Background:Antibiotic resistance is a threat to public health driven in part by widespread antibiotic administration. Days of antibiotic spectrum coverage (DASC) is a novel metric to quantify both duration and breadth of antibiotic exposure that has not previously been used as an endpoint in a clinical trial. We calculated DASC using data from the Ceftriaxone to Prevent Pneumonia and Inflammation after Cardiac Arrest (PROTECT) trial to determine the association of ceftriaxone prophylaxis with DASC and with the acquisition of antibiotic resistance genes (ARGs). Methods:PROTECT randomized out-of-hospital cardiac arrest subjects to ceftriaxone or placebo for 3 days. ARGs were measured from rectal swabs collected at Days 0, 3 and 7 post randomization. DASC was calculated for each subject and compared using a two-sided Mann-Whitney U-test. Correlations between DASC and new ARGs, antibiotic-free days (AFD) and days of therapy (DOT) were tested using Kendall's tau-alpha. Results:PROTECT enrolled 52 subjects, 26 per treatment group, and treatment groups were similar at baseline. Median DASC scores were lower in the ceftriaxone group (19.5; IQR: 0, 43) compared with placebo (53; IQR: 16, 81). We found no correlation between DASC and new ARGs at either timepoint, or between DASC and AFD. DASC was correlated with DOT. Conclusions:DASC post intervention was lower in the ceftriaxone group, representing less antibiotic exposure following the intervention. There was no correlation between new ARGs and DASC. Further study is needed to understand the relationship between antibiotic prophylaxis, subsequent antibiotic exposure and resistome changes in the critically ill.

The multicenter trial SETPOINT2 comparing early versus delayed tracheostomy in severe stroke was conducted in Germany and the USA. A pre-specified aim was to assess 6-month patient- and caregiver-reported outcomes to better inform clinical decision-making in the acute phase of care, irrespective of tracheostomy timing. Patients had acute ischemic, hemorrhagic, or subarachnoid hemorrhage (SAH) strokes, respiratory failure, and a predicted necessity for tracheostomy (SETscore > 10). Outcome measures assessed by telephone interview 6 months after hospital admission included the modified Rankin scale (mRS), EuroQol 5D-5L (EQ-5D-5L), EuroQol Visual Analog Scale, Burden Scale for Family Caregivers short form (BSFC-s), and questions related to satisfaction with the treatment results. Of 366 patients with available data at 6 months, 118 (32

Introduction: Amantadine, an effective neurostimulant for traumatic brain injury, has limited data supporting its use for other acute brain injuries (ABI). This pragmatic study evaluated amantadine for nontraumatic ABI monitored in the ICU with the Coma Recovery Scale-Revised (CRS-R). Methods: This prospective open-label cohort study developed a protocol to treat impaired consciousness after ABI with amantadine, assessing participants with CRS-R as 0-100 Rasch units, monitoring feasibility, safety, and effectiveness. Results: 40 patients (age 64 [52-73] years, 25 [62%] female) were included during this protocol development phase: 13 ischemic stroke, 10 intracerebral hemorrhage, 7 subarachnoid hemorrhage, 4 hypoxic-ischemic encephalopathy, 3 other ABI. The median baseline CRS-R was 11 (IQR 7-16), including 16 meeting criteria for Disorder of Consciousness. Among 30 participants with an adequate amantadine treatment trial, 27 (90%) responded, with disposition to home (1,4%), skilled nursing facility (6,22%), acute inpatient rehabilitation (15,56%), or withdrawal of life support (5,18%). Pre- versus post-treatment CRS-R increased for responders by 8 (6-11), equivalent to 26 (15-45) Rasch units. Among 10 untreated or inadequate trial patients, 3 (30%) were discharged to rehab, 7 (70%) had support withdrawn. Conclusions: It is feasible to measure responsiveness to amantadine using the CRS-R for ICU patients with ABI.

