKGROUND: Delayed hypothermia, initiated after hospital arrival, several hours after cardiac arrest with 8-10 hours to reach the target temperature, is likely to have limited impact on overall survival. However, the effect of ultrafast hypothermia, i.e., delivered intra-arrest or immediately after return of spontaneous circulation (ROSC), on functional neurologic outcome after out-of-hospital cardiac arrest (OHCA) is unclear. In two prior trials, prehospital trans-nasal evaporative intra-arrest cooling was safe, feasible and reduced time to target temperature compared to delayed cooling. Both studies showed trends towards improved neurologic recovery in patients with shockable rhythms. The aim of the PRINCESS2-study is to assess whether cooling, initiated either intra-arrest or immediately after ROSC, followed by in-hospital hypothermia, significantly increases survival with complete neurologic recovery as compared to standard normothermia care, in OHCA patients with shockable rhythms. METHODS/DESIGN: In this investigator-initiated, randomized, controlled trial, the emergency medical services (EMS) will randomize patients at the scene of cardiac arrest to either trans-nasal cooling within 20 minutes from EMS arrival with subsequent hypothermia at 33°C for 24 hours after hospital admission (intervention), or to standard of care with no prehospital or in-hospital cooling (control). Fever (>37,7°C) will be avoided for the first 72 hours in both groups. All patients will receive post resuscitation care and withdrawal of life support procedures according to current guidelines. Primary outcome is survival with complete neurologic recovery at 90 days, defined as modified Rankin scale (mRS) 0-1. Key secondary outcomes include survival to hospital discharge, survival at 90 days and mRS 0-3 at 90 days. In total, 1022 patients are required to detect an absolute difference of 9% (from 45 to 54%) in survival with neurologic recovery (80% power and one-sided α=0,025, ß=0,2) and assuming 2,5% lost to follow-up. Recruitment starts in Q1 2024 and we expect maximum enrolment to be achieved during Q4 2024 at 20-25 European and US sites. DISCUSSION: This trial will assess the impact of ultrafast hypothermia applied on the scene of cardiac arrest, as compared to normothermia, on 90-day survival with complete neurologic recovery in OHCA patients with initial shockable rhythm. TRIAL REGISTRATION: NCT06025123.

Transthoracic impedance variability to assess quality of chest compression in out-of-hospital cardiac arrest.

BACKGROUND: Chest compression is a lifesaving intervention in out-of-hospital cardiac arrest (OHCA), but the optimal metrics to assess its quality have yet to be identified. The objective of this study was to investigate whether a new parameter, that is, the variability of the chest compression-generated transthoracic impedance (TTI), namely ImpCC , which measures the consistency of the chest compression maneuver, relates to resuscitation outcome. METHODS: This multicenter observational, retrospective study included OHCAs with shockable rhythm. ImpCC variability was evaluated with the power spectral density analysis of the TTI. Multivariate regression model was used to examine the impact of ImpCC variability on defibrillation success. Secondary outcome measures were return of spontaneous circulation and survival. RESULTS: Among 835 treated OHCAs, 680 met inclusion criteria and 565 matched long-term outcomes. ImpCC was significantly higher in patients with unsuccessful defibrillation compared to those with successful defibrillation (p = .0002). Lower ImpCC variability was associated with successful defibrillation with an odds ratio (OR) of 0.993 (95% confidence interval [95% CI], 0.989-0.998, p = .003), while the standard chest compression fraction (CCF) was not associated (OR 1.008 [95 % CI, 0.992-1.026, p = .33]). Neither ImpCC nor CCF was associated with long-term outcomes. CONCLUSIONS: In this population, consistency of chest compression maneuver, measured by variability in TTI, was an independent predictor of defibrillation outcome. ImpCC may be a useful novel metrics for improving quality of care in OHCA.

Impact of "basic life support & defibrillation" training on quality of telephone-assisted cardiopulmonary resuscitation.

While telephone-assisted cardiopulmonary resuscitation (T-CPR) is crucial for improving the chances of survival during cardiac arrest, there is limited information available on the effectiveness of T-CPR when administered by laypeople, especially those who are unfamiliar with these procedures. Therefore, we assessed the influence of basic life support and defibrillation (BLSD) training on the proficiency of T-CPR carried out by volunteer medical students participating in a BLSD course, using a simulated cardiac arrest scenario. The quality of T-CPR maneuvers was compared before and after the BLSD course. The results highlight the positive impact of BLSD training, significantly enhancing the quality of T-CPR and bringing it close to optimal levels.

