Community consultation for Exception from Informed consent (EFIC) before and during the COVID-19 pandemic.

Aim: Describe community consultation and surrogate consent rates for two Exception From Informed Consent (EFIC) trials for out-of-hospital cardiac arrest (OOHCA) - before and during the COVID-19 pandemic. Methods: The PEARL study (2016-2018) randomized OOHCA patients without ST-elevation to early cardiac catheterization or not. Community consultation included flyers, radio announcements, newspaper advertisements, mailings, and in-person surveys at basketball games and ED waiting rooms. The PROTECT trial (2021-present) randomizes OOHCA survivors to prophylactic ceftriaxone or placebo; the community consultation plan during the pandemic included city council presentations, social media posts, outpatient flyers, but no in-person encounters. Demographics for PROTECT community consultation were compared to PEARL and INTCAR registry data, with p-value < 0.05 considered significant. Results: PEARL surveyed 1,362 adults, including 64 % ≥60 years old, 96 % high school graduates or beyond; research acceptance rate was 92 % for the community and 76 % for personal level. PROTECT initially obtained 221 surveys from electronic media - including fewer males (28 % vs 72 %,p < 0.001) and those > 60 years old (14 % vs 53 %;p < 0.001) compared to INTCAR. These differences prompted a revised community consultation plan, targeting 79 adult in-patients with cardiac disease which better matched PEARL and INTCAR data: the majority were ≥ 60 years old (66 %) and male (54 %). Both PEARL and PROTECT enrolled more patients using surrogate consent vs EFIC (57 %, 61 %), including 71 % as remote electronic consents during PROTECT. Conclusions: Community consultation for EFIC studies changed with the COVID-19 pandemic, resulting in different demographic patterns. We describe effective adaptations to community consultation and surrogate consent during the pandemic.

Ceftriaxone to PRevent pneumOnia and inflammaTion aftEr Cardiac arresT (PROTECT): study protocol for a randomized, placebo-controlled trial.

BACKGROUND: Pneumonia is the most common infection after out-of-hospital cardiac arrest (OHCA) occurring in up to 65% of patients who remain comatose after return of spontaneous circulation. Preventing infection after OHCA may (1) reduce exposure to broad-spectrum antibiotics, (2) prevent hemodynamic derangements due to local and systemic inflammation, and (3) prevent infection-associated morbidity and mortality. METHODS: The ceftriaxone to PRevent pneumOnia and inflammaTion aftEr Cardiac arrest (PROTECT) trial is a randomized, placebo-controlled, single-center, quadruple-blind (patient, treatment team, research team, outcome assessors), non-commercial, superiority trial to be conducted at Maine Medical Center in Portland, Maine, USA. Ceftriaxone 2 g intravenously every 12 h for 3 days will be compared with matching placebo. The primary efficacy outcome is incidence of early-onset pneumonia occurring < 4 days after mechanical ventilation initiation. Concurrently, T cell-mediated inflammation bacterial resistomes will be examined. Safety outcomes include incidence of type-one immediate-type hypersensitivity reactions, gallbladder injury, and Clostridioides difficile-associated diarrhea. The trial will enroll 120 subjects over approximately 3 to 4 years. DISCUSSION: The PROTECT trial is novel in its (1) inclusion of OHCA survivors regardless of initial heart rhythm, (2) use of a low-risk antibiotic available in the USA that has not previously been tested after OHCA, (3) inclusion of anti-inflammatory effects of ceftriaxone as a novel mechanism for improved clinical outcomes, and (4) complete metagenomic assessment of bacterial resistomes pre- and post-ceftriaxone prophylaxis. The long-term goal is to develop a definitive phase III trial powered for mortality or functional outcome. TRIAL REGISTRATION: ClinicalTrials.gov NCT04999592 . Registered on August 10, 2021.

Number of Circulating CD 73-Expressing Lymphocytes Correlates With Survival After Cardiac Arrest.

