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.

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.

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.

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.

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.

Randomized Pilot Clinical Trial of Early Coronary Angiography Versus No Early Coronary Angiography After Cardiac Arrest Without ST-Segment Elevation: The PEARL Study.

BACKGROUND: The benefit of emergency coronary angiography after resuscitation from out-of-hospital cardiac arrest is uncertain for patients without ST-segment elevation. The aim of this randomized trial was to evaluate the efficacy and safety of early coronary angiography and to determine the prevalence of acute coronary occlusion in resuscitated patients with out-of-hospital cardiac arrest without ST-segment elevation. METHODS: Adult (>18 years) comatose survivors without ST-segment elevation after resuscitation from out-of-hospital cardiac arrest were prospectively randomized in a 1:1 fashion under exception to informed consent regulations to early coronary angiography versus no early coronary angiography in this multicenter study. Early angiography was defined as ≤120 minutes from arrival at the percutaneous coronary intervention-capable facility. The primary end point was a composite of efficacy and safety measures, including efficacy measures of survival to discharge, favorable neurologic status at discharge (Cerebral Performance Category score ≤2), echocardiographic measures of left ventricular ejection fraction >50%, and a normal regional wall motion score of 16 within 24 hours of admission. Adverse events included rearrest, pulmonary edema on chest x-ray, acute renal dysfunction, bleeding requiring transfusion or intervention, hypotension (systolic arterial pressure ≤90 mm Hg), and pneumonia. Secondary end points included the incidence of culprit vessels with acute occlusion. RESULTS: The study was terminated prematurely before enrolling the target number of patients. A total of 99 patients were enrolled from 2015 to 2018, including 75 with initially shockable rhythms. Forty-nine patients were randomized to early coronary angiography. The primary end point of efficacy and safety was not different between the 2 groups (55.1% versus 46.0%; P=0.64). Early coronary angiography was not associated with any significant increase in survival (55.1% versus 48.0%; P=0.55) or adverse events (26.5% versus 26.0%; P=1.00). Early coronary angiography revealed a culprit vessel in 47%, with a total of 14% of patients undergoing early coronary angiography having an acutely occluded culprit coronary artery. CONCLUSIONS: This underpowered study, when considered together with previous clinical trials, does not support early coronary angiography for comatose survivors of cardiac arrest without ST elevation. Whether early detection of occluded potential culprit arteries leads to interventions that improve outcomes requires additional study. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02387398.

Amantadine and Modafinil as Neurostimulants Following Acute Stroke: A Retrospective Study of Intensive Care Unit Patients.

BACKGROUND/OBJECTIVE: Neurostimulants may improve or accelerate cognitive and functional recovery after intracerebral hemorrhage (ICH), ischemic stroke (IS), or subarachnoid hemorrhage (SAH), but few studies have described their safety and effectiveness in the intensive care unit (ICU). The objective of this study was to describe amantadine and modafinil administration practices during acute stroke care starting in the ICU and to evaluate safety and effectiveness. METHODS: Consecutive adult ICU patients treated with amantadine and/or modafinil following acute non-traumatic IS, ICH, or SAH were evaluated. Neurostimulant administration data were extracted from the electronic medication administration record, including medication (amantadine, modafinil, or both), starting dose, time from stroke to initiation, and whether the neurostimulant was continued at hospital discharge. Patients were considered responders if they met two of three criteria within 9 days of neurostimulant initiation: increase in Glasgow coma scale (GCS) score ≥ 3 points from pre-treatment baseline, improved wakefulness or participation documented in caregiver notes, or clinical improvement documented in physical or occupational therapy notes. Potential confounders of the effectiveness assessment and adverse drug effects were also recorded. RESULTS: A total of 87 patients were evaluable during the 3.7-year study period, including 41 (47%) with ICH, 29 (33%) with IS, and 17 (20%) with SAH. The initial neurostimulant administered was amantadine in 71 (82%) patients, modafinil in 13 (15%), or both in 3 (3%) patients. Neurostimulants were initiated a median of 7 (4.25, 12.75) days post-stroke (range 1-27 days) for somnolence (77%), not following commands (32%), lack of eye opening (28%), or low GCS (17%). The most common starting dose was 100 mg twice daily for both amantadine (86%) and modafinil (54%). Of the 79 patients included in the effectiveness evaluation, 42 (53%) were considered responders, including 34/62 (55%) receiving amantadine monotherapy and 8/24 (33%) receiving both amantadine and modafinil at the time they met the definition of a responder. No patient receiving modafinil monotherapy was considered a responder. The median time from initiation to response was 3 (2, 5) days. Responders were more frequently discharged home or to acute rehabilitation compared to non-responders (90% vs 62%, p = 0.006). Among survivors, 63/72 (88%) were prescribed a neurostimulant at hospital discharge. The most common potential adverse drug effect was sleep disruption (16%). CONCLUSIONS: Neurostimulant administration during acute stroke care may improve wakefulness. Future controlled studies with a neurostimulant administration protocol, prospective evaluation, and discretely defined response and safety criteria are needed to confirm these encouraging findings.

