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The article presents a study which tested the hypothesis that the hyperinflammatory subphenotype is associated with worse acute brain dysfunction in patients who are in mechanically ventilated intensive care units (ICUs). Topics include baseline characteristics of the overall cohort and by subphenotype, associations between hyperinflammatory subphenotype and acute brain dysfunction and death, and strengths of the study.

Despite prior publications of clinical practice guidelines related to ventilator liberation, some questions remain unanswered. Many of these questions relate to the details of bedside implementation. We, therefore, formed a guidelines committee of individuals with experience and knowledge of ventilator liberation as well as a medical librarian. Using Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, we make the following recommendations: (1) We suggest that calculation of a rapid shallow breathing index is not needed to determine readiness for a spontaneous breathing trial (SBT) (conditional recommendation; moderate certainty); (2) We suggest that SBTs can be conducted with or without pressure support ventilation (conditional recommendation, moderate certainty); (3) We suggest a standardized approach to assessment and, if appropriate, completion of an SBT before noon each day (conditional recommendation, very low certainty); and (4) We suggest that FIO2 should not be increased during an SBT (conditional recommendation, very low certainty). These recommendations are intended to assist bedside clinicians to liberate adult critically ill patients more rapidly from mechanical ventilation. [ABSTRACT FROM AUTHOR]

Acute Respiratory Distress Syndrome (ARDS) is one of the most demanding conditions in an Intensive Care Unit (ICU). Management of analgesia and sedation in ARDS is particularly challenging. An expert panel was convened to produce a 'state-of-the-art' article to support clinicians in the optimal management of analgesia/sedation in mechanically ventilated adults with ARDS, including those with COVID-19. Current ICU analgesia/sedation guidelines promote analgesia first and minimization of sedation, wakefulness, delirium prevention and early rehabilitation to facilitate ventilator and ICU liberation. However, these strategies cannot always be applied to patients with ARDS who sometimes require deep sedation and/or paralysis. Patients with severe ARDS may be under-represented in analgesia/sedation studies and currently recommended strategies may not be feasible. With lightened sedation, distress-related symptoms (e.g., pain and discomfort, anxiety, dyspnea) and patient-ventilator asynchrony should be systematically assessed and managed through interprofessional collaboration, prioritizing analgesia and anxiolysis. Adaptation of ventilator settings (e.g., use of a pressure-set mode, spontaneous breathing, sensitive inspiratory trigger) should be systematically considered before additional medications are administered. Managing the mechanical ventilator is of paramount importance to avoid the unnecessary use of deep sedation and/or paralysis. Therefore, applying an 'ABCDEF-R' bundle (R = Respiratory-drive-control) may be beneficial in ARDS patients. Further studies are needed, especially regarding the use and long-term effects of fast-offset drugs (e.g., remifentanil, volatile anesthetics) and the electrophysiological assessment of analgesia/sedation (e.g., electroencephalogram devices, heart-rate variability, and video pupillometry). This review is particularly relevant during the COVID-19 pandemic given drug shortages and limited ICU-bed capacity., Author(s): Gerald Chanques [sup.1] [sup.2], Jean-Michel Constantin [sup.3], John W. Devlin [sup.4] [sup.5], E. Wesley Ely [sup.6] [sup.7] [sup.8], Gilles L. Fraser [sup.9], Céline Gélinas [sup.10], Timothy D. Girard [sup.11], [...]