AIM:To evaluate the impact of adding early processed quantitative EEG biomarkers to health record data for early neurological risk stratification after cardiac arrest using machine learning. METHODS:Data available during ICU admission after return of spontaneous circulation (ROSC) were collected from comatose patients, including the processed EEG metrics suppression ratio (SR) and bispectral index (BIS). Clinical data included demographics, Charlson Comorbidity Index, cardiac arrest and resuscitation details, admission vital signs, and initial laboratory results. Primary outcome was poor Cerebral Performance Category score (CPC 3-5). Six machine learning models were developed to predict hospital discharge and 6-month long-term outcome with clinical data alone, EEG (BIS-SR) data alone, and combined clinical and EEG data. Two additional operating points (high specificity for poor outcome and for good outcome) were also calculated. Feature importance was analyzed to identify the most predictive variables. RESULTS:Among 913 patients, the median age was 59 years, most were male (69%), and 44% had an initial shockable rhythm. Poor outcome was observed in 70% at discharge and 72% at long-term assessment. The best-performing models for combined 6-h EEG and clinical data revealed AUC 0.88 (0.87-0.90) for poor long-term outcome and 0.86 (0.84-0.87) for poor discharge outcome. Combining the processed EEG and clinical data significantly improved the AUC compared to either data set alone (p < 0.001). CONCLUSION:The combination of early processed EEG and clinical data were best able to stratify neurological risk early after cardiac arrest using machine learning algorithms, but external validation is needed.

Acute non-traumatic subarachnoid hemorrhage (SAH) is complicated by systemic inflammation and cardiac dysfunction that contribute to the high rates of morbidity and mortality. To better define the mechanistic relationship between immune response and cardiac complications, we evaluated subpopulations of circulating immune cells and their associations with abnormalities of cardiac rhythm, injury biomarkers, and mechanical function after hemorrhage. In this single-site prospective observational study, we screened all adult patients presenting to our neurocritical care unit with non-traumatic SAH who required external ventricular drain (EVD) placement for treatment of hydrocephalus. Following informed consent, peripheral blood samples were obtained at post-bleed days (PBDs) 1, 3, 5, 7, and 10. Subjects were separated into groups based on evidence of cardiac abnormalities (cAbn(+))” versus “no cardiac abnormalities (cAbn(-)),” and flow cytometric analysis was used to identify and quantify immune cell subpopulations. Circulating neutrophil-secreted factors, including myeloperoxidase (MPO), were measured in plasma using ELISA. We measured associations between these immune factors and cardiac abnormalities. Sixty patients were enrolled between January 2018 and August 2023. Our patient cohort was 65

BACKGROUND:Antibiotic prophylaxis following out-of-hospital cardiac arrest (OHCA) reduces early-onset pneumonia. However, it has an uncertain impact on mortality and noninfectious outcomes, with ongoing concerns about the subsequent development of antibiotic resistance. RESEARCH QUESTION:Does prophylactic ceftriaxone reduce the incidence of early-onset pneumonia without increasing the acquisition of antibiotic resistance genes after OHCA? STUDY DESIGN AND METHODS:Comatose survivors of OHCA treated with targeted temperature management without a clinical diagnosis of pneumonia at admission were randomized to receive ceftriaxone 2 g or matching placebo every 12 hours for 3 days. The primary outcome was early-onset pneumonia occurring ≤ 4 days following intubation confirmed by masked adjudicators. Abundance of antibiotic resistance genes recovered from rectal swabs before and after study drug administration were analyzed with metagenomic sequencing. RESULTS:A total of 411 participants were screened; 53 (13%) were randomized to treatment, and 1 participant withdrew, leaving 26 in each group in the final analysis. Early-onset pneumonia was diagnosed in 10 (38%) participants receiving ceftriaxone and 18 (69%) participants receiving placebo (risk ratio, 0.57; 95% CI, 0.21-1.001; P = .05). Open-label antibiotics were administered to 14 (54%) participants receiving ceftriaxone and 22 (85%) receiving placebo (risk ratio, 0.64; 95% CI, 0.43-0.94); most of the antibiotics were broad-spectrum agents (93% and 100%, respectively). After adjusting for differences in abundance of antibiotic resistance genes prior to study drug administration, participants randomized to receive ceftriaxone acquired significantly fewer antibiotic resistance genes to frequently used antibiotics in the ICU compared with those randomized to receive placebo (incidence risk ratio, 0.30; 95% CI, 0.13-0.70). Serious adverse drug effects were not reported in either treatment group. INTERPRETATION:This trial was inconclusive regarding the impact of ceftriaxone prophylaxis on reducing the incidence of early-onset pneumonia following OHCA. However, ceftriaxone was associated with less frequent administration of open-label antibiotics and reduced acquisition of antibiotic resistance genes to frequently used antibiotics in the ICU. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov; No.: NCT04999592; URL: www. CLINICALTRIALS:gov.