Neurological Pupil Index and Pupillary Light Reflex by Pupillometry Predict Outcome Early After Cardiac Arrest.

BACKGROUND: The absence of the pupillary light reflex (PLR) 3 days after cardiac arrest predicts poor outcome, but quantitative PLR assessment with pupillometry early after recovery of spontaneous circulation (ROSC) and throughout targeted temperature management (TTM) has rarely been evaluated. METHODS: Fifty-five adult patients treated with TTM with available pupillometry data from the NeurOptics NPi-200 were studied. Discharge outcome was classified good if the cerebral performance category score was 1-2, poor if 3-5. Pupil size, PLR percent constriction (%PLR), and constriction velocity (CV) were determined at TTM start and 6 (± 2)-h post-ROSC ("early"), and throughout TTM using data from the worst eye at each assessment. The Neurological Pupil index (NPi) was also determined at each pupil assessment; the NPi is scored from 0 (nonreactive) to 5 (brisk) with values < 3 considered sluggish or abnormal. Prognostic performance to predict poor outcome was assessed with receiver operator characteristic curves. RESULTS: All nine patients with ≥ 1 nonreactive pupil (NPi = 0) within 6 (± 2) h after ROSC died, and 12/14 (86%) with sluggish pupils (0 < NPi < 3) had poor outcomes. 15/29 (52%) patients with normal pupil reactivity (NPi ≥ 3) had poor outcomes, four survived with cerebral performance category = 3, three died of cardiac causes, and eight died of neurologic causes. During TTM, 20/21 (95%) patients with nonreactive pupils had poor outcomes, 9/14 (64%) of patients with sluggish pupils had poor outcomes, and 9/20 (45%) with normal pupil reactivity had poor outcomes. Pupil size did not predict outcome, but NPi (AUC = 0.72 [0.59-0.86], p < 0.001), %PLR (AUC = 0.75 [0.62-0.88], p < 0.001) and CV (AUC = 0.78 [0.66-0.91], p < 0.001) at 6 h predicted poor outcome. When nonreactive pupils were first detected, 75% were < 5 mm. CONCLUSIONS: Very early after resuscitation from cardiac arrest, abnormal Neurological Pupil index and pupillary light reflex measurements by pupillometer are predictive of poor outcome, and are not usually associated with dilated pupils.

Amantadine and Modafinil as Neurostimulants During Post-stroke Care: A Systematic Review.

