A Randomized Trial of Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome from COVID-19.

Rationale: There are limited therapeutic options for patients with coronavirus disease (COVID-19)-related acute respiratory distress syndrome with inflammation-mediated lung injury. Mesenchymal stromal cells offer promise as immunomodulatory agents. Objectives: Evaluation of efficacy and safety of allogeneic mesenchymal cells in mechanically-ventilated patients with moderate or severe COVID-19-induced respiratory failure. Methods: Patients were randomized to two infusions of 2 million cells/kg or sham infusions, in addition to the standard of care. We hypothesized that cell therapy would be superior to sham control for the primary endpoint of 30-day mortality. The key secondary endpoint was ventilator-free survival within 60 days, accounting for deaths and withdrawals in a ranked analysis. Measurements and Main Results: At the third interim analysis, the data and safety monitoring board recommended that the trial halt enrollment as the prespecified mortality reduction from 40% to 23% was unlikely to be achieved (n = 222 out of planned 300). Thirty-day mortality was 37.5% (42/112) in cell recipients versus 42.7% (47/110) in control patients (relative risk [RR], 0.88; 95% confidence interval, 0.64-1.21; P = 0.43). There were no significant differences in days alive off ventilation within 60 days (median rank, 117.3 [interquartile range, 60.0-169.5] in cell patients and 102.0 [interquartile range, 54.0-162.5] in control subjects; higher is better). Resolution or improvement of acute respiratory distress syndrome at 30 days was observed in 51/104 (49.0%) cell recipients and 46/106 (43.4%) control patients (odds ratio, 1.36; 95% confidence interval, 0.57-3.21). There were no infusion-related toxicities and overall serious adverse events over 30 days were similar. Conclusions: Mesenchymal cells, while safe, did not improve 30-day survival or 60-day ventilator-free days in patients with moderate and/or severe COVID-19-related acute respiratory distress syndrome.

Toward harmonization of strategies for investigating lucidity in AD/ADRD: A preliminary research framework.

Episodes of lucidity (ELs) in Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD), have garnered increasing attention as an important area of research. Efforts to study lucidity suffer from a lack of clear definitional criteria, inconsistent conceptualization, and diverse approaches to operationalizing features of these events. To advance systematic investigation of ELs in AD/ADRD, there is a need for clarity and precision in labeling event attributes, markers, and specific measurement strategies that enable operational harmonization across distinct approaches to investigating the relatively broad and nascent phenomenon. To that end, we propose a preliminary research framework to guide harmonization of approaches to investigating ELs in AD/ADRD. Our goal is to provide an initial schematic that encourages uniform labeling of operational decisions about ELs.

Low-Dose Tocilizumab With High-Dose Corticosteroids in Patients Hospitalized for COVID-19 Hypoxic Respiratory Failure Improves Mortality Without Increased Infection Risk.

BACKGROUND: Severe hypoxic respiratory failure from COVID-19 pneumonia carries a high mortality risk. There is uncertainty surrounding which patients benefit from corticosteroids in combination with tocilizumab and the dosage and timing of these agents. The balance of controlling inflammation without increasing the risk of secondary infection is difficult. At present, dexamethasone 6 mg is the standard of care in COVID-19 hypoxia; whether this is the ideal choice of steroid or dosage remains to be proven. OBJECTIVES: The primary objective was to assess the impact on mortality of tocilizumab only, corticosteroids only, and combination therapy in patients with COVID-19 respiratory failure. METHODS: A multihospital, retrospective study of adult patients with severe respiratory failure from COVID-19 who received supportive therapy, corticosteroids, tocilizumab, or combination therapy were assessed for 28-day mortality, biomarker improvement, and relative risk of infection. Propensity-matched analysis was performed between corticosteroid alone and combination therapies to further assess mortality benefit. RESULTS: The steroid-only, tocilizumab-only, and combination groups showed hazard reduction in mortality at 28 days when compared with supportive therapy. In a propensity-matched analysis, the combination group (daily equivalent dexamethasone 10 mg and tocilizumab 400 mg) had an improved 28-day mortality compared with the steroid-only group (daily equivalent dexamethasone 10 mg; hazard ratio (95% CI) = 0.56 (0.38-0.84), P = 0.005] without increasing the risk of infection. CONCLUSION AND RELEVANCE: Combination of tocilizumab and corticosteroids was associated with improved 28-day survival when compared with corticosteroids alone. Modification of steroid dosing strategy as well as steroid type may further optimize therapeutic effect of the COVID-19 treatment.