Introduction: Prophylactic antibiotics can reduce infections after acute brain injury; Ceftriaxone (CTX) also modulates glutamate (GLUT) transporter function, which may reduce excitotoxicity and improve neurological outcomes. No study has described blood GLUT concentration in humans after out-of-hospital cardiac arrest (OHCA). Research Question: Is plasma GLUT associated with neurological outcome after OHCA? Goals/Aim: Assay plasma GLUT in a cohort of OHCA survivors randomized to CTX or placebo (PLAC) in the PROTECT trial (NCT04999592). Methods/Approach: Plasma GLUT concentrations were analyzed with the Promega bioluminescent assay from samples prospectively collected before study drug (baseline) and post-randomization days 1 and 3. Neurological risk was stratified blinded to outcome using the Pittsburgh Cardiac Arrest Category (PCAC) severity score iPhone app and the Vista EEG suppression ratio 6 hours after ROSC (SR6). Plasma GLUT was compared between PLAC and CTX groups and between CPC categories (1-2 = good outcome, 3-5 = poor) with the Mann-Whitney test. Stratification was compared with Area under Receiver Operator Characteristic (AUROC) curves. Results: PROTECT enrolled 52 subjects. Post-hoc stratification identified greater baseline neurological risk for subjects randomized to PLAC by SR6 (88 [63-96] vs 30 [3-84] CTX, p=0.008) but not by PCAC (4 [4-4] PLAC vs 4 [3-4] CTX, p=0.075). Poor neurological outcome was observed in 22/26 (85%) PLAC vs 13/26 (50%, p=0.018) CTX patients. The AUROC to predict poor neurological outcome was 0.93 (0.87-0.99) for SR6 vs 0.73 (0.57-0.89) for PCAC. Plasma GLUT was greater for the PLAC cohort at baseline (118.4 [87-180] vs 88.5 [69-103] µM, p=0.009) and on day 1 (102 [69-119] PLAC vs 70 [50-87] µM CTX, p=0.017). Change in GLUT from baseline to day 1 (p=0.68) or baseline to Day 3 (p=0.20) was similar in CTX and PLAC groups. Baseline (p=0.46), Day 1 (p=0.49), and Day 3 (p=0.99) plasma GLUT were similar among outcome groups. Conclusions: Subjects randomized to CTX had better neurological outcomes after OHCA, mainly related to lower baseline risk. Higher risk in the PLAC group was associated with higher baseline glutamate prior to study drug administration. Plasma GLUT did not differ between patients with good or poor outcome. More research is needed to assess glutamate dynamics beyond plasma levels after OHCA and to investigate the association between improved neurological outcomes and CTX.

Objective:Systematically examine the literature describing midodrine to treat shock and to summarize current administration and dosing strategies. Data sources:Structured literature search conducted in MEDLINE (PubMed) from inception through May 10, 2023. Study Selection and Data Extraction:Abstracts and full texts were assessed for inclusion by two blinded, independent reviewers. English-language publications describing use of midodrine in adult patients with shock were included. Data were extracted by two blinded, independent abstractors using a standardized extraction tool. Quality assessments were completed by paired reviewers using JBI methodology. Data Synthesis:Fifteen of 698 (2%) screened manuscripts were included with 1,714 patients with a variety of shock types. Seven studies (47%) were retrospective, two (13%) prospective observational, and six (40%) randomized controlled studies. Midodrine was initiated to facilitate intravenous vasopressor (IVP) weaning in most (11, 73%) studies; only two (13%) reported IVP weaning protocol use. Starting doses were 10 mg every 8 hours (4, 27%) or three times a day (3, 20%), 20 mg every 8 hours (2, 13%); six studies (40%) did not report initial midodrine dosing. A midodrine titration protocol was reported in 6 (40%) studies. Thirteen (87%) studies evaluated for bradycardia, identified in 6 (46%) studies among 204 patients; only one (0.5%) patient required midodrine discontinuation. Three (20%) studies reported on hypertension with an incidence of 7-11%. Four (27%) studies assessed for ischemia; 5/1128 (0.4%) patients experienced mesenteric ischemia requiring midodrine discontinuation. Relevance to Patient care and Clinical Practice:This review explores the pragmatic details involved in initiating, titrating, and weaning midodrine for the bedside clinician and identifies rates of adverse events and complications. Conclusions:Published literature describing midodrine use for shock is heterogeneous and comprised primarily of low or very low quality data. Future controlled trials addressing the shortcomings identified in this systematic review are warranted.

