Incidence, Predictors and Outcomes of Delirium in Critically Ill Patients With COVID-19.

BACKGROUND AND PURPOSE: A variety of neurological manifestations have been attributed to COVID-19, but there is currently limited evidence regarding risk factors and outcomes for delirium in critically ill patients with COVID-19. The purpose of this study was to identify delirium in a large cohort of ICU patients with COVID-19, and to identify associated features and clinical outcomes at the time of hospital discharge. METHODS: This is an observational cohort study of 213 consecutive patients admitted to an ICU for COVID-19 respiratory illness. Delirium was diagnosed by trained abstractors using the CHART-DEL instrument. The associations between key clinical features, sedation and delirium were examined, as were the impacts of delirium on clinical outcomes. RESULTS: Delirium was identified in 57.3% of subjects. Delirious patients were more likely to receive mechanical ventilation, had lower P: F ratios, higher rates of renal replacement therapy and ECMO, and were more likely to receive enteral benzodiazepines. Only mechanical ventilation remained a significant predictor of delirium in a logistic regression model. Mortality was not significantly different, but delirious patients experienced greater mechanical ventilation duration, ICU/hospital lengths of stay, worse functional outcomes at discharge, and were less likely to be discharged home. CONCLUSIONS: Delirium is common in critically ill patients with COVID-19 and appears to be associated with greater disease severity. When present, delirium is associated with worse functional status at discharge, but not increased mortality. Additional studies are necessary to determine the generalizability of these results and the impact of delirium on longer-term cognitive and functional outcomes.

Case Series: Evidence of Borderzone Ischemia in Critically-Ill COVID-19 Patients Who "Do Not Wake Up".

This article describes the clinical course, radiological findings, and outcome of two patients with the novel 2019 coronavirus disease (COVID-19) who remained comatose for a prolonged duration following discontinuation of all sedation. These two male patients, one aged 59-years and another aged 53-years, both with a history of hypertension and neurologically intact on admission, developed worsening COVID-19 associated acute respiratory distress syndrome (ARDS). Both required benzodiazepine, opioid, neuromuscular blockade, therapeutic anticoagulation, and vasopressor infusions in addition to renal replacement therapy. Echocardiography demonstrated normal chamber size and systolic function in both cases. Each patient demonstrated only trace flexion to pain 7-10 days following discontinuation of all sedation. Magnetic Resonance Imaging on both patients demonstrated multifocal lesions on diffusion weighted imaging with apparent diffusion coefficient correlate in bilateral middle/anterior cerebral artery borderzones, and no large-vessel occlusion or severe stenosis. In both patients, continuous electroencephalography demonstrated no seizures. Neither patient had any documented period of sustained hypotension (mean arterial pressure <60 mmHg) or hypoxia (SpO2 <90%). Ninety days following initial presentation, the 59-years-old man was oriented, with fluent speech and able to ambulate with assistance, while the other 53-years-old man was at home and independent, undertaking the basic activities required by daily living. We conclude that critically-ill COVID-19 patients with prolonged coma following sedation discontinuation may demonstrate imaging features of ischemic injury in borderzone regions despite the absence of documented sustained hypotension or hypoxia. However, substantial neurological recovery is possible despite these findings.

Vibrio vulnificus MO6-24/O lipopolysaccharide stimulates superoxide anion, thromboxane B2, matrix metalloproteinase-9, cytokine and chemokine release by rat brain microglia in vitro.

Although human exposure to Gram-negative Vibrio vulnificus (V. vulnificus) lipopolysaccharide (LPS) has been reported to result in septic shock, its impact on the central nervous system's innate immunity remains undetermined. The purpose of this study was to determine whether V. vulnificus MO6-24/O LPS might activate rat microglia in vitro and stimulate the release of superoxide anion (O2⁻), a reactive oxygen species known to cause oxidative stress and neuronal injury in vivo. Brain microglia were isolated from neonatal rats, and then treated with either V. vulnificus MO6-24/O LPS or Escherichia coli O26:B6 LPS for 17 hours in vitro. O2⁻ was determined by cytochrome C reduction, and matrix metalloproteinase-2 (MMP-2) and MMP-9 by gelatinase zymography. Generation of cytokines tumor necrosis factor alpha (TNF-α), interleukin-1 alpha (IL-1α), IL-6, and transforming growth factor-beta 1 (TGF-ß1), chemokines macrophage inflammatory protein (MIP-1α)/chemokine (C-C motif) ligand 3 (CCL3), MIP-2/chemokine (C-X-C motif) ligand 2 (CXCL2), monocyte chemotactic protein-1 (MCP-1)/CCL2, and cytokine-induced neutrophil chemoattractant-2alpha/beta (CINC-2α/ß)/CXCL3, and brain-derived neurotrophic factor (BDNF), were determined by specific immunoassays. Priming of rat microglia by V. vulnificus MO6-24/O LPS in vitro yielded a bell-shaped dose-response curve for PMA (phorbol 12-myristate 13-acetate)-stimulated O2⁻ generation: (1) 0.1-1 ng/mL V. vulnificus LPS enhanced O2⁻ generation significantly but with limited inflammatory mediator generation; (2) 10-100 ng/mL V. vulnificus LPS maximized O2⁻ generation with concomitant release of thromboxane B2 (TXB2), matrix metalloproteinase-9 (MMP-9), and several cytokines and chemokines; (3) 1000-100,000 ng/mL V. vulnificus LPS, with the exception of TXB2, yielded both attenuated O2⁻ production, and a progressive decrease in MMP-9, cytokines and chemokines investigated. Thus concentration-dependent treatment of neonatal brain microglia with V. vulnificus MO6-24/O LPS resulted in a significant rise in O2⁻ production, followed by a progressive decrease in O2⁻ release, with concomitant release of lactic dehydrogenase (LDH), and generation of TXB2, MMP-9, cytokines and chemokines. We hypothesize that the inflammatory mediators investigated may be cytotoxic to microglia in vitro, by an as yet undetermined autocrine mechanism. Although V. vulnificus LPS was less potent than E. coli LPS in vitro, inflammatory mediator release by the former was clearly more efficacious. Finally, we hypothesize that should V. vulnificus LPS gain entry into the CNS, it would be possible that microglia might become activated, resulting in high levels of O2⁻ as well as neuroinflammatory TXB2, MMP-9, cytokines and chemokines.