Background Patients resuscitated from cardiac arrest ( CA ) have highly variable neurological, circulatory, and systemic ischemia-reperfusion injuries. After the initial hypoxic-ischemic insult, a cascade of immune and inflammatory responses develops and is often fatal. The role of the immune response in pathophysiological characteristics and recovery is not well understood. We studied immune cell activity and its association with outcomes in a cohort of CA survivors. Methods and Results After informed consent, we collected blood samples at intervals over a week after resuscitation from CA . We examined the expression of CD 39 and CD 73 (alias 5'-nucleotidase), production of tumor necrosis factor-α, generation of reactive oxygen species, and secretion of vascular endothelial growth factor by circulating myeloid and lymphoid cells, in comparison to cells obtained from control subjects before coronary artery bypass grafting surgery. The number of circulating total and CD 73-expressing lymphocytes correlated with survival after CA . Incubation of immune cells, obtained from post- CA subjects, with AMP , a substrate for CD 73, resulted in inhibition of tumor necrosis factor-α production and generation of reactive oxygen species. This effect was blocked by adenosine 5'-(α, ß-methylene) diphosphate, a specific inhibitor of CD 73 and ZM 241385, an A2 adenosine receptor antagonist. We also found that AMP -dependent activation of CD 73 induces production of vascular endothelial growth factor. Conclusions CD 73-expressing lymphocytes mediate cellular protection from inflammation after CA through inhibition of proinflammatory activation of myeloid cells and promotion of vascular endothelial growth factor secretion. The contribution of CD 73 lymphocytes in the regulation of acute inflammation and tissue injury after CA warrants further study.

Continuous surface EMG power reflects the metabolic cost of shivering during targeted temperature management after cardiac arrest.

AIM: Shivering may interfere with targeted temperature management (TTM) after cardiac arrest, contributing to secondary brain injury. Early identification of shivering is challenging with existing tools. We hypothesized that shivering detected by continuous surface sEMG monitoring would be validated with calorimetry and detected earlier than by intermittent clinical observation. METHODS: This prospective observational study enrolled a convenience sample of comatose adult cardiac arrest patients treated with TTM at 33 °C. Clinical shivering was monitored hourly using the Bedside Shivering Assessment Scale (BSAS) by bedside nurses who administered intermittent neuromuscular blockade (NMB) when BSAS ≥ 1. The research team monitored independently for shivering with BSAS every 15 min during continuous blinded monitoring of oxygen consumption (VO2) via indirect calorimetry and sEMG power during the maintenance phase of TTM. A sustained 20% increase in the 5-min rolling average of VO2 above baseline identified the Gold Standard shivering threshold (VO2-20). RESULTS: Among 18 patients, clinical shivering was detected 23 times in 14 patients. Hierarchical models to predict a shiver event determined by the VO2-20 for sEMG power and BSAS revealed an AUC for sEMG power of 0.92 (95%CI = 0.88-0.95), and 0.90 (CI = 0.87-0.94) for BSAS. The optimal threshold of sEMG to predict VO2-20 was 32 decibels (dB), and this was exceeded 38 (29-56) min before nurse-detected shivering. CONCLUSIONS: Shivering was detected by sEMG power earlier than by clinical assessment with BSAS, with similar accuracy compared to the indirect calorimetry gold standard. Continuous sEMG monitoring appears useful for clinical assessment and research for shivering during TTM.

Inadequacy of Headache Management After Subarachnoid Hemorrhage.