Importance:Understanding the relationship between patients' clinical characteristics and outcomes is fundamental to medicine. When critically ill patients die after withdrawal of life-sustaining therapy (WLST), the inability to observe the potential for recovery with continued aggressive care could bias future clinical decisions and research. Objective:To quantify the frequency with which experts consider patients who died after WLST following resuscitated cardiac arrest to have had recovery potential if life-sustaining therapy had been continued. Design, Setting, and Participants:This prospective cohort study included comatose adult patients (aged ≥18 years) treated following resuscitation from cardiac arrest at a single academic medical center between January 1, 2010, and July 31, 2022. Patients with advanced directives limiting critical care or who experienced cardiac arrest of traumatic or neurologic etiology were excluded. An international cohort of experts in post-arrest care based on clinical experience and academic productivity was identified. Experts reviewed the cases between August 24, 2022, and February 11, 2024. Exposure:Patients who died after WLST. Main Outcome and Measures:Three or more experts independently estimated recovery potential for each patient had life-sustaining treatment been continued, using a 7-point numerical ordinal scale. In the primary analysis, which involved the patient cases with death after WLST, a 1% or greater estimated recovery potential was considered to be clinically meaningful. In secondary analyses, thresholds of 5% and 10% estimated recovery probability were explored. Results:A total of 2391 patients (median [IQR] age, 59 [48-69] years; 1455 men [60.9%]) were included, of whom 714 (29.9%) survived to discharge. Cases of uncertain outcome (1431 patients [59.8%]) in which WLST preceded death were reviewed by 38 experts who rendered 4381 estimates of recovery potential. In 518 cases (36.2%; 95% CI, 33.7%-38.7%), all experts believed that recovery potential was less than 1% if life-sustaining therapies had been continued. In the remaining 913 cases (63.8%; 95% CI, 61.3%-66.3%), at least 1 expert believed that recovery potential was at least 1%. In 227 cases (15.9%; 95% CI, 14.0%-17.9%), all experts agreed that recovery potential was at least 1%, and in 686 cases (47.9%; 95% CI, 45.3%-50.6%), expert estimates differed at this threshold. Conclusions and Relevance:In this cohort study of comatose patients resuscitated from cardiac arrest, most who died after WLST were considered by experts to have had recovery potential. These findings suggest that novel solutions to avoiding deaths based on biased prognostication or incomplete information are needed.

Objectives:To describe the dosing strategy, safety, and effectiveness of amantadine in patients admitted to inpatient rehabilitation after stroke. Design:Retrospective, single-center, cohort study. Setting:Ninety-bed, inpatient rehabilitation hospital. Participants:Twenty-eight patients (N=28) with amantadine started in a neuro-intensive care unit after stroke and continued after transfer to rehabilitation; the median age was 67 years and 61% were men. Interventions:Oral amantadine. Main Outcome Measures:Amantadine prescribing practices, adverse drug effects, and changes in recovery trajectory relative to dose changes. Results:This cohort included 14 adult patients with intracerebral hemorrhage, 10 with subarachnoid hemorrhage, and 4 with acute ischemic stroke. The most common admitting amantadine dose was 100 mg twice daily. Inpatient rehabilitation lasted 27 (24-35) days, and amantadine was discontinued during rehabilitation in 6 patients (21%). Amantadine was prescribed to 22 patients (79%) at discharge from rehabilitation, most commonly 100 mg daily or twice daily, and was continued for 105 (39-510) days after admission to rehabilitation among the 17 patients with this data available. Twenty-one potential adverse events were identified among 16 (57%) patients, including confusion or delirium, sleeplessness, agitation, fatigue or lethargy, and spasticity; 8 of these (38%) occurred after reductions in amantadine dose. Conclusions:Amantadine dosing was highly variable during inpatient rehabilitation, with trends for longer dosing after acute ischemic stroke and shorter for subarachnoid hemorrhage. Amantadine appeared well tolerated during and after inpatient rehabilitation, and most (22/28) patients were prescribed amantadine at discharge. Strategies to guide long-term use of amantadine after acute stroke require further prospective study.

Riker, Richard1; Schlichting, Erica2; Seder, David2; Sorcher, Mary3; Gagnon, David4; May, Teresa2 Author Information

