Ruthenium red alleviates post-resuscitation myocardial dysfunction by upregulating mitophagy through inhibition of USP33 in a cardiac arrest rat model.

Cardiac arrest (CA) remains a leading cause of death, with suboptimal survival rates despite efforts involving cardiopulmonary resuscitation and advanced life-support technology. Post-resuscitation myocardial dysfunction (PRMD) is an important determinant of patient outcomes. Myocardial ischemia/reperfusion injury underlies this dysfunction. Previous reports have shown that ruthenium red (RR) has a protective effect against cardiac ischemia-reperfusion injury; however, its precise mechanism of action in PRMD remains unclear. This study investigated the effects of RR on PRMD and analyzed its underlying mechanisms. Ventricular fibrillation was induced in rats, which were then subjected to cardiopulmonary resuscitation to establish an experimental CA model. At the onset of return of spontaneous circulation, RR (2.5 mg/kg) was administered intraperitoneally. Our study showed that RR improved myocardial function and reduced the production of oxidative stress markers such as malondialdehyde (MDA), glutathione peroxidase (GSSG), and reactive oxygen species (ROS) production. RR also helped maintain mitochondrial structure and increased ATP and GTP levels. Additionally, RR effectively attenuated myocardial apoptosis. Furthermore, we observed downregulation of proteins closely related to mitophagy, including ubiquitin-specific protease 33 (USP33) and P62, whereas LC3B (microtubule-associated protein light chain 3B) was upregulated. The upregulation of mitophagy may play a critical role in reducing myocardial injury. These results demonstrate that RR may attenuate PRMD by promoting mitophagy through the inhibition of USP33. These effects are likely mediated through diverse mechanisms, including antioxidant activity, apoptosis suppression, and preservation of mitochondrial integrity and energy metabolism. Consequently, RR has emerged as a promising therapeutic approach for addressing post-resuscitation myocardial dysfunction.

The physiology of venoarterial extracorporeal membrane oxygenation - A comprehensive clinical perspective.

Venoarterial extracorporeal membrane oxygenation (VA ECMO) has become a standard of care for severe cardiogenic shock, refractory cardiac arrest and related impending multiorgan failure. The widespread clinical use of this complex temporary circulatory support modality is still contrasted by a lack of formal scientific evidence in the current literature. This might at least in part be attributable to VA ECMO related complications, which may significantly impact on clinical outcome. In order to limit adverse effects of VA ECMO as much as possible an indepth understanding of the complex physiology during extracorporeally supported cardiogenic shock states is critically important. This review covers all relevant physiological aspects of VA ECMO interacting with the human body in detail. This, to provide a solid basis for health care professionals involved in the daily management of patients supported with VA ECMO and suffering from cardiogenic shock or cardiac arrest and impending multiorgan failure for the best possible care.

Consciousness and the Dying Brain.

The near-death experience has been reported since antiquity and is often characterized by the perception of light, interactions with other entities, and life recall. Near-death experiences can occur in a variety of situations, but they have been studied systematically after in-hospital cardiac arrest, with an incidence of 10 to 20%. Long attributed to metaphysical or supernatural causes, there have been recent advances in understanding the neurophysiologic basis of this unique category of conscious experience. This article reviews the epidemiology and neurobiology of near-death experiences, with a focus on clinical and laboratory evidence for a surge of neurophysiologic gamma oscillations and cortical connectivity after cardiac and respiratory arrest.

Shining a light on cerebral autoregulation: Are we anywhere near the truth?

The near-infrared spectroscopy (NIRS)-derived cerebral oximetry index (COx) has become popularized for non-invasive neuromonitoring of cerebrovascular function in post-cardiac arrest patients with hypoxic-ischemic brain injury (HIBI). We provide commentary on the physiologic underpinnings and assumptions of NIRS and the COx, potential confounds in the context of HIBI, and the implications for the assessment of cerebral autoregulation.