BACKGROUND: Headache profoundly affects management of spontaneous subarachnoid hemorrhage but is poorly characterized. OBJECTIVE: To characterize headache after spontaneous subarachnoid hemorrhage. METHODS: Medical records of patients with Hunt and Hess grades I-III subarachnoid hemorrhage admitted from 2011 to 2013 were reviewed. Demographics, clinical and radiographic features, medications, and pain scores were recorded through day 14 after hemorrhage. Headache pain was characterized on the basis of a numeric rating scale and analgesic use. Severe headache was defined as 2 or more days with maximum pain scores of 8 or greater or need for 3 or more different analgesics for 2 or more days. Univariate and multivariable models were used to analyze factors associated with severe headache. RESULTS: Of the 77 patients in the sample, 57% were women; median age was 57 years. Severe headache (73% overall) was associated nonlinearly with Hunt and Hess grade: grade I, 58%; grade II, 88%; and grade III, 56% (P = .01), and with Hijdra score: score 0-10, 56%; score 11-20, 86%; score 21-30, 76% (P = .03). By univariate analysis, patients with low Hijdra scores were less likely to have severe headache (27% vs 57%; P = .02). In a multivariable model, younger age and higher Hijdra score tended to be associated with severe headache. CONCLUSIONS: Headache after spontaneous subarachnoid hemorrhage was often severe, necessitating multiple opioid and nonopioid analgesics. Many patients reported persistent headache and inadequate pain control.

Moderate-dose sedation and analgesia during targeted temperature management after cardiac arrest.

BACKGROUND: Sedation and analgesia regimens during targeted temperature management (TTM), after cardiac arrest varies widely, are poorly described in the literature and may have a negative impact on outcome. Since implementing TTM in 2005, we have used moderate-dose sedation and describe our experience with this approach. METHODS: In this retrospective review, we included patients treated with TTM for cardiac arrest at our institution for 2008-2012. Patients received TTM if they did not follow verbal commands following cardiac arrest, regardless of place of arrest or rhythm. Utstein-compatible data were prospectively entered into the International Cardiac Arrest Registry, supplemented by review of nursing, pharmacy, and physical therapy records. We report analgesic and sedative medications and doses during the 24 h of active TTM at 33 °C, resource utilization, and important clinical events. RESULTS: 166 patients treated with TTM after in- and out-of-hospital cardiac arrest with complete data were included. Overall survival was 42 %, median time to following commands was 3 h after rewarming (-6, 14), time to spontaneous breathing trial was 19 h (5-35), time to extubation was 28 h (9-60), and 59 % of survivors were discharged directly home at 13 (10-20) days. The incidence of seizure was 6 %, septic shock 4 %, and pneumonia 32 %. Four survivors required tracheostomy at 8, 8, 12, and 16 days. CONCLUSIONS: A moderate-dose sedation and analgesia regimen was well tolerated and effective during therapeutic hypothermia after cardiac arrest and is an effective alternative to very deep sedation. We recommend more complete description of sedation and analgesia protocols in future studies, including expanded outcome reporting to include variables affected by sedation therapy. Further study is required to define which sedation approach for TTM may be best.

Feasibility of bispectral index monitoring to guide early post-resuscitation cardiac arrest triage.

INTRODUCTION: Triage after resuscitation from cardiac arrest is hindered by reliable early estimation of brain injury. We evaluated the performance of a triage model based on early bispectral index (BIS) findings and cardiac risk classes. METHODS: Retrospective evaluation of serial patients resuscitated from cardiac arrest, unable to follow commands, and undergoing hypothermia. Patients were assigned to a cardiac risk group: STEMI, VT/VF shock, VT/VF no shock, or PEA/asystole, and to a neurological dysfunction group, based on the BIS score following first neuromuscular blockade (BISi), and classified as BISi>20, BISi 10-20, or BISi<10. Cause of death was described as neurological or circulatory. RESULTS: BISi in 171 patients was measured at 267(±177)min after resuscitation and 35(±1.7)°C. BISi<10 suffered 82% neurological-cause and 91% overall mortality, BISi 10-20 35% neurological and 55% overall mortality, and BISi>20 12% neurological and 36% overall mortality. 33 patients presented with STEMI, 15 VT/VF-shock, 41 VT/VF-no shock, and 80 PEA/asystole. Among BISi>20 patients, 75% with STEMI underwent urgent cardiac catheterization (cath) and 94% had good outcome. When BISi>20 with VT/VF and shock, urgent cath was infrequent (33%), and 4 deaths (44%) were uniformly of circulatory etiology. Of 56 VT/VF patients without STEMI, 24 were BISi>20 but did not undergo urgent cath - 5(20.8%) of these had circulatory-etiology death. Circulatory-etiology death also occurred in 26.5% BIS>20 patients with PEA/asystole. When BISi<10, a neurological etiology death dominated independent of cardiac risk group. CONCLUSIONS: Neurocardiac triage based on very early processed EEG (BIS) is feasible, and may identify patients appropriate for individualized post-resuscitation care. This and other triage models warrant further study.