Background Tracheostomy in mechanically ventilated patients with severe stroke can be performed surgically or dilationally. Prospective data comparing both methods in patients with stroke are scarce. The randomized Stroke-Related Early Tracheostomy vs Prolonged Orotracheal Intubation in Neurocritical Care Trial2 (SETPOINT2) assigned 382 mechanically ventilated patients with stroke to early tracheostomy versus extubation or standard tracheostomy. Surgical tracheostomy (ST) was performed in 41 of 307 SETPOINT2 patients, and the majority received dilational tracheostomy (DT). We aimed to compare ST and DT in these patients with patients. Methods All SETPOINT2 patients with ST were compared with a control group of patients with stroke undergoing DT (1:2), selected by propensity score matching that included the factors stroke type, SETPOINT2 randomization group, Stroke Early Tracheostomy score, patient age, and premorbid functional status. Successful decannulation was the primary outcome, and secondary outcome parameters included functional outcome at 6 months and adverse events attributable to tracheostomy. Potential predictors of decannulation were evaluated by regression analysis. Results Baseline characteristics were comparable in the two groups of patients with stroke undergoing ST ( n = 41) and matched patients with stroke undergoing DT ( n = 82). Tracheostomy was performed significantly later in the ST group than in the DT group (median 9 [interquartile range {IQR} 5–12] vs. 9 [IQR 4–11] days after intubation, p = 0.025). Patients with ST were mechanically ventilated longer (median 19 [IQR 17–24] vs.14 [IQR 11–19] days, p = 0.008) and stayed in the intensive care unit longer (median 23 [IQR 16–27] vs. 17 [IQR 13–24] days, p = 0.047), compared with patients with DT. The intrahospital infection rate was significantly higher in the ST group compared to the DT group (14.6% vs. 1.2%, p = 0.002). At 6 months, decannulation rates (56% vs. 61%), functional outcomes, and mortality were not different. However, decannulation was performed later in the ST group compared to the DT group (median 81 [IQR 66–149] vs. 58 [IQR 32–77] days, p = 0.004). Higher baseline Stroke Early Tracheostomy score negatively predicted decannulation. Conclusions In ventilated patients with severe stroke in need of tracheostomy, surgical and dilational methods are associated with comparable decannulation rate and functional outcome at 6 months. However, ST was associated with longer time to decannulation and higher rates of early infections, supporting the dilational approach to tracheostomy in ventilated patients with stroke.

Chemokines, a family of chemotactic cytokines, mediate leukocyte migration to and entrance into inflamed tissue, contributing to the intensity of local inflammation. We performed an analysis of chemokine and immune cell responses to cardiac arrest (CA). Forty-two patients resuscitated from cardiac arrest were analyzed, and twenty-two patients who underwent coronary artery bypass grafting (CABG) surgery were enrolled. Quantitative antibody array, chemokines, and endotoxin quantification were performed using the patients blood. Analysis of CCL23 production in neutrophils obtained from CA patients and injected into immunodeficient mice after CA and cardiopulmonary resuscitation (CPR) were done using flow cytometry. The levels of CCL2, CCL4, and CCL23 are increased in CA patients. Temporal dynamics were different for each chemokine, with early increases in CCL2 and CCL4, followed by a delayed elevation in CCL23 at forty-eight hours after CA. A high level of CCL23 was associated with an increased number of neutrophils, neuron-specific enolase (NSE), worse cerebral performance category (CPC) score, and higher mortality. To investigate the role of neutrophil activation locally in injured brain tissue, we used a mouse model of CA/CPR. CCL23 production was increased in human neutrophils that infiltrated mouse brains compared to those in the peripheral circulation. It is known that an early intense inflammatory response (within hours) is associated with poor outcomes after CA. Our data indicate that late activation of neutrophils in brain tissue may also promote ongoing injury via the production of CCL23 and impair recovery after cardiac arrest.

Objective We hypothesized that the administration of amantadine would increase awakening of comatose patients resuscitated from cardiac arrest. Methods We performed a prospective, randomized, controlled pilot trial, randomizing subjects to amantadine 100 mg twice daily or placebo for up to 7 days. The study drug was administered between 72 and 120 hours after resuscitation and patients with absent N20 cortical responses, early cerebral edema, or ongoing malignant electroencephalography patterns were excluded. Our primary outcome was awakening, defined as following two-step commands, within 28 days of cardiac arrest. Secondary outcomes included length of stay, awakening, time to awakening, and neurologic outcome measured by Cerebral Performance Category at hospital discharge. We compared the proportion of subjects awakening and hospital survival using Fisher exact tests and time to awakening and hospital length of stay using Wilcoxon rank sum tests. Results After 2 years, we stopped the study due to slow enrollment and lapse of funding. We enrolled 14 subjects (12% of goal enrollment), seven in the amantadine group and seven in the placebo group. The proportion of patients who awakened within 28 days after cardiac arrest did not differ between amantadine (n=2, 28.6%) and placebo groups (n=3, 42.9%; P>0.99). There were no differences in secondary outcomes. Study medication was stopped in three subjects (21.4%). Adverse events included a recurrence of seizures (n=2; 14.3%), both of which occurred in the placebo group. Conclusion We could not determine the effect of amantadine on awakening in comatose survivors of cardiac arrest due to small sample size.