Amantadine and modafinil are neurostimulants that may improve cognitive and functional recovery post-stroke, but the existing study results vary, and no comprehensive review has been published. This systematic review describes amantadine and modafinil administration practices post-stroke, evaluates timing and impact on clinical effectiveness measures, and identifies the incidence of potential adverse drug effects. A librarian-assisted search of the MEDLINE (PubMed) and EMBASE databases identified all English-language publications with "amantadine" or "modafinil" in the title or abstract from inception through February 1, 2020. Publications meeting predefined Patient, Intervention, Comparator, Outcome (PICO) criteria were included: Patients (≥ 18 years of age post-stroke); Intervention (amantadine or modafinil administration); Comparison (pretreatment baseline or control group); Outcomes (cognitive or functional outcome). Amantadine and modafinil administration practices, cognitive and functional outcomes, and incidence of potential adverse drug effects were collected following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidance. Quantitative analyses were not performed due to heterogeneity in the clinical effectiveness measures; descriptive data are presented as number (percent) or median (interquartile range). Of 12,620 publications initially identified, 10 amantadine publications (n = 121 patients) and 12 modafinil publications (n = 120 patients) were included. Amantadine was initiated 39 (16, 385) days post-stroke, with most common initial doses of 100 mg once or twice daily (range 100-200 mg/day), and final daily dose of 200 (188, 200) mg/day. Modafinil was initiated 170 (17, 496) days post-stroke, with initial and final daily doses of 100 (100, 350) mg/day and 200 (100, 350) mg/day, respectively. The most common indication was consciousness disorders for amantadine (n = 3/10 publications; 30%) and fatigue for modafinil (n = 5/12; 42%). Forty unique clinical effectiveness measures (1.8 per study) with 141 domains (6.4 per study) were described across all studies. A positive response in at least one clinical effectiveness measure was reported in 70% of amantadine publications and 83% of modafinil publications. Only one publication each for amantadine (10%; n = 5 patients) and modafinil (8%; n = 21 patients) studied acutely hospitalized or ICU patients; both were randomized studies showing improvements in neurocognitive function for amantadine and fatigue for modafinil. Potential adverse drug effects were reported in approximately 50% of publications, most commonly visual hallucinations with amantadine (2% of patients) and dizziness (5% of patients) and dry eyes or mouth (5% of patients). Amantadine and modafinil may improve cognitive and functional recovery post-stroke, but higher-quality data are needed to confirm this conclusion, especially in the acute care setting.

Derivation and Validation of the CREST Model for Very Early Prediction of Circulatory Etiology Death in Patients Without ST-Segment-Elevation Myocardial Infarction After Cardiac Arrest.

BACKGROUND: No practical tool quantitates the risk of circulatory-etiology death (CED) immediately after successful cardiopulmonary resuscitation in patients without ST-segment-elevation myocardial infarction. We developed and validated a prediction model to rapidly determine that risk and facilitate triage to individualized treatment pathways. METHODS: With the use of INTCAR (International Cardiac Arrest Registry), an 87-question data set representing 44 centers in the United States and Europe, patients were classified as having had CED or a combined end point of neurological-etiology death or survival. Demographics and clinical factors were modeled in a derivation cohort, and backward stepwise logistic regression was used to identify factors independently associated with CED. We demonstrated model performance using area under the curve and the Hosmer-Lemeshow test in the derivation and validation cohorts, and assigned a simplified point-scoring system. RESULTS: Among 638 patients in the derivation cohort, 121 (18.9%) had CED. The final model included preexisting coronary artery disease (odds ratio [OR], 2.86; confidence interval [CI], 1.83-4.49; P≤0.001), nonshockable rhythm (OR, 1.75; CI, 1.10-2.77; P=0.017), initial ejection fraction<30% (OR, 2.11; CI, 1.32-3.37; P=0.002), shock at presentation (OR, 2.27; CI, 1.42-3.62; P<0.001), and ischemic time >25 minutes (OR, 1.42; CI, 0.90-2.23; P=0.13). The derivation model area under the curve was 0.73, and Hosmer-Lemeshow test P=0.47. Outcomes were similar in the 318-patient validation cohort (area under the curve 0.68, Hosmer-Lemeshow test P=0.41). When assigned a point for each associated factor in the derivation model, the average predicted versus observed probability of CED with a CREST score (coronary artery disease, initial heart rhythm, low ejection fraction, shock at the time of admission, and ischemic time >25 minutes) of 0 to 5 was: 7.1% versus 10.2%, 9.5% versus 11%, 22.5% versus 19.6%, 32.4% versus 29.6%, 38.5% versus 30%, and 55.7% versus 50%. CONCLUSIONS: The CREST model stratified patients immediately after resuscitation according to risk of a circulatory-etiology death. The tool may allow for estimation of circulatory risk and improve the triage of survivors of cardiac arrest without ST-segment-elevation myocardial infarction at the point of care.

