Delayed CCL23 response is associated with poor outcomes after cardiac arrest.

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.

Surgical Versus Dilational Tracheostomy in Patients with Severe Stroke: A SETPOINT2 Post hoc Analysis.

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.

A multi-center, randomized, double blinded, placebo-controlled trial of amantadine to stimulate awakening in comatose patients resuscitated from cardiac arrest.

Objectives: 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 100mg twice daily or placebo for up to 7 days. The study drug was administered between 72-120 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 (CPC) at hospital discharge. We compared the proportion of subjects awakening and hospital survival using Fisher's 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), 7 in the amantadine arm and 7 in the placebo arm. The proportion of patients who awakened within 28 days after cardiac arrest did not differ between amantadine (n=2, 28.57%) and placebo groups (n=3, 42.86%) (p = 1.00). There were no differences in secondary outcomes. Study medication was stopped in three (21%) subjects. Adverse events included a recurrence of seizures (n=2; 14%), both of which occurred in the placebo arm. Conclusion: We could not determine the effect of amantadine on awakening in comatose survivors of cardiac arrest due to small sample size.

Derivation and Validation of a New Equation for Estimating Free Valproate Concentration in Critically Ill Adult Patients.

IMPORTANCE: Protein binding of valproate varies among ICU patients, altering the biologically active free valproate concentration (VPAC). Free VPAC is measured at few laboratories and is often discordant with total VPAC. Existing equations to predict free VPAC are either not validated or are inaccurate in ICU patients. OBJECTIVES: We designed this study to derive and validate a novel equation to predict free VPAC using data from ICU patients and to compare its performance to published equations. DESIGN: Retrospective cohort study. SETTING: Two academic medical centers. PARTICIPANTS: Patients older than 18 years old with concomitant free and total VPACs measured in the ICU were included in the derivation cohort if admitted from 2014 to 2018, and the validation cohort if admitted from 2019 to 2022. MAIN OUTCOMES AND MEASURES: Multivariable linear regression was used to derive an equation to predict free VPAC. Modified Bland-Altman plots and the rate of therapeutic concordance between the measured and predicted free VPAC were compared. RESULTS: Demographics, median free and total VPACs, and valproate free fractions were similar among 115 patients in the derivation cohort and 147 patients in the validation cohort. The Bland-Altman plots showed the new equation performed better (bias, 0.3 [95% limits of agreement, -13.6 to 14.2]) than the Nasreddine (-9.2 [-26.5 to 8.2]), Kodama (-9.7 [-30.0 to 10.7]), Conde Giner (-7.9 [-24.9 to 9.1]), and Parent (-9.9 [-30.7 to 11.0]) equations, and similar to Doré (-2.0 [-16.0 to 11.9]). The Doré and new equations had the highest therapeutic concordance rate (73%). CONCLUSIONS AND RELEVANCE: For patients at risk of altered protein binding such as ICU patients, existing equations to predict free VPAC are discordant with measured free VPAC. A new equation had low bias but was imprecise. External validation should be performed to improve its precision and generalizability. Until then, monitoring free valproate is recommended during critical illness.

Medications for opioid use disorder prescribed at hospital discharge associated with decreased opioid agonist dispensing in patients with opioid use disorder requiring critical care: A retrospective study.

INTRODUCTION: Buprenorphine is highly effective for the treatment of opioid use disorder (OUD), and, in recent years, the rates of patients maintained on buprenorphine requiring critical care have been steadily increasing. Currently, no unified guidance exists for buprenorphine management during critical illness. Likewise, we do not know if patients maintained on buprenorphine for OUD are prescribed medications for OUD (MOUD) following hospital discharge or if buprenorphine management influences mu opioid agonist dispensing. METHODS: In our cohort of adults over the age of 18 with OUD, receiving buprenorphine formulations in the 3 months preceding their ICU admission, we sought to investigate the relationship between receipt of MOUD and non-MOUD opioid prescribing up to 12 months following hospital discharge. This was a single-center, retrospective cohort study approved by the MaineHealth institutional review board. The study analyzed differences in prescription rates between discharge and subsequent time points using chi square or Fisher's exact test, as appropriate. We performed analyses using SPSS Statistical Software version 28 (IBM SPSS Inc., Armonk, NY) with significance set at p < 0.05. RESULTS: We identified a statistically significant increase in MOUD prescribing 3 months posthospital discharge in patients who received MOUD at time of discharge (87.9 % vs 40 % p = 0.002.) The study found a significant increase in nonbuprenorphine opioid prescribing in patients who did not receive an MOUD prescription at time of discharge (24.2 % vs 70 % p = 0.007). This trend persisted at the 6-month and 12-month time points; however, it did not reach statistical significance. Additionally, the study identified a significant reduction in the incidence of non-MOUD opioid dispensing in patients prescribed MOUD at each time point measured (p = 0.007, p < 0.001. p < 0.001 and p = 0.008 at discharge, 3, 6, and 12 months, respectively). CONCLUSIONS: These findings support continuing buprenorphine dispensing following hospital discharge.