Prevalence and Outcomes of D-Dimer Elevation in Hospitalized Patients With COVID-19.

OBJECTIVE: To determine the prevalence of D-dimer elevation in coronavirus disease 2019 (COVID-19) hospitalization, trajectory of D-dimer levels during hospitalization, and its association with clinical outcomes. Approach and Results: Consecutive adults admitted to a large New York City hospital system with a positive polymerase chain reaction test for SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) between March 1, 2020 and April 8, 2020 were identified. Elevated D-dimer was defined by the laboratory-specific upper limit of normal (>230 ng/mL). Outcomes included critical illness (intensive care, mechanical ventilation, discharge to hospice, or death), thrombotic events, acute kidney injury, and death during admission. Among 2377 adults hospitalized with COVID-19 and ≥1 D-dimer measurement, 1823 (76%) had elevated D-dimer at presentation. Patients with elevated presenting baseline D-dimer were more likely than those with normal D-dimer to have critical illness (43.9% versus 18.5%; adjusted odds ratio, 2.4 [95% CI, 1.9-3.1]; P<0.001), any thrombotic event (19.4% versus 10.2%; adjusted odds ratio, 1.9 [95% CI, 1.4-2.6]; P<0.001), acute kidney injury (42.4% versus 19.0%; adjusted odds ratio, 2.4 [95% CI, 1.9-3.1]; P<0.001), and death (29.9% versus 10.8%; adjusted odds ratio, 2.1 [95% CI, 1.6-2.9]; P<0.001). Rates of adverse events increased with the magnitude of D-dimer elevation; individuals with presenting D-dimer >2000 ng/mL had the highest risk of critical illness (66%), thrombotic event (37.8%), acute kidney injury (58.3%), and death (47%). CONCLUSIONS: Abnormal D-dimer was frequently observed at admission with COVID-19 and was associated with higher incidence of critical illness, thrombotic events, acute kidney injury, and death. The optimal management of patients with elevated D-dimer in COVID-19 requires further study.

Monitoring the Relationship Between Changes in Cerebral Oxygenation and Electroencephalography Patterns During Cardiopulmonary Resuscitation: A Feasibility Study.

OBJECTIVES: To date, no studies have examined real-time electroencephalography and cerebral oximetry monitoring during cardiopulmonary resuscitation as markers of the magnitude of global ischemia. We therefore sought to assess the feasibility of combining cerebral oximetry and electroencephalography in patients undergoing cardiopulmonary resuscitation and further to evaluate the electroencephalography patterns during cardiopulmonary resuscitation and their relationship with cerebral oxygenation as measured by cerebral oximetry. DESIGN: Extended case series of in-hospital and out-of-hospital cardiac arrest subjects. SETTING: Tertiary Medical Center. PATIENTS: Inclusion criteria: Convenience sample of 16 patients undergoing cardiopulmonary resuscitation during working hours between March 2014 and March 2015, greater than or equal to 18 years. A portable electroencephalography (Legacy; SedLine, Masimo, Irvine, CA) and cerebral oximetry (Equanox 7600; Nonin Medical, Plymouth, MN) system was used to measure cerebral resuscitation quality. INTERVENTIONS: Real-time regional cerebral oxygen saturation and electroencephalography readings were observed during cardiopulmonary resuscitation. The regional cerebral oxygen saturation values and electroencephalography patterns were not used to manage patients by clinical staff. MEASUREMENTS AND MAIN RESULTS: In total, 428 electroencephalography images from 16 subjects were gathered; 40.7% (n = 174/428) were artifactual, therefore 59.3% (n = 254/428) were interpretable. All 16 subjects had interpretable images. Interpretable versus noninterpretable images were not related to a function of time or duration of cardiopulmonary resuscitation but to artifacts that were introduced to the raw data such as diaphoresis, muscle movement, or electrical interference. Interpretable data were able to be obtained immediately after application of the electrode strip. Seven distinct electroencephalography patterns were identified. Voltage suppression was commonest and seen during 78% of overall cardiopulmonary resuscitation time and in 15 of 16 subjects at some point during their cardiopulmonary resuscitation. Other observed patterns and their relative prevalence in relation to overall cardiopulmonary resuscitation time were theta background activity 8%, delta background activity 5%, bi frontotemporal periodic discharge 4%, burst suppression 2%, spike and wave 2%, and rhythmic delta activity 1%. Eight of 16 subjects had greater than one interpretable pattern. At regional cerebral oxygen saturation levels less than or equal to 19%, the observed electroencephalography pattern was exclusively voltage suppression. Delta background activity was only observed at regional cerebral oxygen saturation levels greater than 40%. The remaining patterns were observed throughout regional cerebral oxygen saturation categories above a threshold of 20%. CONCLUSIONS: Real-time monitoring of cerebral oxygenation and function during cardiac arrest resuscitation is feasible. Although voltage suppression is the commonest electroencephalography pattern, other distinct patterns exist that may correlate with the quality of cerebral resuscitation and oxygen delivery.