Blood-brain barrier permeability for the first 24 hours in hypoxic-ischemic brain injury following cardiac arrest.

BACKGROUND: This study aimed to explore the changes in blood-brain barrier (BBB) permeability and intracranial pressure (ICP) for the first 24 h after the return of spontaneous circulation (ROSC) and their association with injury severity of cardiac arrest. METHODS: This prospective study analysed the BBB permeability assessed using the albumin quotient (Qa) and ICP every 2 h for the first 24 h after ROSC. The injury severity of cardiac arrest was assessed using Pittsburgh Cardiac Arrest Category (PCAC) scores. The primary outcome was the time course of changes in the BBB permeability and ICP for the first 24 h after ROSC and their association with injury severity (PCAC scores of 1-4). RESULTS: Qa and ICP were measured 274 and 197 times, respectively, in 32 enrolled patients. Overall, the BBB permeability increased progressively over time after ROSC, and then it increased significantly at 18 h after ROSC compared with the baseline. In contrast, the ICP revealed non-significant changes for the first 24 h after ROSC. The Qa in the PCAC 2 group was < 0.01, indicating normal or mild BBB disruption at all time points, whereas the PCAC 3 and 4 groups showed a significant increase in BBB permeability at 14 and 22 h, and 12 and 14 h after ROSC, respectively. CONCLUSION: BBB permeability increased progressively over time for the first 24 h after ROSC despite post-resuscitation care, whereas ICP did not change over time. BBB permeability has an individual pattern when stratified by injury severity.

Parada cardiorrespiratoria intrahospitalaria: incidencia, factores pronósticos y resultados / In-hospital cardiac arrest: incidence, prognostic factors and results

Introducción y objetivos: La parada cardiorrespiratoria (PCR) intrahospitalaria es una entidad clínica con elevada morbimortalidad que presentan hasta el 2% de los pacientes ingresados. La PCR supone un importante problema de salud pública a nivel económico, social y sanitario, susceptible de revisión y mejora. El objetivo de este estudio es determinar su incidencia, la recuperación de la circulación espontánea (RCE) y la supervivencia en el Hospital de la Princesa, así como las características clínicas y demográficas de los pacientes que la sufren. Material y métodos: Estudio observacional, retrospectivo, descriptivo, de tipo registro de casos, durante un periodo de 12 meses, de pacientes por los que se avisó por PCR al equipo de intervención rápida (EIR) compuesto por el servicio de Anestesiología y Reanimación. Resultados: Un total de 44 pacientes fueron incluidos en el estudio, de los cuales 22 (50%) eran mujeres. La edad media fue de 75,70 años (±15,78 años). La incidencia obtenida fue de 2,88 PCR por cada 100.000 ingresos hospitalarios; 22 (50%) pacientes consiguieron la RCE y 11 (25%) obtuvieron la supervivencia al alta hospitalaria. La comorbilidad más prevalente en los pacientes con PCR fue la hipertensión arterial (63,64%). No fueron presenciadas el 66,7% de las PCR y solo el 15,9% presentaron un ritmo desfibrilable. Conclusiones: Los resultados obtenidos son similares a los presentados en otros grandes estudios. Por esta razón, recomendamos implementar EIR y dedicar tiempo a la formación del personal hospitalario en torno a la PCR.(AU)