The Present State of Neurointensivist Training in the United States: A Comparison to Other Critical Care Training Programs.

OBJECTIVE: This manuscript describes the state of neurocritical care fellowship training, compares its written standards to those of other critical care fellowship programs, and discusses how programmatic oversight by the United Council for Neurological Subspecialties should evolve to meet American College of Graduate Medical Education standards. This review is a work product of the Society of Critical Care Medicine Neuroscience section and was reviewed and approved by the Council of the Society of Critical Care Medicine. DATA SOURCES: We evaluated the published training criteria and requirements of American College of Graduate Medical Education Critical Care subspecialty fellowships programs of Internal Medicine, Surgery, and Anesthesia and compared them with the training criteria and required competencies for neurocritical care. STUDY SELECTION: We have reviewed the published training standards from American College of Graduate Medical Education as well as the United Council for Neurologic Subspecialties subspecialty training documents and clarified the definition and responsibilities of an intensivist with reference to the Leapfrog Group, the National Quality Forum, and the Joint Commission. DATA EXTRACTION: No data at present exist to test the concept of similarity across specialty fellowship critical care training programs. DATA SYNTHESIS: Neurocritical care training differs in its exposure to clinical entities that are directly associated to other critical care subspecialties. However, the core critical care knowledge, procedural skills, and competencies standards for neurocritical care appears to be similar with some important differences compared with American College of Graduate Medical Education critical care training programs. CONCLUSIONS: The United Council for Neurologic Subspecialties has developed a directed program development strategy to emulate American College of Graduate Medical Education standards with the goal to have standards that are similar or identical to American College of Graduate Medical Education standards.

Variation in Sedation and Neuromuscular Blockade Regimens on Outcome After Cardiac Arrest.

OBJECTIVES: Sedation and neuromuscular blockade protocols in patients undergoing targeted temperature management after cardiac arrest address patient discomfort and manage shivering. These protocols vary widely between centers and may affect outcomes. DESIGN: Consecutive patients admitted to 20 centers after resuscitation from cardiac arrest were prospectively entered into the International Cardiac Arrest Registry between 2006 and 2016. Additional data about each center's sedation and shivering management practice were obtained via survey. Sedation and shivering practices were categorized as escalating doses of sedation and minimal or no neuromuscular blockade (sedation and shivering practice 1), sedation with continuous or scheduled neuromuscular blockade (sedation and shivering practice 2), or sedation with as-needed neuromuscular blockade (sedation and shivering practice 3). Good outcome was defined as Cerebral Performance Category score of 1 or 2. A logistic regression hierarchical model was created with two levels (patient-level data with standard confounders at level 1 and hospitals at level 2) and sedation and shivering practices as a fixed effect at the hospital level. The primary outcome was dichotomized Cerebral Performance Category at 6 months. SETTING: Cardiac arrest receiving centers in Europe and the United states from 2006 to 2016 PATIENTS:: Four-thousand two-hundred sixty-seven cardiac arrest patients 18 years old or older enrolled in the International Cardiac Arrest Registry. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The mean age was 62 ± 15 years, 36% were female, 77% out-of-hospital arrests, and mean ischemic time was 24 (± 18) minutes. Adjusted odds ratio (for age, return of spontaneous circulation, location of arrest, witnessed, initial rhythm, bystander cardiopulmonary resuscitation, defibrillation, medical history, country, and size of hospital) was 1.13 (0.74-1.73; p = 0.56) and 1.45 (1.00-2.13; p = 0.046) for sedation and shivering practice 2 and sedation and shivering practice 3, respectively, referenced to sedation and shivering practice 1. CONCLUSION: Cardiac arrest patients treated at centers using as-needed neuromuscular blockade had increased odds of good outcomes compared with centers using escalating sedation doses and avoidance of neuromuscular blockade, after adjusting for potential confounders. These findings should be further investigated in prospective studies.