Concomitant hypokalemia and hypocalcemia: a very rare but life-threating combination of reversible causes of cardiac arrest - an unusual first manifestation of coeliac disease.

The causes of cardiac arrest are extremely heterogeneous. Among these, both hypokalemia and hypocalcemia are known reversible factors that can lead to cardiac arrest. In this report, we present a unique case report of a patient with previously undiagnosed coeliac disease who experienced cardiac arrest due a combination of hypokalemia and hypocalcemia resulting from malabsorption. A 66-year-old male presented to the emergency department with symptoms of malaise, weakness, weight loss, and persistent diarrhea. The patient exhibited characteristic signs of hypokalemia and hypocalcemia, including fasciculations, weakness, and swelling. An electrocardiogram showed a normal rhythm, and blood tests confirmed the electrolyte imbalances. Despite initial treatment, the patient experienced sudden cardiac arrest. Prompt resuscitation efforts were successful in restoring spontaneous circulation. However, recurrent episodes of ventricular arrhythmias and cardiac arrest occurred. Large doses of intravenous potassium chloride, in conjunction with magnesium, were needed prior to restore electrolyte balance. The concomitant severe hypocalcemia required caution calcium supplementation, to avoid further decreases in serum potassium levels. Appropriate ion replacements ultimately led to successful resuscitation with good functional recovery. During the hospital stay, the patient was diagnosed with coeliac disease. This case is noteworthy for its uniqueness, as there are no documented instances in the scientific literature linking cardiac arrest directly to coeliac disease. It is important to emphasize the need for investigating potential reversible causes of cardiac arrest, such as hypokalemia and hypocalcemia, and implementing appropriate interventions to address these factors.

The impact of ACLS training in theoretical knowledge.

BACKGROUND AND AIM: Italy has a public health system where also young physicians hold various jobs, including Emergency Services. Advanced Cardiovascular Life Support (ACLS) course is developed for the management of cardiovascular emergencies. This study evaluates the preparation of Italian physicians on ACLS and their perceived need to be trained on it. METHODS: surveys had been administered to 4698 Medical Doctors. They consisted of questions on sociodemographic characteristics, knowledge of ACLS protocol, and willingness to attend an ACLS course. RESULTS: Online survey reached 4698 physicians, 137 of them had been excluded for invalid answering. People who had attended an ACLS course scored significantly higher on the test (M=5.68 SD=1.89) than those who had not (M=4.71 SD=1.91). Experienced physicians scored significantly higher (M=5.25 SD=1.96) than recently licensed ones (M=4.84 SD=1.94). Multiple regression was used to predict the ACLS test score. CONCLUSIONS: ACLS training has a stronger effect on Cardiovascular Emergency management knowledge (d=-.510) than general working experience (d=-.212). The median score in ACLS knowledge is low (5/10), despite its importance. Multiple linear regression reveals that ACLS has the greatest impact on the score. A small portion of doctors have attended an ACLS course (22%), but the majority of them would participate (89%).

Management of possible stroke by laypeople in pre-hospital setting: who should we train?

BACKGROUND AND AIM: The pre-hospital management of a possible stroke is fundamental for the transport of patients to the correct HUB facility; thus, they must be transported to the Emergency Department (ED) by EMS vehicles. Our study aims to analyze the factors correlated with a higher probability of accessing the ED through the EMS in this event. METHODS: This is a retrospective observational study. All accesses in the 120 EDs of the Lombardy region, with a diagnosis of discharge whose symptoms could resemble CPSS, were analyzed between 1 January 2019 and 31 December 2019. RESULTS: We identified an increased probability of using the EMS vehicles of 0,05% (I.C. 95%: 0.04% - 0.06%; p<0.0001) for each additional year of age, considering patients aged 20 to 100 years and the percentage was significantly higher in the female population (58% vs 49%; p<0.001). Moreover, we calculated that the incidence of stroke was approximately 140 cases per 100,000 inhabitants. CONCLUSIONS: Only half of the citizens in the Lombardy region use the EMS in case of suspicion of stroke; further information campaigns are essential to educate citizens. Information strategies should be directed especially at men between 30 and 59 years old.

Amplitude spectrum area measured in real-time during cardiopulmonary resuscitation - How does this technology work?