Association of Arterial Oxygen Tension During In-Hospital Cardiac Arrest With Return of Spontaneous Circulation and Survival.

BACKGROUND: Despite numerous advances in the delivery of resuscitative care, in-hospital cardiac arrest (IHCA) continues to be associated with high morbidity and mortality. We sought to study the impact of arterial oxygen tension (Pao2) on return of spontaneous circulation (ROSC) and survival to discharge in patients with IHCA. METHODS: The study population included 255 consecutive patients who underwent advanced cardiac life support-guided resuscitation from January 2012 to December 2013 for IHCA at an academic tertiary medical center. Of these patients, 167 underwent arterial blood gas testing at the time of the arrest. Baseline demographic, clinical, laboratory, and clinical outcome data were recorded. The primary outcome of interest was survival to hospital discharge. Secondary outcome of interest was presence of ROSC. RESULTS: Of the 167 patients studied, Pao2 categorization included the following: Pao2 < 60 mm Hg (n = 38), Pao2 of 60-92 mm Hg (n = 44), Pao2 of 93 to 159 mm Hg (n = 43), Pao2 of 160 to 299 mm Hg (n = 24), and Pao2 ≥ 300 mm Hg (n = 18). Patients with higher Pao2 levels during the time of cardiac arrest were noted to have higher rates of hypertension and chronic kidney disease. Clinical presentation of IHCA, in particular, the initial rhythm, location of IHCA, and duration of cardiopulmonary resuscitation, was similar in all groups. Patients with higher Pao2 levels had higher platelet count, higher arterial pH, and lower arterial carbon dioxide tension (Pco2). With respect to outcomes, patients with higher intra-arrest Pao2 levels had progressively higher rates of ROSC (58% vs 71% vs 72% vs 79% vs 100%, P = .021) and survival to discharge (16% vs 23% vs 30% vs 33% vs 56%, P = .031). In multivariate analysis, Pao2 ≥ 300 mm Hg was independently associated with higher survival to discharge (odds ratio 60.68; 95% confidence interval: 3.04-1210.28; P = .007; referent Pao2 < 60 mm Hg). CONCLUSION: Higher intra-arrest Pao2 is independently associated with higher rates of survival to discharge in adults with IHCA.

Cerebral oximetry versus end tidal CO2 in predicting ROSC after cardiac arrest.