Background and aims: In-hospital cardiac arrest (CA) is a clinical entity with high morbidity and mortality that occurs in up to 2% of hospitalized patients. It is a public health problem with important economic, social, and medical repercussions, and as such its incidence needs to be reviewed and improved. The aim of this study was to determine the incidence of in-hospital CA, return of spontaneous circulation (ROSC), and survival rates at Hospital de la Princesa, and to define the clinical and demographic characteristics of patients with in-hospital CA. Material and methods: Retrospective observational chart review of patients presenting in-hospital CA and treated by anaesthesiologists from the hospital's rapid intervention team. Data were collected over 1 year. Results: Forty-four patients were included in the study, of which 22 (50%) were women. Mean age was 75.70 years (±15.78 years), and incidence of in-hospital CA was 2.88 per 100,000 hospital admissions. Twenty-two patients (50%) achieved ROSC and 11 patients (25%) survived until discharge home. The most prevalent comorbidity was arterial hypertension (63.64%); 66.7% of cases were not witnessed, and only 15.9% presented a shockable rhythm. Conclusions: These results are similar to those reported in other larger studies. We recommend introducing immediate intervention teams and devoting time to training hospital staff in in-hospital CA.(AU)

Perioperative Point of Care Ultrasound for Hemodynamic Assessment: A Narrative Review.

While transesophageal echocardiography (TEE) has traditionally been used in perioperative care, there is growing evidence supporting point of care ultrasound (POCUS) for the anesthesiologist in guiding patient care. It is a quick way to non-invasively evaluate hemodynamically unstable patients and ascertain their state of shock, determine volume status, and guide resuscitation in cardiac arrest. In addition, through use of POCUS, the anesthesiologist is able to identify signs of chronic heart disease to provide a more tailored and safer approach to perioperative care.

Regional cerebral blood flow in a patient with asystole episodes associated with anti-NMDA receptor encephalitis.

Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a rare and severe autoimmune encephalitis that displays neuropsychiatric symptoms and autonomic instability, e.g., hypoventilation and cardiac arrhythmia. Severe arrhythmia including asystole associated with this encephalitis is rare. Several causes have been suggested. Nevertheless, no report of the literature has described examination by functional brain imaging of a patient with asystole during anti-NMDA receptor encephalitis. This case is that of a 34-year-old woman diagnosed as having anti-NMDA receptor encephalitis. She repeatedly showed 10-20 s asystole episodes necessitating a temporary transvenous pacemaker. After resection of the bilateral ovarian cystic tumor, her symptoms improved. Regional cerebral blood flow (rCBF) was evaluated using single-photon emission computed tomography. The rCBF was increased in the amygdala, hypothalamus, anterior cingulate, hippocampus, and anterior temporal lobes, but decreased in the dorsolateral frontal lobes, parietal lobes, and occipital lobes. Findings in this case suggest that altered rCBF in the patient with asystole episodes associated with anti-NMDA receptor encephalitis was observed in several brain lesions. The rCBF increases in the central autonomic networks, i.e., the amygdala, hypothalamus, and anterior cingulate, might be associated with dysregulation of sympathetic and parasympathetic nervous systems leading to asystole.

Target temperature management following cardiac arrest: a systematic review and Bayesian meta-analysis.

BACKGROUND: Temperature control with target temperature management (TTM) after cardiac arrest has been endorsed by expert societies and adopted in international clinical practice guidelines but recent evidence challenges the use of hypothermic TTM. METHODS: Systematic review and Bayesian meta-analysis of clinical trials on adult survivors from cardiac arrest undergoing TTM for at least 12 h comparing TTM versus no TTM or with a separation > 2 °C between intervention and control groups using the PubMed/MEDLINE, EMBASE, CENTRAL databases from inception to 1 September 2021 (PROSPERO CRD42021248140). All randomised and quasi-randomised controlled trials were considered. The risk ratio and 95% confidence interval for death (primary outcome) and unfavourable neurological recovery (secondary outcome) were captured using the original study definitions censored up to 180 days after cardiac arrest. Bias was assessed using the updated Cochrane risk-of-bias for randomised trials tool and certainty of evidence assessed using the Grading of Recommendation Assessment, Development and Evaluation methodology. A hierarchical robust Bayesian model-averaged meta-analysis was performed using both minimally informative and data-driven priors and reported by mean risk ratio (RR) and its 95% credible interval (95% CrI). RESULTS: In seven studies (three low bias, three intermediate bias, one high bias, very low to low certainty) recruiting 3792 patients the RR by TTM 32-34 °C was 0.95 [95% CrI 0.78-1.09] for death and RR 0.93 [95% CrI 0.84-1.02] for unfavourable neurological outcome. The posterior probability for no benefit (RR ≥ 1) by TTM 32-34 °C was 24% for death and 12% for unfavourable neurological outcome. The posterior probabilities for favourable treatment effects of TTM 32-34 °C were the highest for an absolute risk reduction of 2-4% for death (28-53% chance) and unfavourable neurological outcome (63-78% chance). Excluding four studies without active avoidance of fever in the control arm reduced the probability to achieve an absolute risk reduction > 2% for death or unfavourable neurological outcome to ≤ 50%. CONCLUSIONS: The posterior probability distributions did not support the use of TTM at 32-34 °C compared to 36 °C also including active control of fever to reduce the risk of death and unfavourable neurological outcome at 90-180 days. Any likely benefit of hypothermic TTM is smaller than targeted in RCTs to date.