Decreased circulating CD73 and adenosine deaminase are associated with disease severity in hospitalized patients with COVID-19.

OBJECTIVE: SARS-CoV-2 infection has been shown to result in increased circulating levels of adenosine triphosphate and adenosine diphosphate and decreased levels of adenosine, which has important anti-inflammatory activity. The goal of this pilot project was to assess the levels of soluble CD73 and soluble Adenosine Deaminase (ADA) in hospitalized patients with COVID-19 and determine if levels of these molecules are associated with disease severity. METHODS: Plasma from 28 PCR-confirmed hospitalized COVID-19 patients who had varied disease severity based on WHO classification (6 mild/moderate, 10 severe, 12 critical) had concentrations of both soluble CD73 and ADA determined by ELISA. These concentrations were compared to healthy control plasma that is commercially available and was biobanked prior to the start of the pandemic. Additionally, outcomes such as WHO ordinal scale for disease severity, ICU admission, needed for invasive ventilation, hospital length of stay, and development of thrombosis during admission were used as markers of disease severity. RESULTS: Our results show that both CD73 and ADA are decreased during SARS-CoV-2 infection. The level of circulating CD73 is directly correlated to the severity of the disease defined by the need for ICU admission, invasive ventilation, and hospital length of stay. Low level of CD73 is also associated with clinical thrombosis, a severe complication of SARS-CoV-2 infection. CONCLUSION: Our study indicates that adenosine metabolism is down-regulated in patients with COVID-19 and associated with severe infection. Further large-scale studies are warranted to investigate the role of the adenosinergic anti-inflammatory CD73/ADA axis in protection against COVID-19.

External validation of the CREST model to predict early circulatory-etiology death after out-of-hospital cardiac arrest without initial ST-segment elevation myocardial infarction.

BACKGROUND: The CREST model is a prediction model, quantitating the risk of circulatory-etiology death (CED) after cardiac arrest based on variables available at hospital admission, and intend to guide the triage of comatose patients without ST-segment-elevation myocardial infarction after successful cardiopulmonary resuscitation. This study assessed performance of the CREST model in the Target Temperature Management (TTM) trial cohort. METHODS: We retrospectively analyzed data from resuscitated out-of-hospital cardiac arrest (OHCA) patients in the TTM-trial. Demographics, clinical characteristics, and CREST variables (history of coronary artery disease, initial heart rhythm, initial ejection fraction, shock at admission and ischemic time > 25 min) were assessed in univariate and multivariable analysis. The primary outcome was CED. The discriminatory power of the logistic regression model was assessed using the C-statistic and goodness of fit was tested according to Hosmer-Lemeshow. RESULTS: Among 329 patients eligible for final analysis, 71 (22%) had CED. History of ischemic heart disease, previous arrhythmia, older age, initial non-shockable rhythm, shock at admission, ischemic time > 25 min and severe left ventricular dysfunction were variables associated with CED in univariate analysis. CREST variables were entered into a logistic regression model and the area under the curve for the model was 0.73 with adequate calibration according to Hosmer-Lemeshow test (p = 0.602). CONCLUSIONS: The CREST model had good validity and a discrimination capability for predicting circulatory-etiology death after resuscitation from cardiac arrest without ST-segment elevation myocardial infarction. Application of this model could help to triage high-risk patients for transfer to specialized cardiac centers.

Buprenorphine Continuation During Critical Illness Associated With Decreased Inpatient Opioid Use in Individuals Maintained on Buprenorphine for Opioid Use Disorder in a Retrospective Study.