STUDY OBJECTIVE: Both end tidal CO2 (ETCO2) and cerebral oxygen saturations (rSO2) have been studied to determine their ability to monitor the effectiveness of CPR and predict return of spontaneous circulation (ROSC). We compared the accuracy of ETCO2 and rSO2 at predicting ROSC in ED patients with out-of-hospital cardiac arrest (OHCA). METHODS: We performed a prospective, observational study of adult ED patients presenting in cardiac arrest. We collected demographic and clinical data including age, gender, presenting rhythm, rSO2, and ETCO2. We used receiver operating characteristic curves to compare how well rSO2 and ETCO2 predicted ROSC. RESULTS: 225 patients presented to the ED with cardiac arrest between 10/11 and 10/14 of which 100 had both rSO2 and ETCO2 measurements. Thirty three patients (33%) had sustained ROSC, only 2 survived to discharge. The AUCs for rSO2 and ETCO2 were similar (0.69 [95% CI, 0.59-0.80] and 0.77 [95% CI, 0.68-0.86], respectively), however, rSO2 and ETCO2 were poorly correlated (0.12, 95% CI, -0.08-0.31). The optimal cutoffs for rSO2 and ETCO2 were 50% and 20mm Hg respectively. At these cutoffs, ETCO2 was more sensitive (100%, 95% CI 87-100 vs. 48%, 31-66) but rSO2 was more specific (85%, 95% CI, 74-92 vs. 45%, 33-57). CONCLUSIONS: While poorly correlated, rSO2 and ETCO2 have similar diagnostic characteristics. ETCO2 is more sensitive and rSO2 is more specific at predicting ROSC in OHCA.

Monitoring the Brain After Cardiac Arrest: a New Era.

PURPOSE OF REVIEW: Of the approximately 350,000 out-of-hospital, and 750,000 after in-hospital cardiac arrest (CA) events in the US annually approximately 5-9% and 20% respectively may achieve return of spontaneous circulation (ROSC) after attempted cardiopulmonary resuscitation (CPR). Up to 2/3 of these initial survivors may go on die in the subsequent 24-72 hours after ROSC due to a combination of (1) on-going cerebral injury, (2) myocardial dysfunction and (3) massive systemic inflammatory response. In order to successfully manage patients more effectively, monitoring methods are needed to aid clinicians in the detection and quantification of intra-cardiac arrest and post-resuscitation pathophysiological cerebral injury processes in the intensive care unit. RECENT FINDINGS: Over the last few years many modalities have been used for cerebral monitoring during and after CA, these include quantitative pupillometry, transcranial doppler sonography, optic nerve sheath diameter measurements, microdialysis, tissue oxygenation monitoring, intra-cranial pressure monitoring, and electroencephalography. Current studies indicate that these modalities may be used for the purpose of neurological monitoring during cardiac arrest resuscitation as well as in the post-resuscitation period. Multiple overlapping processes, including alterations in cerebral blood flow (CBF), raised intracerebralpressure, disorders of metabolism, imbalanced oxygen delivery and reperfusion injury contribute to cell death during the post-resuscitation period has led to the birth of post-resuscitation management strategies in the 21st century. This review provides a succinct overview of currently available bedside invasive and non-invasive neuro-monitoring methods after CA.

Cerebral Oximetry During Cardiac Arrest: A Multicenter Study of Neurologic Outcomes and Survival.

OBJECTIVES: Cardiac arrest is associated with morbidity and mortality because of cerebral ischemia. Therefore, we tested the hypothesis that higher regional cerebral oxygenation during resuscitation is associated with improved return of spontaneous circulation, survival, and neurologic outcomes at hospital discharge. We further examined the validity of regional cerebral oxygenation as a test to predict these outcomes. DESIGN: Multicenter prospective study of in-hospital cardiac arrest. SETTING: Five medical centers in the United States and the United Kingdom. PATIENTS: Inclusion criteria are as follows: in-hospital cardiac arrest, age 18 years old or older, and prolonged cardiopulmonary resuscitation greater than or equal to 5 minutes. Patients were recruited consecutively during working hours between August 2011 and September 2014. Survival with a favorable neurologic outcome was defined as a cerebral performance category 1-2. INTERVENTIONS: Cerebral oximetry monitoring. MEASUREMENTS AND MAIN RESULTS: Among 504 in-hospital cardiac arrest events, 183 (36%) met inclusion criteria. Overall, 62 of 183 (33.9%) achieved return of spontaneous circulation, whereas 13 of 183 (7.1%) achieved cerebral performance category 1-2 at discharge. Higher mean ± SD regional cerebral oxygenation was associated with return of spontaneous circulation versus no return of spontaneous circulation (51.8% ± 11.2% vs 40.9% ± 12.3%) and cerebral performance category 1-2 versus cerebral performance category 3-5 (56.1% ± 10.0% vs 43.8% ± 12.8%) (both p < 0.001). Mean regional cerebral oxygenation during the last 5 minutes of cardiopulmonary resuscitation best predicted the return of spontaneous circulation (area under the curve, 0.76; 95% CI, 0.69-0.83); regional cerebral oxygenation greater than or equal to 25% provided 100% sensitivity (95% CI, 94-100) and 100% negative predictive value (95% CI, 79-100); regional cerebral oxygenation greater than or equal to 65% provided 99% specificity (95% CI, 95-100) and 93% positive predictive value (95% CI, 66-100) for return of spontaneous circulation. Time with regional cerebral oxygenation greater than 50% during cardiopulmonary resuscitation best predicted cerebral performance category 1-2 (area under the curve, 0.79; 95% CI, 0.70-0.88). Specifically, greater than or equal to 60% cardiopulmonary resuscitation time with regional cerebral oxygenation greater than 50% provided 77% sensitivity (95% CI,:46-95), 72% specificity (95% CI, 65-79), and 98% negative predictive value (95% CI, 93-100) for cerebral performance category 1-2. CONCLUSIONS: Cerebral oximetry allows real-time, noninvasive cerebral oxygenation monitoring during cardiopulmonary resuscitation. Higher cerebral oxygenation during cardiopulmonary resuscitation is associated with return of spontaneous circulation and neurologically favorable survival to hospital discharge. Achieving higher regional cerebral oxygenation during resuscitation may optimize the chances of cardiac arrest favorable outcomes.