Amplitude spectrum area (AMSA) is one of the most accurate predictors of defibrillation outcome. Details on functioning and use of the available technology to measure AMSA during cardiopulmonary resuscitation (CPR) in the real clinical scenario are described. During chest compression (CC) pauses for ventilations, AMSA is promptly calculated and values displayed through a modified defibrillator. In addition, real-time AMSA analysis has the additional promise to monitor CPR quality, being AMSA threshold values contingent on CC depth. Future larger studies employing this new technology are now needed to demonstrate the impact of AMSA on survival of cardiac arrest.

Indoleamine 2,3-Dioxygenase Deletion to Modulate Kynurenine Pathway and to Prevent Brain Injury after Cardiac Arrest in Mice.

BACKGROUND: The catabolism of the essential amino acid tryptophan to kynurenine is emerging as a potential key pathway involved in post-cardiac arrest brain injury. The aim of this study was to evaluate the effects of the modulation of kynurenine pathway on cardiac arrest outcome through genetic deletion of the rate-limiting enzyme of the pathway, indoleamine 2,3-dioxygenase. METHODS: Wild-type and indoleamine 2,3-dioxygenase-deleted (IDO-/-) mice were subjected to 8-min cardiac arrest. Survival, neurologic outcome, and locomotor activity were evaluated after resuscitation. Brain magnetic resonance imaging with diffusion tensor and diffusion-weighted imaging sequences was performed, together with microglia and macrophage activation and neurofilament light chain measurements. RESULTS: IDO-/- mice showed higher survival compared to wild-type mice (IDO-/- 11 of 16, wild-type 6 of 16, log-rank P = 0.036). Neurologic function was higher in IDO-/- mice than in wild-type mice after cardiac arrest (IDO-/- 9 ± 1, wild-type 7 ± 1, P = 0.012, n = 16). Indoleamine 2,3-dioxygenase deletion preserved locomotor function while maintaining physiologic circadian rhythm after cardiac arrest. Brain magnetic resonance imaging with diffusion tensor imaging showed an increase in mean fractional anisotropy in the corpus callosum (IDO-/- 0.68 ± 0.01, wild-type 0.65 ± 0.01, P = 0.010, n = 4 to 5) and in the external capsule (IDO-/- 0.47 ± 0.01, wild-type 0.45 ± 0.01, P = 0.006, n = 4 to 5) in IDO-/- mice compared with wild-type ones. Increased release of neurofilament light chain was observed in wild-type mice compared to IDO-/- (median concentrations [interquartile range], pg/mL: wild-type 1,138 [678 to 1,384]; IDO-/- 267 [157 to 550]; P < 0.001, n = 3 to 4). Brain magnetic resonance imaging with diffusion-weighted imaging revealed restriction of water diffusivity 24 h after cardiac arrest in wild-type mice; indoleamine 2,3-dioxygenase deletion prevented water diffusion abnormalities, which was reverted in IDO-/- mice receiving l-kynurenine (apparent diffusion coefficient, µm2/ms: wild-type, 0.48 ± 0.07; IDO-/-, 0.59 ± 0.02; IDO-/- and l-kynurenine, 0.47 ± 0.08; P = 0.007, n = 6). CONCLUSIONS: The kynurenine pathway represents a novel target to prevent post-cardiac arrest brain injury. The neuroprotective effects of indoleamine 2,3-dioxygenase deletion were associated with preservation of brain white matter microintegrity and with reduction of cerebral cytotoxic edema.

"De trop" meta-analyses and systematic reviews in cardiopulmonary resuscitation - A way to rapidly improve authors' citation index at a price of real science.

Meta-analyses and systematic reviews (MSR) have been conceived as tools to summarize evidence on a specific health question. However, in the last years, an exaggerated number of MSRs published by scientific journals has been observed, i.e. 286 MSRs in the field of Resuscitation Science over the last 3 years, i.e. approximately 95 per year. Thus, doubts on the real scientific need of such a high number of MSRs may arise, potentially being only a way to rapidly improve authors' citation index and fame and sometimes the journals' impact factor.

One-Year Review in Cardiac Arrest: The 2022 Randomized Controlled Trials.