The number of patients maintained on buprenorphine is steadily increasing. To date, no study has reported buprenorphine management practices for these patients during critical illness, nor its relationship with supplemental full-agonist opioid administration during their hospital stay. In this single-center retrospective study, we have explored the incidence of buprenorphine continuation during critical illness among patients receiving buprenorphine for the treatment of opioid use disorder. Additionally, we investigated the relationship between nonbuprenorphine opioid exposure and buprenorphine administration during the intensive care unit (ICU) and post-ICU phases of care. Our study included adults maintained on buprenorphine for opioid use disorder admitted to the ICU between December 1, 2014, and May 31, 2019. Nonbuprenorphine, full agonist opioid doses were converted to fentanyl equivalents (FEs). Fifty-one (44%) patients received buprenorphine during the ICU phase of care, with an average dose of 8 (8-12) mg/day. During the post-ICU phase of care, 68 (62%) received buprenorphine, with an average dose of 10 (7-14) mg/day. Lack of mechanical ventilation and acetaminophen use were also associated with buprenorphine use. Full agonist opioid use was more frequent on days when buprenorphine was not given (odds ratio [OR], 6.2 [95% CI, 2.3-16.4]; P < .001). Additionally, the average cumulative dose of opioids given on nonbuprenorphine administration days was significantly higher both in the ICU (OR, 1803 [95% CI, 1271-2553] vs OR, 327 [95% CI, 152-708] FEs/day; P < 0.001) and after ICU discharge (OR, 1476 [95% CI, 962-2265] vs OR, 238 [95% CI, 150-377] FEs/day; P < .001). Given these findings, buprenorphine continuation during critical illness should be considered, as it is associated with significantly decreased full agonist opioid use.

Circulating neutrophil extracellular trap (NET)-forming 'rogue' neutrophil subset, immunotype [DEspR + CD11b +], mediate multi-organ failure in COVID-19-an observational study.

Background: Cumulative research show association of neutrophils and neutrophil extracellular traps (NETs) with poor outcomes in severe COVID-19. However, to date, there is no curative intent therapy able to block neutrophil/NETs-mediated progression of multi-organ dysfunction. Because of emerging neutrophil heterogeneity, the study of subsets of circulating NET-forming neutrophils [NET + Ns] as mediators of multi-organ failure progression among patients with COVID-19 is critical to identification of therapeutic targets. Methods: We conducted a prospective observational study of circulating levels of CD11b + [NET + N] immunotyped for dual endothelin-1/signal peptide receptor (DEspR ±) expression by quantitative immunofluorescence-cytology and causal mediation analysis. In 36 consented adults hospitalized with mod-severe COVID-19, May to September 2020, we measured acute multi-organ failure via SOFA-scores and respiratory failure via SaO2/FiO2 (SF)-ratio at time points t1 (average 5.5 days from ICU/hospital admission) and t2 (the day before ICU-discharge or death), and ICU-free days at day28 (ICUFD). Circulating absolute neutrophil counts (ANC) and [NET + N] subset-specific counts were measured at t1. Spearman correlation and causal mediation analyses were conducted. Results: Spearman correlation analyses showed correlations of t1-SOFA with t2-SOFA (rho r S = 0.80) and ICUFD (r S = -0.76); circulating DEspR + [NET + Ns] with t1-SOFA (r S = 0.71), t2-SOFA (r S = 0.62), and ICUFD (r S = -0.63), and ANC with t1-SOFA (r S = 0.71), and t2-SOFA (r S = 0.61).Causal mediation analysis identified DEspR + [NET + Ns] as mediator of 44.1% [95% CI:16.5,110.6] of the causal path between t1-SOFA (exposure) and t2-SOFA (outcome), with 46.9% [15.8,124.6] eliminated when DEspR + [NET + Ns] were theoretically reduced to zero. Concordantly, DEspR + [NET + Ns] mediated 47.1% [22.0,72.3%] of the t1-SOFA to ICUFD causal path, with 51.1% [22.8,80.4%] eliminated if DEspR + [NET + Ns] were reduced to zero. In patients with t1-SOFA > 1, the indirect effect of a hypothetical treatment eliminating DEspR + [NET + Ns] projected a reduction of t2-SOFA by 0.98 [0.29,2.06] points and ICUFD by 3.0 [0.85,7.09] days. In contrast, there was no significant mediation of SF-ratio through DEspR + [NET + Ns], and no significant mediation of SOFA-score through ANC. Conclusions: Despite equivalent correlations, DEspR + [NET + Ns], but not ANC, mediated progression of multi-organ failure in acute COVID-19, and its hypothetical reduction is projected to improve ICUFD. These translational findings warrant further studies of DEspR + [NET + Ns] as potential patient-stratifier and actionable therapeutic target for multi-organ failure in COVID-19. Supplementary Information: The online version contains supplementary material available at 10.1186/s41231-023-00143-x.