Venoarterial Extracorporeal Membrane Oxygenation in Adults With Cardiac Arrest.

Cardiac arrest (CA) is a major cause of morbidity and mortality worldwide. Despite the use of conventional cardiopulmonary resuscitation (CPR), rates of return of spontaneous circulation and survival with minimal neurologic impairment remain low. Utilization of venoarterial extracorporeal membrane oxygenation (ECMO) for CA in adults is steadily increasing. Propensity-matched cohort studies have reported outcomes associated with ECMO use to be superior to that of conventional CPR alone in in-hospital patients with CA. In this review, we discuss the mechanism, indications, complications, and evidence for ECMO in CA in adults.

Making sense of clinical outcomes following cardiac arrest.

PURPOSE OF REVIEW: To provide a summary of the recent literature on clinical outcomes in adults with cardiac arrest, focusing on the impact of patient-specific factors in combination with cardio-pulmonary resuscitation (CPR) related, and postresuscitative-related factors. RECENT FINDINGS: Cardiac arrest is a major cause of morbidity and mortality worldwide. Despite the use of conventional cardiopulmonary resuscitation, rates of return of spontaneous circulation and survival with minimal neurologic impairment remain low. A number of recent studies have examined the impact of patient-specific factors (duration of cardiac arrest, initial rhythm, age, premorbid states), CPR-related (the use of mechanical CPR, the use of impedance threshold device, vasopressors, extra-corporeal membrane oxygenation, active compression-decompression, and impedance threshold device), and postresuscitative-related factors (hypothermia, coronary angiography, hyperoxia, hyper/hypocapnia, mean arterial blood pressure) on cardiac arrest outcomes. SUMMARY: Further studies, namely randomized controlled trials, assessing the impact of advanced therapies are warranted to evaluate their impact on survival and neurologic function in adults with cardiac arrest.

Cerebral oximetry levels during CPR are associated with return of spontaneous circulation following cardiac arrest: an observational study.

OBJECTIVES: Cerebral oximetry using near-infrared spectroscopy measures regional cerebral oxygen saturation (rSO2) non-invasively and may provide information regarding the quality of cerebral oxygen perfusion. We determined whether the level of rSO2 obtained during cardiopulmonary resuscitation is associated with return of spontaneous circulation (ROSC) and survival in Emergency Department (ED) patients presenting with cardiac arrest. METHODS: We conducted a retrospective, observational study of adult ED patients presenting at an academic medical centre with cardiac arrest in whom continuous cerebral oximetry was performed. Demographic and clinical data including age, gender, presenting rhythm and mean rSO2 readings were abstracted. Cerebral oxygenation was measured with a commercially available oximeter. RESULTS: A convenience study sample included 59 patients ages 18-102 years (mean age 68.7±14.9 years); 50 (84.7%) were men. Presenting rhythms included pulseless electrical activity (21), asystole (20) and ventricular fibrillation/tachycardia (17). 24 patients (40.6%) had ROSC and only 1 (1.7%) survived to hospital discharge. Patients with and without ROSC were similar in age and presenting cardiac rhythms. The mean of mean rSO2 levels was higher in patients with ROSC, 43.8 (95% CI 40.1 to 47.6) compared with those without ROSC, 34.2 (95% CI 30.6 to 37.8); p=0.001. 91.7% of patients with ROSC had a rSO2 of 30% or greater compared with 62.9% in those without ROSC (p=0.01). The area under the curve for mean rSO2 as a predictor of ROSC was 0.76 (95% CI 0.64 to 0.89). CONCLUSIONS: In ED patients with cardiac arrest higher cerebral oxygen saturations are associated with higher rates of ROSC.