BACKGROUND: Delirium, a common syndrome with heterogeneous etiologies and clinical presentations, is associated with poor long‐term outcomes. Recording and analyzing all delirium equally could be hindering the field's understanding of pathophysiology and identification of targeted treatments. Current delirium subtyping methods reflect clinically evident features but likely do not account for underlying biology. METHODS: The Delirium Subtyping Initiative (DSI) held three sessions with an international panel of 25 experts. RESULTS: Meeting participants suggest further characterization of delirium features to complement the existing Diagnostic and Statistical Manual of Mental Disorders Fifth Edition Text Revision diagnostic criteria. These should span the range of delirium‐spectrum syndromes and be measured consistently across studies. Clinical features should be recorded in conjunction with biospecimen collection, where feasible, in a standardized way, to determine temporal associations of biology coincident with clinical fluctuations. DISCUSSION: The DSI made recommendations spanning the breadth of delirium research including clinical features, study planning, data collection, and data analysis for characterization of candidate delirium subtypes. Highlights: Delirium features must be clearly defined, standardized, and operationalized.Large datasets incorporating both clinical and biomarker variables should be analyzed together.Delirium screening should incorporate communication and reasoning. [ABSTRACT FROM AUTHOR]

The article discusses ventilator-associated brain injury (VABI) as a potential complication of mechanical ventilation, presenting evidence from preclinical studies and observational data. It defines VABI as brain injury resulting directly from positive pressure mechanical ventilation, independent of other factors like sedation. It highlights the need for further research to understand the mechanisms of VABI and evaluate potential therapeutic strategies.

Purpose of review: The A2F intensive care unit (ICU) liberation bundle is a multi-component management strategy that has been shown to improve hospital survival and reduce rates of delirium and ICU readmission. In this review, we aim to highlight the potential role of the A2F bundle in neurocritical care settings while further delineating its individual components. Recent findings: The A2F bundle and its components are supported by a robust evidence base that continues to develop regarding the management of critically ill patients. Recent additions include the DEXACET trial, which found that scheduled intravenous acetaminophen reduced delirium, breakthrough analgesia, and ICU length of stay for post-operative patients. Meanwhile, although previous trials indicated that dexmedetomidine for light sedation reduces delirium when compared with benzodiazepine sedation, the MENDS2 and SPICE-III trials did not find that dexmedetomidine as a first-line sedative for mechanically ventilated ICU patients improved outcomes compared with propofol. Trials of family engagement support more frequent goals of care discussions and improvements in quality of communication and patient-centered care. However, evidence specific to neurocritically ill patients remains limited. A small trial found utility for goals of care decision aids to support shared decision-making in patients with severe acute brain injury. Recent studies have also suggested that delirium may have a unique impact on outcomes in neurocritically ill patients, and new tools may have utility in delirium identification in patients with acute neurological injury. Finally, there is accumulating evidence to suggest that early mobilization is safe and feasible in neurocritically ill patients, even those with external ventricular drains, and that it may improve outcomes. Summary: Although the A2F bundle in its entirety has not been specifically studied in neurocritically ill patients, many of its goals overlap with contemporary neurocritical care practices. Future studies are needed to determine optimal ICU liberation strategies that can be safely and effectively implemented in patients with acute neurological injury. [ABSTRACT FROM AUTHOR]

Delirium is a common condition in intensive care unit (ICU) patients and is associated with negative outcomes. While non-pharmacologic treatments have shown some success in reducing delirium, there is currently no recommended pharmacologic treatment. Haloperidol, a commonly used medication, has not been found to be more effective than a placebo in reducing delirium. However, a recent study found that haloperidol may have a positive effect on long-term mortality in ICU patients. Further research is needed to determine the optimal dose of haloperidol and to explore other factors that may influence long-term outcomes. ICU clinicians should not increase their use of haloperidol until more research is conducted. [Extracted from the article]