Circulating neutrophil extracellular trap (NET)-forming 'rogue' neutrophil subset, immunotype [DEspR+CD11b+], mediate multi-organ failure in COVID-19 - an observational study.

Background: Cumulative research show association of neutrophils and neutrophil extracellular traps (NETs) with poor outcomes in severe COVID-19. However, to date, no curative intent therapy has been identified to block neutrophil/NETs-mediated progression of multi-organ dysfunction. Because of emerging neutrophil heterogeneity, the study of subsets of circulating neutrophil-extracellular trap (NET)-forming neutrophils [NET+Ns] as mediators of multi-organ failure progression among patients with COVID-19 is critical to identification of therapeutic targets. Methods: We conducted a prospective observational study of circulating levels of CD11b+[NET+N] immunotyped for dual endothelin-1/signal peptide receptor, (DEspR±) expression by quantitative immunofluorescence-cytology and causal mediation analysis. In 36 consented adults hospitalized with mod-severe COVID-19, May to September 2020, we measured acute multi-organ failure via SOFA-scores and respiratory failure via SaO2/FiO2 (SF)ratio at time points t1 (average 5.5 days from ICU/hospital admission) and t2 (the day before ICU-discharge or death), and ICU-free days at day28 (ICUFD). Circulating absolute neutrophil counts (ANC) and [NET+N] subset-specific counts were measured at t1. Spearman correlation and causal mediation analyses were conducted. Results: Spearman correlation analyses showed correlations of t1-SOFA with t2-SOFA ( rho r S =0.80) and ICUFD ( r S =-0.76); circulating DEspR+[NET+Ns] with t1-SOFA ( r S = 0.71), t2-SOFA ( r S =0.62), and ICUFD ( r S =-0.63), and ANC with t1-SOFA ( r S =0.71), and t2-SOFA ( r S =0.61). Causal mediation analysis identified DEspR+[NET+Ns] as mediator of 44.1% [95% CI:16.5,110.6] of the causal path between t1-SOFA (exposure) and t2-SOFA (outcome), with 46.9% [15.8,124.6] eliminated when DEspR+[NET+Ns] were theoretically reduced to zero. Concordantly, DEspR+[NET+Ns] mediated 47.1% [22.0,72.3%] of the t1-SOFA to ICUFD causal path, with 51.1% [22.8,80.4%] eliminated if DEspR+[NET+Ns] were reduced to zero. In patients with t1-SOFA >1, the indirect effect of a hypothetical treatment eliminating DEspR+[NET+Ns] projected a reduction of t2-SOFA by 0.98 [0.29,2.06] points and ICUFD by 3.0 [0.85,7.09] days. In contrast, there was no significant mediation of SF-ratio through DEspR+[NET+Ns], and no significant mediation of SOFA-score through ANC. Conclusions: Despite equivalent correlations, DEspR+[NET+Ns], but not ANC, mediated progression of multi-organ failure in acute COVID-19, and its hypothetical reduction is projected to improve ICUFD. These translational findings warrant further studies of DEspR+[NET+Ns] as potential patient-stratifier and actionable therapeutic target for multi-organ failure in COVID-19.

The number of circulating CD26 expressing cells is decreased in critical COVID-19 illness.