A feasibility study of cerebral oximetry during in-hospital mechanical and manual cardiopulmonary resuscitation*.

OBJECTIVE: A major hurdle limiting the ability to improve the quality of resuscitation has been the lack of a noninvasive real-time detection system capable of monitoring the quality of cerebral and other organ perfusion, as well as oxygen delivery during cardiopulmonary resuscitation. Here, we report on a novel system of cerebral perfusion targeted resuscitation. DESIGN: An observational study evaluating the role of cerebral oximetry (Equanox; Nonin, Plymouth, MI, and Invos; Covidien, Mansfield, MA) as a real-time marker of cerebral perfusion and oxygen delivery together with the impact of an automated mechanical chest compression system (Life Stat; Michigan Instruments, Grand Rapids, MI) on oxygen delivery and return of spontaneous circulation following in-hospital cardiac arrest. SETTING: Tertiary medical center. PATIENTS: In-hospital cardiac arrest patients (n = 34). MAIN RESULTS: Cerebral oximetry provided real-time information regarding the quality of perfusion and oxygen delivery. The use of automated mechanical chest compression device (n = 12) was associated with higher regional cerebral oxygen saturation compared with manual chest compression device (n = 22) (53.1% ± 23.4% vs 24% ± 25%, p = 0.002). There was a significant difference in mean regional cerebral oxygen saturation (median % ± interquartile range) in patients who achieved return of spontaneous circulation (n = 15) compared with those without return of spontaneous circulation (n = 19) (47.4% ± 21.4% vs 23% ± 18.42%, p < 0.001). After controlling for patients achieving return of spontaneous circulation or not, significantly higher mean regional cerebral oxygen saturation levels during cardiopulmonary resuscitation were observed in patients who were resuscitated using automated mechanical chest compression device (p < 0.001). CONCLUSIONS: The integration of cerebral oximetry into cardiac arrest resuscitation provides a novel noninvasive method to determine the quality of cerebral perfusion and oxygen delivery to the brain. The use of automated mechanical chest compression device during in-hospital cardiac arrest may lead to improved oxygen delivery and organ perfusion.

Autocrine ligands of the epithelial growth factor receptor mediate inflammatory responses to diesel exhaust particles.

BACKGROUND: Diesel exhaust is associated with cardiovascular and respiratory mortality and morbidity. Acute exposure leads to increased IL-8 expression and airway neutrophilia, however the mechanism of this response is unknown. OBJECTIVES: As cigarette smoke-induced IL-8 expression by epithelial cells involves transactivation of the epidermal growth factor receptor (EGFR), we studied the effects of diesel exhaust particles (DEP) on IL-8 release and the role of the EGFR. METHODS: Primary bronchial epithelial cells (PBEC) were exposed to DEPs or carbon black. IL-8 and EGFR ligand expression (transforming growth factor alpha (TGFα), heparin-binding EGF-like growth factor, and amphiregulin (AR)) were assessed by quantitative RT-PCR and ELISA. RESULTS: DEP, but not carbon black, caused a dose-dependent increase in mitogen-activated protein kinase (MAPK) activation and IL-8 expression, however above 50 µg/ml there was an increase in cytotoxicity. At 50 µg/ml, DEPs stimulated transcription and release of IL-8 and EGFR ligands. IL-8 release was blocked by EGFR neutralizing antibodies, an EGFR-selective tyrosine kinase inhibitor and by the metalloprotease inhibitor, GM6001, which blocks EGFR ligand shedding. Neutralizing antibodies to AR, TGFα and heparin-binding (HB)-EGF reduced DEP-induced IL-8 by >50%. Conclusion Expression of IL-8 in response to DEPs is dependent on EGFR activation and that autocrine production of EGFR ligands makes a substantial contribution to this response. CAPSULE SUMMARY: This study identifies a mechanism whereby diesel particles stimulates IL-8 release from bronchial epithelial cells. This mechanism may help to explain the recruitment of neutrophils into the airways of people exposed to particulate air pollution.