Background: 7T MRI allows implementation of high‐resolution quantitative susceptibility mapping (QSM) which can be used to assess the cerebral microvascular/hypoperfusion pathogenic hypothesis in Alzheimer's disease (AD) and in the post‐SARS‐CoV2 setting to explore if there may be similarities in brain changes in these two conditions. The magnetic susceptibility (reflective of tissue iron) of hippocampal subfields was assessed in patients with 1) CSF‐Amyloidß‐status AD; 2) mild COVID‐19 over 6 months previously (Cv); 3) severe COVID‐19 with ICU admission >6 months previously (ICU‐Cv); and 4) age‐matched healthy controls (HC). Methods: 33 participants (10 HC, 14 Cv, 9 ICU‐Cv) for the COVID study and 24 participants (14 AD, 11HC) from AD patients with confirmed CSF‐Amyloidß levels, aged 42‐79, were scanned on a 7T scanner with the following protocol T2* GRE for the AD groups (0.7×0.7×0.7mm3,TE/TR = 20/31ms) and T2* multi‐echo GRE for the Cv groups (0.38×0.38×0.75mm3,TE1/TE2/TR = 8.2/18.4/24ms). Data were processed using QSMbox1 to produce susceptibility maps. PSIR (0.55×0.55×0.55mm3,TE/TR = 3.1/6.9ms) and T2‐weighted FSE (0.38×0.39×1.5mm3, TE/TR = 117/5900ms) images were used to segment the hippocampal subfields (Figure 1)2. One‐way analyses were used in SPSS for comparison between the HC group and each of the Cv, ICU‐Cv, and AD groups. Results: There was no change in susceptibility for the whole hippocampus between AD and HC, but there was a significant difference for the DG subfield (p = 0.045), Figure 2. For COVID patients, there was a significant difference between the susceptibility of the whole hippocampus in the ICU‐Cv group (p = 0.035), but not in the Cv group (p = 0.788), Figure 3, compared to HC. In subfield analyses there was a trend towards decreased susceptibility in the subiculum, an area known to be affected by Alzheimer pathology, in the ICU‐Cv group (p = 0.032) compared to HC. Conclusion: The lower susceptibility within the hippocampal structures observed in AD and ICU‐Cv patients may reflect less iron either from cerebral hypoperfusion or vascular injuries in AD or additionally result from sequelae of hypoxaemia in ICU‐Cv. The study provides preliminary evidence of detectable in vivo microstructural changes in hippocampal subfields in both AD and post‐COVID settings. Funding: Medical Research Council, UK (MR/T005580/1); National Institute of Health, USA (1R56AG074467‐01) References: 1. https://doi.org/10.1016/j.neuroimage.2018.07.065 2. https://doi.org/10.1002/hbm.22627 [ABSTRACT FROM AUTHOR]

Background: The COVID‐19 pandemic has disproportionately affected ethno‐racial minority populations and people with greater social deprivation. It is unknown whether such disparities influence research participation for investigations of long‐term neuro‐cognitive effects of SARS‐CoV‐2 infection. Method: Across 3 US and 1 UK sites, we are enrolling a multi‐racial cohort of SARS‐CoV‐2 infected individuals and age, sex, race‐matched non‐infected controls. Utilizing harmonized protocols for cognitive assessments and 7‐Tesla MRI, we aim to provide ultra‐high‐field data on natural history of COVID‐19 driven microstructural and microvascular cerebral changes and associated cognitive trajectories. We will also compare the imaging markers to those observed in an existing cohort of early onset Alzheimer's Disease and Related Dementias (ADRD). We analyzed screening and enrollment data to determine potential age, sex, race, ethnicity, and social deprivation disparities in research participation. We derived address‐based Area Deprivation Index (ADI) (scale 1 ‐10), with higher ADI indicating greater deprivation. Logistic regression models were fit to evaluate associates of non‐response and refusal. Odds Ratios (OR) and 95% confidence intervals (CI) are reported. Result: Over a 11‐month period, at a single US site, a total of 1,046 SARS‐CoV‐2 infected people and their controls were contacted, and 379 (36.2%) responded. In univariable analyses, non‐response was associated with younger age, male sex, non‐White race, and higher ADI (Table 1). In the fully adjusted model, non‐White race was independently associated with higher likelihood of non‐response [OR (CI) for Black vs. White: 1.49 (1.04, 2.12) and for Asian vs. White: 1.88 (1.28, 2.76)]., Independent of race, higher ADI was also associated with likelihood of non‐response (Table 2 and Figure 1). Among the responders, 228 (60.2%) refused. Although, no socio‐demographic factors were significantly associated with likelihood of refusal, the point estimates in the fully adjusted model suggest potential racial disparities in providing consent (Tables 1 and 2). Aggregated data from all sites will be presented. Conclusion: It is imperative to recognize and mitigate persistent disparities in the COVID‐19 pandemic, particularly pertaining to participation in long‐COVID research. Mechanisms of such persistent disparities need to be studied in context of cultures, beliefs, access, and clinical factors. [ABSTRACT FROM AUTHOR]

