Faculty Bibliography

BACKGROUND/UNASSIGNED:In‑hospital cardiac arrest (IHCA) is associated with high mortality despite advances in resuscitation and post-cardiac arrest care. While individual inflammatory and neurologic biomarkers have been studied, less is known about coordinated proteomic and pathway‑level responses associated with survival after IHCA. METHODS/UNASSIGNED:In this prospective observational study, adult patients resuscitated after IHCA were enrolled at a tertiary academic medical center. Plasma samples were obtained at baseline (T0), 6 h (T6), and 24 h (T24) following return of spontaneous circulation (ROSC), when clinically feasible. High‑dimensional proteomic profiling was performed using the Olink® Explore 1536 platform. Survival‑associated proteins were identified using linear mixed‑effects models, and gene set enrichment analysis (GSEA) was performed to identify biologically coherent pathways. RESULTS/UNASSIGNED: = 49). Individual protein‑level differences were limited at baseline. The greatest divergence between survivors and non‑survivors occurred at 6 h, characterized by enrichment of immune‑metabolic, mitochondrial, and transcriptional pathways. At 24 h, pathway enrichment narrowed toward chemokine signaling, GPCR‑mediated responses, and oxidative stress. Baseline pathway signals were nominal and did not meet false discovery rate thresholds. CONCLUSIONS/UNASSIGNED:Survival following IHCA is associated with dynamic, time‑dependent proteomic and pathway‑level signatures, with the most pronounced biological divergence occurring early after resuscitation. These findings support the concept of time‑sensitive molecular phenotyping in post-cardiac arrest care and provide a foundation for future translational studies.

BACKGROUND:Antivirals remain an important treatment strategy for persons who experience severe and life-threatening COVID-19. Ensitrelvir is an oral 3CL protease inhibitor with potent antiviral activity. METHODS:We conducted an international randomized, placebo-controlled trial of ensitrelvir with standard of care (SOC) among adults hospitalized for COVID-19. The primary outcome was clinical recovery assessed by the Days to Recovery Scale through Day 60 (DRS-60), analyzed using a Van Elteren test. RESULTS:From 2023 to 2025, 589 participants received blinded study treatment (293 ensitrelvir and 296 placebo). Median age was 69 years, 49% were female, 68% were White, and SOC commonly included corticosteroids (61% and 54%) and remdesivir (62% and 60%) in ensitrelvir and placebo groups, respectively. Median DRS-60 category was 6 (IQR: 3-15) in the ensitrelvir and 5.5 (IQR: 3-12) in the placebo group (p=0.19), and the OR was 0.82 (95% CI: 0.62-1.09) for a better DRS-60 category with ensitrelvir. Ensitrelvir participants had lower detectable viral antigen in plasma at Day 5 (13.4% vs 25.1%; p<0.001). There was no difference in secondary clinical outcomes or pre-specified safety outcomes, though the mortality rate was 6.1% vs 4.4% and the frequency of hemorrhagic events was 3.4% vs 0.3% among ensitrelvir and placebo groups, respectively. CONCLUSIONS:Ensitrelvir treatment did not improve clinical recovery in addition to SOC for adults hospitalized for COVID-19. The lower illness severity in the Omicron era compared to earlier periods in the COVID-19 pandemic, and high use of remdesivir and corticosteroids, may have contributed to the lack of clinical benefit.

BACKGROUND:Ischemic/anoxic brain injury is often assumed to occur within minutes of severe cerebral ischemia. However, emerging evidence suggests brain tissue may be more resilient, with important implications for resuscitation. We hypothesized that during prolonged cardiac arrest, cortical electrical activity may be restorable if cerebral oxygenation thresholds are met and may be associated with return of spontaneous circulation (ROSC). METHODS:) during cardiopulmonary resuscitation (CPR). RESULTS:≥16%, and alpha at >40%. Alpha activity was seen up to 35 min, and delta/theta up to 60 min into CPR. Suppression reverted to near-normal in 12% of transitions. Alpha activity was associated with ROSC (OR 5.4; 95% CI 1.08-29.20; p = 0.045), while suppression predicted lower ROSC odds (OR 0.12; 95% CI 0.02-0.53; p = 0.002). Survival analysis was limited by small sample size. CONCLUSION/CONCLUSIONS:Near-physiologic brain activity may be restored during prolonged CPR if oxygenation thresholds are met and is associated with ROSC. Further research is needed to evaluate survival outcomes.

BACKGROUND:Current CPR guidelines recommend 10 breaths/min in adult cardiac arrest patients with an advanced airway, though this is largely based on animal studies. We evaluated the association between ventilation rate and return of spontaneous circulation (ROSC) in in-hospital cardiac arrest (IHCA). METHODS:) monitoring. Patients were enrolled from 25 tertiary centers in the U.S. and U.K. A subset had intra-arrest arterial blood gases collected per routine care. RESULTS:did not differ significantly, suggesting a hemodynamic mechanism. CONCLUSIONS:monitors. Thus, more studies are needed to determine the need to re-evaluate current ventilation targets during CPR in intubated patients.

BACKGROUND:Studies have not explored consciousness during deep hypothermic circulatory arrest (DHCA). However, as studies in cardiac arrest have identified a spectrum of consciousness, we sought to establish the feasibility of studying consciousness during DHCA. METHODS:This was a prospective study across 10 hospitals with 36 DHCA patients undergoing thoracic aortic aneurysm repair or pulmonary endarterectomy. A tablet computer delivered audiovisual stimuli (images and names of three fruits) using headphones during each procedure as a potential test of implicit learning and explicit recall. We also established electroencephalography (EEG) and near-infrared spectroscopy (NIRS) to measure electrocortical markers of consciousness and cerebral oxygenation. Post-procedure interviews were carried out to test patients' ability to recall the audiovisual stimuli as well other explicit memories. PRIMARY OUTCOMES/METHODS:1) Feasibility of establishing tests of explicit recall and implicit learning, 2) Electroencephalography testing during DHCA. SECONDARY OUTCOMES/RESULTS:1) Signs of explicit recall of memories or implicit learning, and 2) identification of electrocortical biomarkers of consciousness during DHCA. RESULTS:Overall, 29/36 (81%) had the tablet set up. All 36 had NIRS and EEG set up, but 9 (25%) had useable EEG data, and 23 (66%) NIRS data. Delta EEG waves were observed during circulatory arrest in 3/9 (33%) patients, while 1/9 (11%) had theta waves just prior to circulatory arrest. All others showed isoelectric pattern. 35/36 (97%) agreed to follow up interviews. None had explicit recall of the names of the three fruits, but 3/36 (9%) correctly guessed them as a potential sign of implicit learning and 3 (9%) recalled other memories including events around the procedure and themes consistent with a recalled experience of death. CONCLUSIONS:A spectrum of consciousness and awareness, including signs of implicit learning and electrocortical biomarkers of consciousness may be present during DHCA, despite absence of visible signs of consciousness. This can be further used to help explain the negative psychological outcomes that cardiac arrest survivors face.

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.

INTRODUCTION/UNASSIGNED:Physiology-guided cardiopulmonary resuscitation (CPR) offers the potential to optimize resuscitation and enable early prognosis. METHODS/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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.