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Anaesthesia ; 77 Suppl 1: 49-58, 2022 01.
Article in English | MEDLINE | ID: covidwho-1612834


Delirium is a common condition affecting hospital inpatients, including those having surgery and on the intensive care unit. Delirium is also common in patients with COVID-19 in hospital settings, and the occurrence is higher than expected for similar infections. The short-term outcomes of those with COVID-19 delirium are similar to that of classical delirium and include increased length of stay and increased mortality. Management of delirium in COVID-19 in the context of a global pandemic is limited by the severity of the syndrome and compounded by the environmental constraints. Practical management includes effective screening, early identification and appropriate treatment aimed at minimising complications and timely escalation decisions. The pandemic has played out on the national stage and the effect of delirium on patients, relatives and healthcare workers remains unknown but evidence from the previous SARS outbreak suggests there may be long-lasting psychological damage.

COVID-19/epidemiology , COVID-19/psychology , Delirium/epidemiology , Delirium/psychology , Health Personnel/psychology , Brain/metabolism , COVID-19/metabolism , COVID-19/therapy , Delirium/metabolism , Delirium/therapy , Humans , Inflammation Mediators/metabolism , Intensive Care Units/trends
Sci Rep ; 11(1): 10629, 2021 05 20.
Article in English | MEDLINE | ID: covidwho-1387475


Delirium is an acute change in attention and cognition occurring in ~ 65% of severe SARS-CoV-2 cases. It is also common following surgery and an indicator of brain vulnerability and risk for the development of dementia. In this work we analyzed the underlying role of metabolism in delirium-susceptibility in the postoperative setting using metabolomic profiling of cerebrospinal fluid and blood taken from the same patients prior to planned orthopaedic surgery. Distance correlation analysis and Random Forest (RF) feature selection were used to determine changes in metabolic networks. We found significant concentration differences in several amino acids, acylcarnitines and polyamines linking delirium-prone patients to known factors in Alzheimer's disease such as monoamine oxidase B (MAOB) protein. Subsequent computational structural comparison between MAOB and angiotensin converting enzyme 2 as well as protein-protein docking analysis showed that there potentially is strong binding of SARS-CoV-2 spike protein to MAOB. The possibility that SARS-CoV-2 influences MAOB activity leading to the observed neurological and platelet-based complications of SARS-CoV-2 infection requires further investigation.

COVID-19/metabolism , Delirium/metabolism , Monoamine Oxidase/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Aged , Aged, 80 and over , Female , Humans , Male , Metabolomics
Am J Respir Cell Mol Biol ; 65(4): 403-412, 2021 10.
Article in English | MEDLINE | ID: covidwho-1237350


Mechanical ventilation is a known risk factor for delirium, a cognitive impairment characterized by dysfunction of the frontal cortex and hippocampus. Although IL-6 is upregulated in mechanical ventilation-induced lung injury (VILI) and may contribute to delirium, it is not known whether the inhibition of systemic IL-6 mitigates delirium-relevant neuropathology. To histologically define neuropathological effects of IL-6 inhibition in an experimental VILI model, VILI was simulated in anesthetized adult mice using a 35 cc/kg tidal volume mechanical ventilation model. There were two control groups, as follow: 1) spontaneously breathing or 2) anesthetized and mechanically ventilated with 10 cc/kg tidal volume to distinguish effects of anesthesia from VILI. Two hours before inducing VILI, mice were treated with either anti-IL-6 antibody, anti-IL-6 receptor antibody, or saline. Neuronal injury, stress, and inflammation were assessed using immunohistochemistry. CC3 (cleaved caspase-3), a neuronal apoptosis marker, was significantly increased in the frontal (P < 0.001) and hippocampal (P < 0.0001) brain regions and accompanied by significant increases in c-Fos and heat shock protein-90 in the frontal cortices of VILI mice compared with control mice (P < 0.001). These findings were not related to cerebral hypoxia, and there was no evidence of irreversible neuronal death. Frontal and hippocampal neuronal CC3 were significantly reduced with anti-IL-6 antibody (P < 0.01 and P < 0.0001, respectively) and anti-IL-6 receptor antibody (P < 0.05 and P < 0.0001, respectively) compared with saline VILI mice. In summary, VILI induces potentially reversible neuronal injury and inflammation in the frontal cortex and hippocampus, which is mitigated with systemic IL-6 inhibition. These data suggest a potentially novel neuroprotective role of systemic IL-6 inhibition that justifies further investigation.

Antibodies/pharmacology , Apoptosis/drug effects , Delirium/metabolism , Interleukin-6/antagonists & inhibitors , Neurons/metabolism , Ventilator-Induced Lung Injury/metabolism , Animals , Delirium/drug therapy , Delirium/pathology , Disease Models, Animal , Female , Frontal Lobe/injuries , Frontal Lobe/metabolism , Frontal Lobe/pathology , HSP90 Heat-Shock Proteins/metabolism , Hippocampus/injuries , Hippocampus/metabolism , Hippocampus/pathology , Inflammation/drug therapy , Inflammation/metabolism , Inflammation/pathology , Interleukin-6/metabolism , Mice , Neurons/pathology , Proto-Oncogene Proteins c-fos/metabolism , Repressor Proteins/metabolism , Tumor Suppressor Proteins/metabolism , Ventilator-Induced Lung Injury/drug therapy , Ventilator-Induced Lung Injury/pathology