The feasibility of extracorporeal cardiopulmonary resuscitation for patients with active cancer who undergo in-hospital cardiac arrest.

Indications of extracorporeal cardiopulmonary resuscitation (ECPR) are still debatable, particularly in patients with cancer. Prediction of the prognosis of in-hospital cardiac arrest (IHCA) in patients with cancer receiving ECPR is important given the increasing prevalence and survival rate of cancer. We compared the neurologic outcomes and survival rates of IHCA patients with and without cancer receiving ECPR. Data from the extracorporeal membrane oxygenation registry between 2015 and 2019 were used in a retrospective manner. The primary outcome was 6-month good neurologic outcome, defined as a Cerebral performance category score of 1 or 2. The secondary outcomes were 1- and 3-month good neurologic outcome, and 6-month survival. Among 247 IHCA patients with ECPR, 43 had active cancer. The 6-month good neurologic outcome rate was 27.9% and 32.4% in patients with and without active cancer, respectively (P > 0.05). Good neurologic outcomes at 1-month (30.2% vs. 20.6%) and 3-month (30.2% vs. 28.4%), and the survival rate at 6-month (39.5% vs. 36.5%) were not significantly different (all P > 0.05) Active cancer was not associated with 6-month good neurologic outcome by logistic regression analyses. Therefore, patients with IHCA should not be excluded from ECPR solely for the presence of cancer itself.

Treating Rhythmic and Periodic EEG Patterns in Comatose Survivors of Cardiac Arrest.

BACKGROUND: Whether the treatment of rhythmic and periodic electroencephalographic (EEG) patterns in comatose survivors of cardiac arrest improves outcomes is uncertain. METHODS: We conducted an open-label trial of suppressing rhythmic and periodic EEG patterns detected on continuous EEG monitoring in comatose survivors of cardiac arrest. Patients were randomly assigned in a 1:1 ratio to a stepwise strategy of antiseizure medications to suppress this activity for at least 48 consecutive hours plus standard care (antiseizure-treatment group) or to standard care alone (control group); standard care included targeted temperature management in both groups. The primary outcome was neurologic outcome according to the score on the Cerebral Performance Category (CPC) scale at 3 months, dichotomized as a good outcome (CPC score indicating no, mild, or moderate disability) or a poor outcome (CPC score indicating severe disability, coma, or death). Secondary outcomes were mortality, length of stay in the intensive care unit (ICU), and duration of mechanical ventilation. RESULTS: We enrolled 172 patients, with 88 assigned to the antiseizure-treatment group and 84 to the control group. Rhythmic or periodic EEG activity was detected a median of 35 hours after cardiac arrest; 98 of 157 patients (62%) with available data had myoclonus. Complete suppression of rhythmic and periodic EEG activity for 48 consecutive hours occurred in 49 of 88 patients (56%) in the antiseizure-treatment group and in 2 of 83 patients (2%) in the control group. At 3 months, 79 of 88 patients (90%) in the antiseizure-treatment group and 77 of 84 patients (92%) in the control group had a poor outcome (difference, 2 percentage points; 95% confidence interval, -7 to 11; P = 0.68). Mortality at 3 months was 80% in the antiseizure-treatment group and 82% in the control group. The mean length of stay in the ICU and mean duration of mechanical ventilation were slightly longer in the antiseizure-treatment group than in the control group. CONCLUSIONS: In comatose survivors of cardiac arrest, the incidence of a poor neurologic outcome at 3 months did not differ significantly between a strategy of suppressing rhythmic and periodic EEG activity with the use of antiseizure medication for at least 48 hours plus standard care and standard care alone. (Funded by the Dutch Epilepsy Foundation; TELSTAR ClinicalTrials.gov number, NCT02056236.).

