The association of brainstem and motor recovery with awakening after out-of-hospital cardiac arrest.

Background: Coma is common following resuscitation from cardiac arrest. Few data describe the trajectory of recovery the first days following resuscitation. The objective of this study is to describe the evolution in neurological examination during the first 5 days after resuscitation and test if subjects who go on to awaken have different patterns of early recovery. Methods: Prospective study of adult subjects resuscitated from out-of-hospital cardiac arrest. We abstracted demographic information and trained clinicians completed daily neurologic examinations using the Glasgow Coma Scale (GCS) and Full Outline of UnResponsiveness brainstem (FOUR-B) and motor (FOUR-M) scores during daily sedation interruption. The change in scores between Day 1 and Day 5 was analyzed using the Kruskal-Wallis Test and logistic regression models. The relationship of FOUR-B, FOUR-M, and GCS with time to death was estimated by fitting cox proportional hazard models. Results: FOUR-M and GCS did not differ over time (p = 0.10; p = 0.07). FOUR B increased over time (p < 0.01). Time to recovery of brainstem or motor function differed between those treated at 33 °C and 36 °C (p = 0.0023 and p = 0.0032, respectively). FOUR-B, FOUR-M, and GCS differed between survivors and non-survivors (p < 0.01). Time to recovery of brainstem and motor function differed between survivors and non-survivors. FOUR-M and FOUR-B differed between those with good outcome and poor outcome. Conclusions: The brainstem clinical examination improved during the first 5 days following resuscitation. Brainstem recovery was common in entire cohort and did not differentiate between survivors and non-survivors. Recovery of motor function, however, was associated with survival.

Biomarker-Based Classification of Patients With Acute Respiratory Failure Into Inflammatory Subphenotypes: A Single-Center Exploratory Study.

OBJECTIVES: Hyper- and hypoinflammatory subphenotypes discovered in patients with acute respiratory distress syndrome predict clinical outcomes and therapeutic responses. These subphenotypes may be important in broader critically ill patient populations with acute respiratory failure regardless of clinical diagnosis. We investigated subphenotyping with latent class analysis in an inclusive population of acute respiratory failure, derived a parsimonious model for subphenotypic predictions based on a small set of variables, and examined associations with clinical outcomes. DESIGN: Prospective, observational cohort study. SETTING: Single-center, academic medical ICU. PATIENTS: Mechanically ventilated patients with acute respiratory failure. MEASUREMENTS AND MAIN RESULTS: We included 498 patients with acute respiratory failure (acute respiratory distress syndrome: 143, at-risk for acute respiratory distress syndrome: 198, congestive heart failure: 37, acute on chronic respiratory failure: 23, airway protection: 61, and multifactorial: 35) in our derivation cohort and measured 10 baseline plasma biomarkers. Latent class analysis considering clinical variables and biomarkers determined that a two-class model offered optimal fit (23% hyperinflammatory subphenotype). Distribution of hyperinflammatory subphenotype varied among acute respiratory failure etiologies (acute respiratory distress syndrome: 31%, at-risk for acute respiratory distress syndrome: 27%, congestive heart failure: 22%, acute on chronic respiratory failure 0%, airway protection: 5%, and multifactorial: 14%). Hyperinflammatory patients had higher Sequential Organ Failure Assessment scores, fewer ventilator-free days, and higher 30- and 90-day mortality (all p < 0.001). We derived a parsimonious model consisting of angiopoietin-2, soluble tumor necrosis factor receptor-1, procalcitonin, and bicarbonate and classified subphenotypes in a validation cohort (n = 139). Hyperinflammatory patients (19%) demonstrated higher levels of inflammatory biomarkers not included in the model (p < 0.01) and worse outcomes. CONCLUSIONS: Host-response subphenotypes are observable in a heterogeneous population with acute respiratory failure and predict clinical outcomes. Simple, biomarker-based models can offer prognostic enrichment in patients with acute respiratory failure. The differential distribution of subphenotypes by specific etiologies of acute respiratory failure indicates that subphenotyping may be more relevant in patients with hypoxemic causes of acute respiratory failure and not in patients intubated for airway protection or acute on chronic decompensation.

Effect of sedation on quantitative electroencephalography after cardiac arrest.

BACKGROUND: Electroencephalography (EEG) has clinical and prognostic importance after cardiac arrest (CA). Recently, interest in quantitative EEG (qEEG) analysis has grown. The qualitative effects of sedation on EEG are well known, but potentially confounding effects of sedatives on qEEG after anoxic injury are poorly characterized. We hypothesize that sedation increases suppression ratio (SR) and decreases alpha/delta ratio (ADR) and amplitude-integrated EEG (aEEG), and that the magnitude of sedation effects will be associated with outcome. METHODS: We routinely monitor comatose post-arrest patients with EEG for 48-72h. We included comatose EEG-monitored patients after CA who had protocolized daily sedation interruptions. We used Persyst v12 to quantify qEEG parameters and calculated medians for 10min immediately prior to sedation interruption and for the last 5min of interruption. We used paired t-tests to determine whether qEEG parameters changed with sedation cessation, and logistic regression to determine whether these changes predicted functional recovery or survival at discharge. RESULTS: 78 subjects were included (median age 56, 65% male). Interruptions occurred a median duration of 34h post-arrest and lasted a median duration of 60min. Prior to interruption, higher aEEG predicted survival, while lower SR predicted both survival and favorable outcome. During interruption, SR decreased (p<0.001), aEEG increased (p=0.002), and ADR did not change. Larger decreases in SR predicted decreased survival (OR=1.04 per percent change; 95% CI 1.00-1.09). CONCLUSION: Higher aEEG and lower SR predict survival after CA. Sedation alters aEEG and SR, but importantly does not appear to affect the relationship between these parameter values and outcome.

The translation inhibitor silvestrol exhibits direct anti-tumor activity while preserving innate and adaptive immunity against EBV-driven lymphoproliferative disease.

Treatment options for patients with Epstein-Barr Virus-driven lymphoproliferative diseases (EBV-LPD) are limited. Chemo-immunotherapeutic approaches often lead to immune suppression, risk of lethal infection and EBV reactivation, thus it is essential to identify agents that can deliver direct anti-tumor activity while preserving innate and adaptive host immune surveillance. Silvestrol possesses direct anti-tumor activity in multiple hematologic malignancies while causing minimal toxicity to normal mononuclear cells. However, the effects of silvestrol on immune function have not been described. We utilized in vitro and in vivo models of EBV-LPD to simultaneously examine the impact of silvestrol on both tumor and normal immune function. We show that silvestrol induces direct anti-tumor activity against EBV-transformed lymphoblastoid cell lines (LCL), with growth inhibition, decreased expression of the EBV oncogene latent membrane protein-1, and inhibition of the downstream AKT, STAT1 and STAT3 signaling pathways. Silvestrol promoted potent indirect anti-tumor effects by preserving expansion of innate and EBV antigen-specific adaptive immune effector subsets capable of effective clearance of LCL tumor targets in autologous co-cultures. In an animal model of spontaneous EBV-LPD, silvestrol demonstrated significant therapeutic activity dependent on the presence of CD8-positive T-cells. These findings establish a novel immune-sparing activity of silvestrol, justifying further exploration in patients with EBV-positive malignancies.