Hemodynamic, Biochemical, and Ventilatory Parameters are Independently Associated with Outcome after Cardiac Arrest.

BACKGROUND: Hypotension, hyperglycemia, dysoxia, and dyscarbia may contribute to reperfusion injury, and each is independently associated with poor outcome (PO) after cardiac arrest. We investigated whether the combined effects of these physiological derangements are associated with cardiac arrest outcomes. METHODS: This institutional review board-approved retrospective cohort study included consecutive resuscitated cardiac arrest patients that received targeted temperature management at Maine Medical Center from 2013 to 2015. We abstracted demographics, intra-arrest factors, and physiological parameters. The primary outcome was dichotomized cerebral performance category (CPC 1-2 vs 3-5) at hospital discharge. After comparing demographics, clinical factors, and persistent post-arrest physiological derangements in patients with good and PO, we constructed a logistic regression model comprised of clinical and demographic factors separately associated with severity, and physiology variables, attempting to evaluate the independent effects of persistent physiological derangements on outcome. RESULTS: Sixty-eight of 222 (31%) patients had CPC 1-2 (good outcome [GO]) at discharge. In bivariate analysis, factors associated with PO included increased time from collapse to resuscitation, non-shockable rhythm, and age-combined Charlson comorbidity index. In multivariate analysis, each persistent physiological derangement incrementally decreased the likelihood of GO [OR GO per derangement 0.71 (interquartile range [IQR] 0.51-0.99), p = 0.042, area under the curve (AUC) for final model 0.769]. CONCLUSIONS: Uncorrected physiological derangements in the first 24 h after cardiac arrest are independently associated with PO. Although causality cannot be established, these findings support preclinical models suggesting that aggressive normalization of physiology after resuscitation may be a reasonable strategy to decrease reperfusion injury.

Cefepime-induced neurotoxicity: a systematic review.

BACKGROUND: Cefepime is a widely used antibiotic with neurotoxicity attributed to its ability to cross the blood-brain barrier and exhibit concentration-dependent ϒ-aminobutyric acid (GABA) antagonism. Neurotoxic symptoms include depressed consciousness, encephalopathy, aphasia, myoclonus, seizures, and coma. Data suggest that up to 15% of ICU patients treated with cefepime may experience these adverse effects. Risk factors include renal dysfunction, excessive dosing, preexisting brain injury, and elevated serum cefepime concentrations. We aimed to characterize the clinical course of cefepime neurotoxicity and response to interventions. METHODS: A librarian-assisted search identified publications describing cefepime-associated neurotoxicity from January 1980 to February 2016 using the CINAHL and MEDLINE databases. Search terms included cefepime, neurotoxicity, encephalopathy, seizures, delirium, coma, non-convulsive status epilepticus, myoclonus, confusion, aphasia, agitation, and death. Two reviewers independently assessed identified articles for eligibility and used the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) for data reporting. RESULTS: Of the 123 citations identified, 37 (representing 135 patient cases) were included. Patients had a median age of 69 years, commonly had renal dysfunction (80%) and required intensive care (81% of patients with a reported location). All patients exhibited altered mental status, with reduced consciousness (47%), myoclonus (42%), and confusion (42%) being the most common symptoms. All 98 patients (73% of cohort) with electroencephalography had abnormalities, including non-convulsive status epilepticus (25%), myoclonic status epilepticus (7%), triphasic waves (40%), and focal sharp waves (39%). As per Food and Drug Administration (FDA)-approved dosing guidance, 48% of patients were overdosed; however, 26% experienced neurotoxicity despite appropriate dosing. Median cefepime serum and cerebrospinal fluid (CSF) concentrations were 45 mg/L (n = 21) and 13 mg/L (n = 4), respectively. Symptom improvement occurred in 89% of patients, and 87% survived to hospital discharge. The median delay from starting the drug to symptom onset was 4 days, and resolution occurred a median of 2 days after the intervention, which included cefepime discontinuation, antiepileptic administration, or hemodialysis. CONCLUSIONS: Cefepime-induced neurotoxicity is challenging to recognize in the critically ill due to widely varying symptoms that are common in ICU patients. This adverse reaction can occur despite appropriate dosing, usually resolves with drug interruption, but may require additional interventions such as antiepileptic drug administration or dialysis.