Arterial Pulsatility Augments Microcirculatory Perfusion and Maintains the Endothelial Integrity during Extracorporeal Membrane Oxygenation via hsa_circ_0007367 Upregulation in a Canine Model with Cardiac Arrest.

BACKGROUND: The impairment of microcirculation is associated with the unfavorable outcome for extracorporeal membrane oxygenation (ECMO) patients. Studies revealed that pulsatile modification improves hemodynamics and attenuates inflammation during ECMO support. However, whether flow pattern impacts microcirculation and endothelial integrity is rarely documented. The objective of this work was to explore how pulsatility affects microcirculation during ECMO. METHODS: Canine animal models with cardiac arrest were supported by ECMO, with the i-Cor system used to generate nonpulsatile or pulsatile flow. The sublingual microcirculation parameters were examined using the CytoCam microscope system. The expression of hsa_circ_0007367, a circular RNA, was measured during ECMO support. In vitro validation was performed in pulmonary vascular endothelial cells (PMVECs) exposed to pulsatile or nonpulsatile flow, and the expressions of hsa_circ_0007367, endothelial tight junction markers, endothelial adhesive molecules, endothelial nitric oxide synthases (eNOS), and NF-κB signaling activity were analyzed. RESULTS: The pulsatile modification of ECMO enhanced microcirculatory perfusion, attenuated pulmonary inflammation, and stabilized endothelial integrity in animal models; meanwhile, the expression of hsa_circ_0007367 was significantly upregulated both in animals and PMVECs exposed to pulsatile flow. In particular, upregulation of hsa_circ_0007367 stabilized the expressions of endothelial tight junction markers zonula occludens- (ZO-) 1 and occludin, followed by modulating the endothelial nitric oxide synthases (eNOS) activity and inhibiting the NF-κB signaling pathway. CONCLUSION: The modification of pulsatility contributes to microcirculatory perfusion and endothelial integrity during ECMO. The expression of hsa_circ_0007367 plays a pivotal role in this protective mechanism.

A walk through the progression of resuscitation medicine.

Cardiac arrest (CA) is a sudden and devastating disease process resulting in more deaths in the United States than many cancers, metabolic diseases, and even car accidents. Despite such a heavy mortality burden, effective treatments have remained elusive. The past century has been productive in establishing the guidelines for resuscitation, known as cardiopulmonary resuscitation (CPR), as well as developing a scientific field whose aim is to elucidate the underlying mechanisms of CA and develop therapies to save lives. CPR has been successful in reinitiating the heart after arrest, enabling a survival rate of approximately 10% in out-of-hospital CA. Although current advanced resuscitation methods, including hypothermia and extracorporeal membrane oxygenation, have improved survival in some patients, they are unlikely to significantly improve the national survival rate any further without a paradigm shift. Such a change is possible with sustained efforts in the basic and clinical sciences of resuscitation and their implementation. This review seeks to discuss the current landscape in resuscitation medicine-how we got here and where we are going.

Outcome and prognostication after cardiac arrest.