Integrating rSO2 and EEG monitoring in cardiopulmonary resuscitation: A novel methodology.

Despite improvements in cardiopulmonary resuscitation (CPR), survival and neurologic recovery after cardiac arrest remain poor due to ischemia and subsequent reperfusion injury. As the likelihood of survival and favorable neurologic outcome decreases with increasing severity of ischemia during CPR, developing methods to measure the magnitude of ischemia during resuscitation is critical for improving overall outcomes. Cerebral oximetry, which measures regional cerebral oxygen saturation (rSO2) by near-infrared spectroscopy, has emerged as a potentially beneficial marker of cerebral ischemia during CPR. In numerous preclinical and clinical studies, higher rSO2 during CPR has been associated with improved cardiac arrest survival and neurologic outcome. There is also emerging evidence that this can be integrated with electroencephalogram (EEG) monitoring to provide a bimodal system of brain monitoring during CPR. In this method's review, we discuss the feasibility, application, and implications of this integrated monitoring approach, highlighting its significance for improving clinical outcomes in cardiac arrest management and guiding future research directions.

Association of Arterial Carbon Dioxide Tension Following In-Hospital Cardiac Arrest With Survival and Favorable Neurologic Outcome.

BACKGROUND: In-hospital cardiac arrest (IHCA) continues to be associated with high morbidity and mortality. The objective of this study was to study the association of arterial carbon dioxide tension (PaCO2) on survival to discharge and favorable neurologic outcomes in adults with IHCA. METHODS: The study population included 353 adults who underwent resuscitation from 2011 to 2019 for IHCA at an academic tertiary care medical center with arterial blood gas testing done within 24 hours of arrest. Outcomes of interest included survival to discharge and favorable neurologic outcome, defined as Glasgow outcome score of 4-5. RESULTS: Of the 353 patients studied, PaCO2 classification included: hypocapnia (PaCO2 <35 mm Hg, n = 89), normocapnia (PaCO2 35-45 mm Hg, n = 151), and hypercapnia (PaCO2 >45 mm Hg, n = 113). Hypercapnic patients were further divided into mild (45 mm Hg < PaCO2 ≤55 mm Hg, n = 62) and moderate/severe hypercapnia (PaCO2 > 55 mm Hg, n = 51). Patients with normocapnia had the highest rates of survival to hospital discharge (52.3% vs. 32.6% vs. 30.1%, P < 0.001) and favorable neurologic outcome (35.8% vs. 25.8% vs. 17.9%, P = 0.005) compared those with hypocapnia and hypercapnia respectively. In multivariable analysis, compared to normocapnia, hypocapnia [odds ratio (OR), 2.06; 95% confidence interval (CI), 1.15-3.70] and hypercapnia (OR, 2.67; 95% CI, 1.53-4.66) were both found to be independently associated with higher rates of in-hospital mortality. Compared to normocapnia, while mild hypercapnia (OR, 2.53; 95% CI, 1.29-4.97) and moderate/severe hypercapnia (OR, 2.86; 95% CI, 1.35-6.06) were both independently associated with higher in-hospital mortality compared to normocapnia, moderate/severe hypercapnia was also independently associated with lower rates of favorable neurologic outcome (OR, 0.28; 95% CI, 0.11-0.73), while mild hypercapnia was not. CONCLUSIONS: In this prospective registry of adults with IHCA, hypercapnia noted within 24 hours after arrest was independently associated with lower rates of survival to discharge and favorable neurologic outcome.

Wolf Creek XVII Part 6: Physiology-Guided CPR.