We evaluated the number of CD26 expressing cells in peripheral blood of patients with COVID-19 within 72 h of admission and on day 4 and day 7 after enrollment. The majority of CD26 expressing cells were presented by CD3+ CD4+ lymphocytes. A low number of CD26 expressing cells were found to be associated with critical-severity COVID-19 disease. Conversely, increasing numbers of CD26 expressing T cells over the first week of standard treatment was associated with good outcomes. Clinically, the number of circulating CD26 cells might be a marker of recovery or the therapeutic efficacy of anti-COVID-19 treatment. New therapies aimed at preserving and increasing the level of CD26 expressing T cells may prove useful in the treatment of COVID-19 disease.

Cardiac Arrest Treatment Center Differences in Sedation and Analgesia Dosing During Targeted Temperature Management.

BACKGROUND: Sedation and analgesia are recommended during targeted temperature management (TTM) after cardiac arrest, but there are few data to provide guidance on dosing to bedside clinicians. We evaluated differences in patient-level sedation and analgesia dosing in an international multicenter TTM trial to better characterize current practice and clinically important outcomes. METHODS: A total 950 patients in the international TTM trial were randomly assigned to a TTM of 33 °C or 36 °C after resuscitation from cardiac arrest in 36 intensive care units. We recorded cumulative doses of sedative and analgesic drugs at 12, 24, and 48 h and normalized to midazolam and fentanyl equivalents. We compared number of medications used, dosing, and titration among centers by using multivariable models, including common severity of illness factors. We also compared dosing with time to awakening, incidence of clinical seizures, and survival. RESULTS: A total of 614 patients at 18 centers were analyzed. Propofol (70%) and fentanyl (51%) were most frequently used. The average dosages of midazolam and fentanyl equivalents were 0.13 (0.07, 0.22) mg/kg/h and 1.16 (0.49, 1.81) µg/kg/h, respectively. There were significant differences in number of medications (p < 0.001), average dosages (p < 0.001), and titration at all time points between centers (p < 0.001), and the outcomes of patients in these centers were associated with all parameters described in the multivariate analysis, except for a difference in the titration of sedatives between 12 and 24 h (p = 0.40). There were associations between higher dosing at 48 h (p = 0.003, odds ratio [OR] 1.75) and increased titration of analgesics between 24 and 48 h (p = 0.005, OR 4.89) with awakening after 5 days, increased titration of sedatives between 24 and 48 h with awakening after 5 days (p < 0.001, OR > 100), and increased titration of sedatives between 24 and 48 h with a higher incidence of clinical seizures in the multivariate analysis (p = 0.04, OR 240). There were also significant associations between decreased titration of analgesics and survival at 6 months in the multivariate analysis (p = 0.048). CONCLUSIONS: There is significant variation in choice of drug, dosing, and titration when providing sedation and analgesics between centers. Sedation and analgesia dosing and titration were associated with delayed awakening, incidence of clinical seizures, and survival, but the causal relation of these findings cannot be proven.

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.

Opioid Prescribing Patterns Before, During, and After Critical Illness: An Observational Study.

OBJECTIVES: The association between opioid therapy during critical illness and persistent opioid use after discharge is understudied relative to ICU opioid exposure and modifiable risk factors. Our objectives were to compare persistent opioid use after discharge among patients with and without chronic opioid use prior to admission (OPTA) and identify risk factors associated with persistent use. DESIGN: Retrospective cohort study. SETTING: Medical, trauma/surgical, or neurologic ICU at an academic hospital. PARTICIPANTS: Adult patients surviving hospital admission. INTERVENTIONS: Opioid use during the ICU and post-ICU stays. MEASUREMENTS AND MAIN RESULTS: The primary outcome was persistent opioid use accounting for greater than 70% of days 4-6 months after discharge. Among 2,975 included patients, 257 (8.6%) were classified as OPTA, and 305 (10.2%) persistently filled opioid prescriptions, including 186/257 (72%) OPTA and 119/2,718 (4.4%) with no chronic opioid fills prior to admission. Among all patients, OPTA was strongly associated with persistent opioid use (odds ratio, 57.2 [95% CI, 41.4-80.0]). Multivariable logistic regression revealed that male sex, surgical procedure, and ICU opioid-free days were associated with reduced persistent opioid use for OPTA patients. Age and ICU opioid-free days were associated with reduced persistent opioid use for non-OPTA patients. Total ICU opioid dose and dose per day of ICU exposure were not associated with persistent use for either group. CONCLUSIONS: In this mixed cohort of ICU patients, 10.2% persistently filled opioid prescriptions 4-6 months after discharge. Although ICU opioid doses were not associated with persistent use, duration of ICU opioid administration is a modifiable risk factor that may reduce persistent opioid use after critical illness.