The outcome after out-of-hospital cardiac arrest has historically been grim at best. The current overall survival rate of patients admitted to a hospital is approximately 10%, making cardiac arrest one of the leading causes of death in the United States. The situation is improving with the incorporation of therapeutic temperature modulation, aggressive prevention of secondary brain injury, and improved access to advanced cardiovascular support, all of which have decreased mortality and allowed for better outcomes. Mortality after cardiac arrest is often the direct result of active withdrawal of life-sustaining therapy based on the perception that neurological recovery is not possible. This reality highlights the importance of providing accurate estimates of neurological prognosis to decision makers when discussing goals of care. The current standard of care for assessing neurological status in patients with hypoxic-ischemic encephalopathy emphasizes a multimodal approach that includes five elements: (1) neurological examination off sedation, (2) continuous electroencephalography, (3) serum neuron-specific enolase levels, (4) magnetic resonance brain imaging, and (5) somatosensory-evoked potential testing. Sophisticated decision support systems that can integrate these clinical, imaging, and biomarker and neurophysiologic data and translate it into meaningful projections of neurological outcome are urgently needed.

Heart rate complexity: An early prognostic marker of patient outcome after cardiac arrest.

OBJECTIVE: Early prognostication in comatose patients after cardiac arrest (CA) is difficult but essential to inform relatives and optimize treatment. Here we investigate the predictive value of heart-rate variability captured by multiscale entropy (MSE) for long-term outcomes in comatose patients during the first 24 hours after CA. METHODS: In this retrospective analysis of prospective multi-centric cohort, we analyzed MSE of the heart rate in 79 comatose patients after CA while undergoing targeted temperature management and sedation during the first day of coma. From the MSE, two complexity indices were derived by summing values over short and long time scales (CIs and CIl). We splitted the data in training and test datasets for analysing the predictive value for patient outcomes (defined as best cerebral performance category within 3 months) of CIs and CIl. RESULTS: Across the whole dataset, CIl provided the best sensitivity, specificity, and accuracy (88%, 75%, and 82%, respectively). Positive and negative predictive power were 81% and 84%. CONCLUSIONS: Characterizing the complexity of the ECG in patients after CA provides an accurate prediction of both favorable and unfavorable outcomes. SIGNIFICANCE: The analysis of heartrate variability by means of MSE provides accurate outcome prediction on the first day of coma.

QRS duration predicts outcomes in cardiac arrest survivors undergoing therapeutic hypothermia.

BACKGROUND: Whether the electrocardiography (ECG) serial changes predict outcomes in cardiac arrest survivors undergoing therapeutic hypothermia remains unclear. METHODS AND RESULTS: This retrospective observational study enrolled 366 adult nontraumatic cardiac arrest survivors who underwent therapeutic hypothermia in a tertiary transfer center during 2006-2018. The ECG at return of spontaneous circulation (ROSC), during hypothermia and after rewarming were analyzed. 295 cardiac arrest survivors were included. Compared with the survivors, the non-survivors had longer QRS durations at the ROSC (118.33 ± 32.47 ms vs 106.88 ± 29.78 ms, p < 0.001) and after rewarming (99.26 ± 25.07 ms vs 93.03 ± 19.09 ms, p = 0.008). The enrolled patients were classified into 4 groups based on QRS duration at the ROSC and after rewarming, namely (1) narrow-narrow (narrow QRS at ROSC and narrow QRS after rewarming, n = 156), (2) narrow-wide (n = 29), (3) wide-narrow (n = 87), and (4) wide-wide (n = 23) group. The wide-wide group had the worst survival rates [odds ratio (OR) = 0.141, p = 0.001], followed by the narrow-wide group (OR 0.223, p = 0.003) and the wide-narrow group (OR 0.389, p = 0.003). CONCLUSIONS: In cardiac arrest survivors given therapeutic hypothermia, QRS durations at the ROSC, after rewarming and their changes may predict survival to hospital discharge.