Introduction: Physiology-guided cardiopulmonary resuscitation (CPR) offers the potential to optimize resuscitation and enable early prognosis. Methods: Physiology-Guided CPR was one of six focus topic for the Wolf Creek XVII Conference held on June 14-17, 2023 in Ann Arbor, Michigan, USA. International thought leaders and scientists in the field of cardiac arrest resuscitation from academia and industry were invited. 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, which was then debated, revised and ranked by all attendees to identify the top 5 for each category. Results: Top knowledge gaps include identifying optimal strategies for the evaluation of physiology-guided CPR and the optimal values for existing patients using patient outcomes. The main barriers to translation are the limited usability outside of critical care environments and the training and equipment required for monitoring. The top research priorities are the development of clinically feasible and reliable methods to continuously and non-invasively monitor physiology during CPR and prospective human studies proving targeting parameters during CPR improves outcomes. Conclusion: Physiology-guided CPR has the potential to provide individualized resuscitation and move away from a one-size-fits-all approach. Current understanding is limited, and clinical trials are lacking. Future developments need to consider the clinical application and applicability of measurement to all healthcare settings. Therefore, clinical trials using physiology-guided CPR for individualisation of resuscitation efforts are needed.

AWAreness during REsuscitation - II: A multi-center study of consciousness and awareness in cardiac arrest.

INTRODUCTION: Cognitive activity and awareness during cardiac arrest (CA) are reported but ill understood. This first of a kind study examined consciousness and its underlying electrocortical biomarkers during cardiopulmonary resuscitation (CPR). METHODS: In a prospective 25-site in-hospital study, we incorporated a) independent audiovisual testing of awareness, including explicit and implicit learning using a computer and headphones, with b) continuous real-time electroencephalography(EEG) and cerebral oxygenation(rSO2) monitoring into CPR during in-hospital CA (IHCA). Survivors underwent interviews to examine for recall of awareness and cognitive experiences. A complementary cross-sectional community CA study provided added insights regarding survivors' experiences. RESULTS: Of 567 IHCA, 53(9.3%) survived, 28 of these (52.8%) completed interviews, and 11(39.3%) reported CA memories/perceptions suggestive of consciousness. Four categories of experiences emerged: 1) emergence from coma during CPR (CPR-induced consciousness [CPRIC]) 2/28(7.1%), or 2) in the post-resuscitation period 2/28(7.1%), 3) dream-like experiences 3/28(10.7%), 4) transcendent recalled experience of death (RED) 6/28(21.4%). In the cross-sectional arm, 126 community CA survivors' experiences reinforced these categories and identified another: delusions (misattribution of medical events). Low survival limited the ability to examine for implicit learning. Nobody identified the visual image, 1/28(3.5%) identified the auditory stimulus. Despite marked cerebral ischemia (Mean rSO2 = 43%) normal EEG activity (delta, theta and alpha) consistent with consciousness emerged as long as 35-60 minutes into CPR. CONCLUSIONS: Consciousness. awareness and cognitive processes may occur during CA. The emergence of normal EEG may reflect a resumption of a network-level of cognitive activity, and a biomarker of consciousness, lucidity and RED (authentic "near-death" experiences).

Cerebral oximetry: a developing tool for monitoring cerebral oxygenation during cardiopulmonary resuscitation.

Despite improvements in cardiopulmonary resuscitation (CPR), survival and neurologic recovery after cardiac arrest remain very poor because of the impact of severe ischemia and subsequent reperfusion injury. As the likelihood of survival and favorable neurologic outcome decreases with increasing severity of ischemia during CPR, developing methods to measure the magnitude of ischemia during resuscitation, particularly cerebral ischemia, is critical for improving overall outcomes. Cerebral oximetry, which measures regional cerebral oxygen saturation (rSO2 ) by near-infrared spectroscopy, has emerged as a potentially beneficial marker of cerebral ischemia during CPR. In numerous preclinical and clinical studies, higher rSO2 during CPR has been associated with improved cardiac arrest survival and neurologic outcome. In this narrative review, we summarize the scientific rationale and validation of cerebral oximetry across populations and pathophysiologic states, discuss the evidence surrounding its use to predict return of spontaneous circulation, rearrest, and neurologic outcome, and provide suggestions for incorporation of cerebral oximetry into CPR practice.