Emergency Neurological Life Support: Airway, Ventilation, and Sedation.

Airway management and ventilation are central to the resuscitation of the neurologically ill. These patients often have evolving processes that threaten the airway and adequate ventilation. Furthermore, intubation, ventilation, and sedative choices directly affect brain perfusion. Therefore, Airway, Ventilation, and Sedation was chosen as an Emergency Neurological Life Support protocol. Topics include airway management, when and how to intubate with special attention to hemodynamics and preservation of cerebral blood flow, mechanical ventilation settings and the use of sedative agents based on the patient's neurological status.

Low-dose Prothrombin Complex Concentrate for Warfarin-Associated Intracranial Hemorrhage with INR Less Than 2.0.

BACKGROUND: Prothrombin complex concentrates (PCCs) have become the first-line therapy for warfarin reversal in the setting of central nervous system (CNS) hemorrhage. Randomized, controlled studies comparing agents for warfarin reversal excluded patients with international normalized ratio (INR) <2, yet INR values of 1.6-1.9 are also associated with poor outcomes. METHODS: We retrospectively reviewed our use of a low-dose (15 units/kg) strategy of 4-factor PCC (4F-PCC) on warfarin reversal (INR 1.6-1.9) in the setting of both traumatic and spontaneous intracranial bleeding. RESULTS: A total of 21/134 (15.7%) patients with either spontaneous or traumatic intracranial hemorrhage presented with an INR value of 1.6-1.9. Nine patients (43%) presented with traumatic bleeding and 12 (57%) with spontaneous bleeding. The median (IQR) presenting INR was 1.8 (1.7, 1.9) which decreased to 1.3 (1.2, 1.3) following the administration of low-dose 4F-PCC (median dose = 1062 units; 15.2 units/kg). A total of 19/20 (95%) patients achieved a goal INR value of ≤1.5 on the first check following dosing and 17/20 (85%) achieved an INR value ≤1.3. One patient did not have follow-up INR testing due to withdrawal of life support. No patient experienced hematoma expansion within 48 h of 4F-PCC, and there were no thromboembolic events within 72 h of administration. CONCLUSIONS: The administration of low dose (15 units/kg) of 4F-PCC for urgent warfarin reversal in the setting of CNS hemorrhage was effective in correcting the INR in patients presenting with INR values of 1.6-1.9. Further assessment of low-dose PCC for urgent reversal of modest INR elevation is warranted.

The Insertion and Management of External Ventricular Drains: An Evidence-Based Consensus Statement : A Statement for Healthcare Professionals from the Neurocritical Care Society.

External ventricular drains (EVDs) are commonly placed to monitor intracranial pressure and manage acute hydrocephalus in patients with a variety of intracranial pathologies. The indications for EVD insertion and their efficacy in the management of these various conditions have been previously addressed in guidelines published by the Brain Trauma Foundation, American Heart Association and combined committees of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons. While it is well recognized that placement of an EVD may be a lifesaving intervention, the benefits can be offset by procedural and catheter-related complications, such as hemorrhage along the catheter tract, catheter malposition, and CSF infection. Despite their widespread use, there are a lack of high-quality data regarding the best methods for placement and management of EVDs to minimize these risks. Existing recommendations are frequently based on observational data from a single center and may be biased to the authors' view. To address the need for a comprehensive set of evidence-based guidelines for EVD management, the Neurocritical Care Society organized a committee of experts in the fields of neurosurgery, neurology, neuroinfectious disease, critical care, pharmacotherapy, and nursing. The Committee generated clinical questions relevant to EVD placement and management. They developed recommendations based on a thorough literature review using the Grading of Recommendations Assessment, Development, and Evaluation system, with emphasis placed not only on the quality of the evidence, but also on the balance of benefits versus risks, patient values and preferences, and resource considerations.