Effect of Early vs Standard Approach to Tracheostomy on Functional Outcome at 6 Months Among Patients With Severe Stroke Receiving Mechanical Ventilation: The SETPOINT2 Randomized Clinical Trial.

Importance: Many patients with severe stroke have impaired airway protective reflexes, resulting in prolonged invasive mechanical ventilation. Objective: To test whether early vs standard tracheostomy improved functional outcome among patients with stroke receiving mechanical ventilation. Design, Setting, and Participants: In this randomized clinical trial, 382 patients with severe acute ischemic or hemorrhagic stroke receiving invasive ventilation were randomly assigned (1:1) to early tracheostomy (≤5 days of intubation) or ongoing ventilator weaning with standard tracheostomy if needed from day 10. Patients were randomized between July 28, 2015, and January 24, 2020, at 26 US and German neurocritical care centers. The final date of follow-up was August 9, 2020. Interventions: Patients were assigned to an early tracheostomy strategy (n = 188) or to a standard tracheostomy (control group) strategy (n = 194). Main Outcomes and Measures: The primary outcome was functional outcome at 6 months, based on the modified Rankin Scale score (range, 0 [best] to 6 [worst]) dichotomized to a score of 0 (no disability) to 4 (moderately severe disability) vs 5 (severe disability) or 6 (death). Results: Among 382 patients randomized (median age, 59 years; 49.8% women), 366 (95.8%) completed the trial with available follow-up data on the primary outcome (177 patients [94.1%] in the early group; 189 patients [97.4%] in the standard group). A tracheostomy (predominantly percutaneously) was performed in 95.2% of the early tracheostomy group in a median of 4 days after intubation (IQR, 3-4 days) and in 67% of the control group in a median of 11 days after intubation (IQR, 10-12 days). The proportion without severe disability (modified Rankin Scale score, 0-4) at 6 months was not significantly different in the early tracheostomy vs the control group (43.5% vs 47.1%; difference, -3.6% [95% CI, -14.3% to 7.2%]; adjusted odds ratio, 0.93 [95% CI, 0.60-1.42]; P = .73). Of the serious adverse events, 5.0% (6 of 121 reported events) in the early tracheostomy group vs 3.4% (4 of 118 reported events) were related to tracheostomy. Conclusions and Relevance: Among patients with severe stroke receiving mechanical ventilation, a strategy of early tracheostomy, compared with a standard approach to tracheostomy, did not significantly improve the rate of survival without severe disability at 6 months. However, the wide confidence intervals around the effect estimate may include a clinically important difference, so a clinically relevant benefit or harm from a strategy of early tracheostomy cannot be excluded. Trial Registration: ClinicalTrials.gov Identifier: NCT02377167.

Influence of circulatory shock at hospital admission on outcome after out-of-hospital cardiac arrest.

Hypotension after cardiac arrest could aggravate prolonged hypoxic ischemic encephalopathy. The association of circulatory shock at hospital admission with outcome after cardiac arrest has not been well studied. The objective of this study was to investigate the independent association of circulatory shock at hospital admission with neurologic outcome, and to evaluate whether cardiovascular comorbidities interact with circulatory shock. 4004 adult patients with out-of-hospital cardiac arrest enrolled in the International Cardiac Arrest Registry 2006-2017 were included in analysis. Circulatory shock was defined as a systolic blood pressure below 90 mmHg and/or medical or mechanical supportive measures to maintain adequate perfusion during hospital admission. Primary outcome was cerebral performance category (CPC) dichotomized as good, (CPC 1-2) versus poor (CPC 3-5) outcome at hospital discharge. 38% of included patients were in circulatory shock at hospital admission, 32% had good neurologic outcome at hospital discharge. The adjusted odds ratio for good neurologic outcome in patients without preexisting cardiovascular disease with circulatory shock at hospital admission was 0.60 [0.46-0.79]. No significant interaction was detected with preexisting comorbidities in the main analysis. We conclude that circulatory shock at hospital admission after out-of-hospital cardiac arrest is independently associated with poor neurologic outcome.

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.