What's New in Critical Illness and Injury Science? Delirium, COVID-19, and critical illness.

Delirium is a common manifestation of brain dysfunction in critically ill patients. It is a transient fluctuating global disorder of cognition associated with increased morbidity and mortality and has a prevalence up to 80% among intensive care unit (ICU) patients and a daily probability up to 14%.[123] ICU delirium may be a predictor of increased complications, prolonged ICU and non-ICU hospital length of stay (LOS), increased hospital costs, long-term disability, long-term cognitive impairment, decreased odds of discharge home, and increased hospital mortality.[1] Moreover, ICU delirium has been associated with the development of incident neuropsychiatric disorders, including depression, anxiety, trauma, stress-related disorders, and neurocognitive disorders.[4] The mechanism(s) of delirium remain(s) unclear, and no diagnostic laboratory or imaging test is available. Risk factors are multifactorial and may be divided into patient- and hospital-related factors. Patient-related factors include age, gender, underlying disease, baseline cognitive impairment, illness severity, and presence of delirium at admission.[1] Hospital-related factors include medications, nursing care, staff burnout and turnover, mechanical ventilation, hospital and ICU LOS, isolation, physical-restraint application, and potentially artificial versus natural light exposure.[15]

A number of reports have highlighted the presence and/or severity of delirium in admitted and critically ill coronavirus disease 2019 (COVID-19) patients. To be certain, delirium is common among admitted COVID-19 patients.[67] However, COVID-19 has not reliably been shown to increase the prevalence or duration of delirium relative to non-COVID cohorts,[89] a finding further supported by Smith et al. in this issue of International Journal of Critical Illness and Injury Science.[10] As with non-COVID-19 patients, COVID-19 patients admitted to an ICU display higher rates of delirium when compared to those admitted to non-ICU settings,[11] with advanced age and illness severity correlating to increased risk for delirium incidence.[12] Although COVID-19 may not independently increase the incidence or prevalence of delirium in critically ill patients outside of those other mitigating factors associated with critical illness,[8910] it has been correlated with increased delirium severity,[813] poor hospital outcomes, and increased mortality.[1415]

Current recommendations are to treat delirium in critically ill COVID-19 patients according to usual good practices, for example, the ABCDEF (A2F) bundle. The A2F bundle is a means to facilitate implementation of the 2018 Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU (PADIS) Guidelines. In over 25,000 patients across nearly 100 institutions, the A2F bundle has been shown in a dose–response fashion (i.e., greater bundle compliance) to yield improved survival, LOS, delirium duration, cost, and decrease ICU bounce-backs and discharge to nursing homes.[16] Some have recommended not using routine pharmacological treatment for the prevention or management of delirium in adult COVID-19 patients with critical illness, but rather adoption of nonpharmacological measures, such as early comfort using analgesia, minimal sedatives, and maximal human care (eCASH).[17] Similar to the PADIS clinical practice guidelines, and due to lack of evidence and clinical benefit, others have not recommended the routine use of haloperidol, typical or atypical antipsychotics, or other drugs to prevent or manage delirium.[17] In the event that this strategy is employed, consider restricting use to agitated patients (Richmond Agitation Sedation Scale >1), at low doses, and with prioritized use of short half-life drugs to lower accumulation risk.[17] In addition, it is important to note that the safety and clinical impact of antipsychotic medications on the underlying illness in COVID-19 have not been well studied. For example, neutrophil-derived extracellular traps (NETs) are networks of extracellular fibers composed of double-stranded DNA, histones, myeloperoxidase, and proteinase-3, which allow neutrophils to kill extracellular pathogens while minimizing damage to the host cells, and may play a key role in the pathogenesis of infectious, inflammatory, and thrombotic disorders (e.g., COVID-19).[18] For example, severe acute respiratory syndrome coronavirus 2, the virus responsible for COVID-19, can cause apoptosis of lung epithelial cells in mechanisms dependent on the angiotensin-converting enzyme 2–serine protease axis, virus replication, and PAD-4 signaling by stimulating NET formation (NETosis) in healthy neutrophils.[18] These findings have caused some to hypothesize a significant role for NETosis in the destruction of lung epithelial cells as a part of severe COVID-19 infection.[1819] Moreover, some delirium treatments (e.g., quetiapine) may stimulate NETosis, causing some to question whether such medications may further intensify pulmonary epithelial cell damage among patients with COVID-19.[1920] This remains an under-studied aspect of COVID-19 but underscores the importance of maximizing nonpharmacologic strategies to delirium management.

Research quality and ethics statement

This report was exempt from the requirement of approval by the Institutional Review Board/Ethics Committee. The authors followed applicable EQUATOR Network (http:// www.equator-network.org/) guidelines; however, no specific guideline is available for editorials.