Cardiac arrest, one of the leading causes of death, accounts for numerous clinical studies published each year. This review summarizes the findings of all the randomized controlled clinical trials (RCT) on cardiac arrest published in the year 2022. The RCTs are presented according to the following categories: out-of- and in-hospital cardiac arrest (OHCA, IHCA) and post-cardiac arrest care. Interestingly, more than 80% of the RCTs encompassed advanced life support and post-cardiac arrest care, while no studies focused on the treatment of IHCA, except for one that, however, explored the temperature control after resuscitation in this population. Surprisingly, 9 out of 11 RCTs led to neutral results demonstrating equivalency between the newly tested interventions compared to current practice. One trial was negative, showing that oxygen titration in the immediate pre-hospital post-resuscitation period decreased survival compared to a more liberal approach. One RCT was positive and introduced new defibrillation strategies for refractory cardiac arrest. Overall, data from the 2022 RCTs discussed here provide a solid basis to generate new hypotheses to be tested in future clinical studies.

Amplitude Spectrum Area of ventricular fibrillation to guide defibrillation: a small open-label, pseudo-randomized controlled multicenter trial.

BACKGROUND: Ventricular fibrillation (VF) waveform analysis has been proposed as a potential non-invasive guide to optimize timing of defibrillation. METHODS: The AMplitude Spectrum Area (AMSA) trial is an open-label, multicenter randomized controlled study reporting the first in-human use of AMSA analysis in out-of-hospital cardiac arrest (OHCA). The primary efficacy endpoint was the termination of VF for an AMSA ≥ 15.5 mV-Hz. Adult shockable OHCAs randomly received either an AMSA-guided cardiopulmonary resuscitation (CPR) or a standard-CPR. Randomization and allocation to trial group were carried out centrally. In the AMSA-guided CPR, an initial AMSA ≥ 15.5 mV-Hz prompted for immediate defibrillation, while lower values favored chest compression (CC). After completion of the first 2-min CPR cycle, an AMSA < 6.5 mV-Hz deferred defibrillation in favor of an additional 2-min CPR cycle. AMSA was measured and displayed in real-time during CC pauses for ventilation with a modified defibrillator. FINDINGS: The trial was early discontinued for low recruitment due to the COVID-19 pandemics. A total of 31 patients were recruited in 3 Italian cities, 19 in AMSA-CPR and 12 in standard-CPR, and included in the data analysis. No difference in primary outcome was observed between the two groups. Termination of VF occurred in 74% of patients in the AMSA-CPR compared to 75% in the standard CPR (OR 0.93 [95% CI 0.18-4.90]). No adverse events were reported. INTERPRETATION: AMSA was used prospectively in human patients during ongoing CPR. In this small trial, an AMSA-guided defibrillation provided no evidence of an improvement in termination of VF. TRIAL REGISTRATION: NCT03237910. FUNDING: European Commission - Horizon 2020; ZOLL Medical Corp., Chelmsford, USA (unrestricted grant); Italian Ministry of Health - Current research IRCCS.

Quality indicators for post-resuscitation care after out-of-hospital cardiac arrest: a joint statement from the Association for Acute Cardiovascular Care of the European Society of Cardiology, the European Resuscitation Council, the European Society of Intensive Care Medicine, and the European Society for Emergency Medicine.

AIMS: Quality of care (QoC) is a fundamental tenet of modern healthcare and has become an important assessment tool for healthcare authorities, stakeholders and the public. However, QoC is difficult to measure and quantify because it is a multifactorial and multidimensional concept. Comparison of clinical institutions can be challenging when QoC is estimated solely based on clinical outcomes. Thus, measuring quality through quality indicators (QIs) can provide a foundation for quality assessment and has become widely used in this context. QIs for the evaluation of QoC in acute myocardial infarction are now well-established, but no such indicators exist for the process from resuscitation of cardiac arrest and post-resuscitation care in Europe. METHODS AND RESULTS: The Association of Acute Cardiovascular Care of the European Society Cardiology, the European Resuscitation Council, European Society of Intensive Care Medicine and the European Society for Emergency Medicine, have reflected on the measurement of QoC in cardiac arrest. A set of QIs have been proposed, with the scope to unify and evolve QoC for the management of cardiac arrest across Europe. CONCLUSION: We present here the list of QIs (6 primary QIs and 12 secondary Qis), with descriptions of the methodology used, scientific justification and motives for the choice for each measure with the aim that this set of QIs will enable assessment of the quality of postout-of-hospital cardiac arrest management across Europe.