Initial bispectral index may identify patients who will awaken during therapeutic hypothermia after cardiac arrest: a retrospective pilot study.

AIM: Patients sustain a range of neurologic injuries after cardiac arrest, and determining which patients should be treated with therapeutic hypothermia (TH) is complex, often confounded by sedation and neuromuscular blockade (NMB). We evaluated bispectral index (BIS) monitoring as a tool to identify adult patients that awakened during therapeutic hypothermia. METHODS: Review of prospectively collected registry data, with retrospective chart review of patient descriptions during hypothermia. Data are presented as median (interquartile range). RESULTS: 7 of 309 patients (2.2%) treated with TH over 6 years awoke (followed commands) prior to completing hypothermia. Median age was 58 (54-66) years; 71% were male, cardiac arrest was witnessed in 6 (86%) and out-of-hospital in 6 (86%), and 4 patients (57%) were transferred from another hospital. 5 patients (71%) had an initial rhythm of ventricular tachycardia or fibrillation, time to return of spontaneous circulation was 17 (12-23)min. The BIS value after first NMB dose during TH was 63, 45, 43, 52, 62, 54, and 42 (median 52, IQR 44-58, 95% confidence interval 46-58). The median BIS value in the remaining data set (n=302) was 18 (6-36), p<0.001, and only 6% of BIS1 values were >46. CONCLUSION: Patients who awakened early had higher BIS values after the first dose of NMB. Processed EEG values after cardiac arrest may provide additional information that could assist with determining best treatment.

Association of the Bedside Shivering Assessment Scale and derived EMG power during therapeutic hypothermia in survivors of cardiac arrest.

INTRODUCTION: Shivering during therapeutic hypothermia (TH) after cardiac arrest (CA) is common, but the optimal means of detection and appropriate threshold for treatment are not established. In an effort to develop a quantitative, continuous tool to measure shivering, we hypothesized that continuous derived electromyography (dEMG) power detected by the Aspect A2000 or VISTA monitor would correlate with the intermittent Bedside Shivering Assessment Scale (BSAS) performed by nurses. METHODS: Among 38 patients treated with TH after CA, 853 hourly BSAS measurements were compared to dEMG power measured every minute by a frontal surface electrode. Patients received intermittent vecuronium by protocol to treat clinically recognized shivering (BSAS>0). Mean dEMG power in decibels (dB) was determined for the hour preceding each BSAS measurement. dEMG and BSAS were compared using ANOVA. RESULTS: The median dEMG power for a BSAS score of 0 (no shivering) was 27 dB (IQR 26-31 dB), BSAS 1 was 30.5 dB (IQR 28-35 dB), BSAS 2 was 34 dB (IQR 30-38 dB), and BSAS 3 was 34.5 dB (IQR 32-44.25). The dEMG for BSAS≥1 (shivering) was statistically different from BSAS 0 (p<0.0001). dEMG and BSAS correlated moderately (r=0.66, p<0.001). CONCLUSION: dEMG power measured from the forehead with the Aspect A2000 or VISTA monitor during therapeutic hypothermia correlated with the Bedside Shivering Assessment Scale. Given its continuous trending of dEMG power, the A2000 or VISTA may be a useful research and clinical tool for objectively monitoring shivering.