Delirium is a common condition in the ICU, and while non-pharmacological interventions are recommended, pharmacological treatment with haloperidol is often used despite recommendations against it. Two recent trials, the MIND-USA Study and the AID-ICU trial, examined the effectiveness and safety of haloperidol for delirium treatment in ICU patients. Both trials found no significant difference in their primary outcomes, but the AID-ICU trial did find lower mortality rates in the haloperidol group. The trials were well-designed and had low bias, but the difference in mortality outcomes is surprising and requires further investigation. Table 1 in the document provides detailed information on the trials' characteristics, interventions, and outcomes. While there were some differences in definitions and participant characteristics, subgroup analyses found no evidence of treatment effect heterogeneity. Differences in exposure to open-label antipsychotics may explain some of the differences in mortality outcomes. The AID-ICU trial showed potential benefits of haloperidol for days alive and out of the hospital, days alive without delirium or coma, and mortality. However, there is still uncertainty about the effects of haloperidol in delirious ICU patients, and more research is needed to understand its mechanisms of action and long-term outcomes. [Extracted from the article]

Background: Patients with acute respiratory failure have multiple risk factors for disability following their intensive care unit stay. Interventions to facilitate independence at hospital discharge may be more effective if personalized for patient subtypes. Objectives: To identify subtypes of patients with acute respiratory failure requiring mechanical ventilation and compare post–intensive care functional disability and intensive care unit mobility level among subtypes. Methods: Latent class analysis was conducted in a cohort of adult medical intensive care unit patients with acute respiratory failure receiving mechanical ventilation who survived to hospital discharge. Demographic and clinical medical record data were collected early in the stay. Clinical characteristics and outcomes were compared among subtypes by using Kruskal-Wallis tests and χ2 tests of independence. Results: In a cohort of 934 patients, the 6-class model provided the optimal fit. Patients in class 4 (obesity and kidney impairment) had worse functional impairment at hospital discharge than patients in classes 1 through 3. Patients in class 3 (alert patients) had the lowest magnitude of functional impairment (P <.001) and achieved the earliest out-of-bed mobility and highest mobility level of all subtypes (P <.001). Conclusions: Acute respiratory failure survivor subtypes identified from clinical data available early in the intensive care unit stay differ in post–intensive care functional disability. Future research should target high-risk patients in early rehabilitation trials in the intensive care unit. Additional investigation of contextual factors and mechanisms of disability is critical to improving quality of life in acute respiratory failure survivors. [ABSTRACT FROM AUTHOR]

Background: Sleep and circadian disruption (SCD) is common and severe in the ICU. On the basis of rigorous evidence in non)ICU populations and emerging evidence in ICU populations, SCD is likely to have a profound negative impact on patient outcomes. Thus, it is urgent that we establish research priorities to advance understanding of ICU SCD. Methods: We convened a multidisciplinary group with relevant expertise to participate in an American Thoracic Society Workshop. Workshop objectives included identifying ICU SCD subtopics of interest, key knowledge gaps, and research priorities. Members attended remote sessions from March to November 2021. Recorded presentations were prepared and viewed by members before Workshop sessions. Workshop discussion focused on key gaps and related research priorities. The priorities listed herein were selected on the basis of rank as established by a series of anonymous surveys. Results: We identified the following research priorities: establish an ICU SCD definition, further develop rigorous and feasible ICU SCD measures, test associations between ICU SCD domains and outcomes, promote the inclusion of mechanistic and patient-centered outcomes within large clinical studies, leverage implementation science strategies to maximize intervention fidelity and sustainability, and collaborate among investigators to harmonize methods and promote multisite investigation. Conclusions: ICU SCD is a complex and compelling potential target for improving ICU outcomes. Given the influence on all other research priorities, further development of rigorous, feasible ICU SCD measurement is a key next step in advancing the field. [ABSTRACT FROM AUTHOR]

Importance: Agitation is common in mechanically ventilated ICU patients, but little is known about physician attitudes regarding agitation in this setting. Objectives: To characterize physician attitudes regarding agitation in mechanically ventilated ICU patients. Design, Setting, and Participants: We surveyed critical care physicians within a multicenter health system in Western Pennsylvania, assessing attitudes regarding agitation during mechanical ventilation and use of and confidence in agitation management options. We used quantitative clinical vignettes to determine whether agitation influences confidence regarding readiness for extubation. We sent our survey to 332 critical care physicians, of whom 80 (24%) responded and 69 were eligible (had cared for a mechanically ventilated patient in the preceding three months). Main Outcomes and Measures: Respondent confidence in patient readiness for extubation (0–100%, continuous) and frequency of use and confidence in management options (1–5, Likert). Results: Of 69 eligible responders, 61 (88%) agreed agitation is common and 49 (71%) agreed agitation is a barrier to extubation, but only 27 (39%) agreed their approach to agitation is evidence-based. Attitudes regarding agitation did not differ much by practice setting or physician demographics, though respondents working in medical ICUs were more likely (P =.04) and respondents trained in surgery or emergency medicine were less likely (P =.03) than others to indicate that agitation is an extubation barrier. Fifty-three (77%) respondents reported they frequently use non-pharmacologic measures to treat agitation, and 42 (70%) of those who reported they used non-pharmacologic measures during the prior 3 months indicated confidence in their effectiveness. In responses to clinical vignettes, confidence in patient's readiness for extubation was significantly lower if the patient was agitated (P <.001) or tachypneic (P <.001), but the presence of both agitation and tachypnea did not reduce confidence compared with tachypnea alone (P =.24). Conclusions and Relevance: Most critical care physicians consider agitation during mechanical ventilation a common problem and agreed that agitation is a barrier to extubation. Treatment practice varies widely. [ABSTRACT FROM AUTHOR]

Background: Intensive care unit (ICU) delirium is associated with a proinflammatory state and poor outcomes. An epigenetic mechanism may modify inflammation. Objective: To identify inflammatory gene methylation trajectory groups and explore their clinical and demographic variability. Methods: Patients were at least 18 years old; received mechanical ventilation for at least 24 hours; had no brain disorder/injury, preexisting dementia, or positive toxicology screen; and were admitted to a medical or surgical/trauma ICU. Delirium was assessed (Confusion Assessment Method for the ICU) and blood samples were collected daily for up to 10 days. Methylation of 3 genes in the inflammatory pathway was quantified. Latent class analysis identified gene methylation trajectories, and variables (including delirium) were compared between trajectory groups. Results: Of 68 patients (53% female, 88% White), 65% developed delirium. Of 3 methylation trajectories for IL6ST, the group with low initial methylation increasing over time included younger male patients who were less likely to have delirium, and the group with high initial methylation decreasing over time included older (P =.01) female (P =.05) patients who more often had delirium (P =.05). IL17C had 2 methylation trajectories without significant differences in delirium, age, or sex. IL13RA1 had 2 methylation trajectories without differences in delirium or age; the group with sustained high methylation had more female patients (P =.003). Conclusions: Temporal variability in inflammatory gene methylation occurs after ICU admission. Delirium, female sex, and older age were more common with higher IL6ST methylation that decreased over time. Larger studies are needed to further elucidate these relationships. [ABSTRACT FROM AUTHOR]