Open research questions in Intensive Care Unit Cognitive Disorders

What the literature leaves open

• While recognized for its association with adverse clinical outcomes, comprehensive population-based studies examining POD incidence and risk factors in this vulnerable population remain scarce.

  Incidence and risk factors of postoperative delirium in children with congenital heart disease · 2026 · DOI

• This was an unexpected finding and warrants further investigation into possible comorbidities or confounding variables (e. Our study is limited by the inability to control for selection bias in the choice of using phenobarbital or lorazepam. A future study in- cluding a longer post-intervention observation period is warranted to see if any significant differences in LOS develop.

  Comparing length of stay between adult patients admitted to the intensive care unit with alcohol withdrawal syndrome treated with phenobarbital versus lorazepam · 2026 · DOI

• ABSTRACT Delirium, experienced by up to 50% of hospitalised older adults, continues to be underrecognised, undertreated, and often confused with depression or dementia.

  Delirium‐Related Distress of Hospitalised Older Adults Within the Framework of the Theory of Unpleasant Symptoms: A Scoping Review of Qualitative Literature · 2026 · DOI

• Brain-derived neurotrophic factor (BDNF) is a key regulator of neuronal survival and synaptic plasticity, and has been implicated in POCD but published findings are inconsistent.

  Association between BDNF and postoperative cognitive dysfunction across surgical stages: a systematic review and meta-analysis · 2026 · DOI

• Postoperative cognitive dysfunction (POCD) is a frequent complication after surgery, particularly among older adults, and its underlying mechanisms remain incompletely understood.

  Association between BDNF and postoperative cognitive dysfunction across surgical stages: a systematic review and meta-analysis · 2026 · DOI

• Furthermore, a key limitation of our study is the relatively small sample size, particularly within certain subgroups where the number of patients was very limited, which may reduce the statistical power, increase the risk of type II error, and necessitate cautious interpretation of the observed associations and significance levels. -based sampling strategy, hypoactive delirium cases—being less clinically overt—may have been underrecognized and underrepresented.

  Delirium in the Coronary Intensive Care Unit: Predictors and Prognostic Impact on Mortality · 2026 · DOI

• Although the its clinical significance has been widely recognized, pathogenesis of POD has not been fully elucidated, and early identification of high-risk patients remains challenging (28).

  Incidence and independent risk factors for postoperative delirium in ICU patients after cardiopulmonary bypass cardiac surgery: a retrospective cohort study · 2026 · DOI

• Moreover, relying solely on discriminative indicators such as AUC is insufficient to evaluate the actual benefits of the prediction model in real clinical decision- making (16).

  Incidence and independent risk factors for postoperative delirium in ICU patients after cardiopulmonary bypass cardiac surgery: a retrospective cohort study · 2026 · DOI

• The Pringle maneuver, or intermittent portal triad clamping, is routinely used to minimize blood loss during low-central-venous-pressure (LCVP) hepatectomy; however, its real-time relationship with cerebral oxygenation remains insufficiently characterized.

  Intraoperative cerebral desaturation during low-central-venous-pressure hepatectomy with intermittent Pringle maneuver: a case report · 2026 · DOI

• However, PMI appeared more effective at preventing delirium relative to MUSE and UC, and the potential additional benefit of earplugs remains uncertain in this study.

  Combined Use of Personalized Music Intervention and Earplugs (MUSE) to Prevent Delirium in Mechanically Ventilated Patients: A Pilot Randomized Controlled Trial · 2026 · DOI

• Although they establish a strong association between delirium and subsequent ADRD, it has not been explored using statistical causal inference which makes the best use of observational data to minimize biases.

  Delirium and Increased Risk of Developing Dementia: An Emulated Target Trial Analysis · 2026 · DOI

• Although the pathophysiology of ICUAW remains poorly understood, several risk factors have been identified, including female sex, advanced age, prolonged mechanical ventilation, extended ICU stay, prolonged immobilization, multiorgan failure, shock, infection, and other factors related to critical illness and its treatment.

  ICU-Acquired Weakness: An Unsolved Clinical Problem: A Narrative Review · 2026 · DOI

• Regards to strengths; most patients were transferred to the general ward after confirming that patients were free from delirium. Therefore, the risk of underestimation may be low. While current study has following limitations. First, this study was retrospective and at single cardiovascular surgery center. Second, we were unable to ascertain the cause of death because electronic medical records did not contain a specific cause-of-death field. Third, most patients were transferred to general wards only after delirium had resolved. Therefore, the risk of underestimation is likely to be low. Fourth, data on preoperative medications prior to emergency surgery was not available. Since there has been lots of miss- ing data, should multiple imputation to be used? Fifth, it should be noted that due to the large number of analyzed variables, we did not include intraoperative hemodynamic aspects, nor medications administered to the patients, in the analysis. With regard to the latter, the literature reports indicate a vast number of medications potentially related to the onset of POD. Attempting to include these medications in the current study would lead to a substantial increase in studied parameters, which is not feasible in this phase of our line of research. Finally, since the primary objective of this study was to determine the variables associated with the onset of POD, we make no reference to the progression or duration of this neurocognitive disorder. These points to be consider in any new retrospective study.

  Does the Development of Delirium Predict Lower Survival and Increased Morbidity After Cardiac Surgery? A Retrospective Cohort Study. · 2026 · DOI

• Future research should focus on enhancing the overall efficiency of RCTs by promoting prospective trial registration, strengthening standardized assessment processes in multicenter collaborations, establishing dedicated publication channels for negative results and ineffective interventions, and providing methodological and international publication support to research teams in high-waste-risk regions, thereby systematically reducing resource waste.

  A cross-sectional analysis of research waste in randomized controlled trials on postoperative cognitive dysfunction · 2026 · DOI

• This study has several limitations. First, the data source was limited to ClinicalTrials.gov, the largest clinical trial registry, but it does not capture all global POCD trials. Consequently, our findings reflect the characteristics of studies registered on this platform 35. Second, the relatively small sample size of this study may have limited statistical power, resulting in observed associations not reaching statistical significance in the univariate regression analysis and limiting the ability to perform more in-depth multivariate analyses to control for confounding factors. Specifically, the wide 95%CI observed in our regression models suggests considerable uncertainty in the effect estimates. Third, during sample screening, we primarily used “Completion Date” as the criterion and did not actively exclude records marked as “Terminated,” “Withdrawn,” or “Unknown” 36. This approach was based on two considerations. On one hand, the initial sample size of Phase III/IV RCTs in the field was limited, and over-exclusion would hinder analysis. On the other hand, “terminated” trials themselves often represent resource investments that failed to meet their intended goals and can be viewed as a form of research waste, while records with “unknown” status may also contain studies that are actually completed or even published 37. Finally, the assessment of “design flaws” was ARTICLE IN PRESS ARTICLE IN PRESS ACCEPTED MANUSCRIPT primarily based on reported information in published articles and publicly available registry data; for unpublished trials, the true methodological quality may be underestimated or misjudged 38.

  A cross-sectional analysis of research waste in randomized controlled trials on postoperative cognitive dysfunction · 2026 · DOI

• Implementing the EDI Protocol provided nurses with a ro- bust knowledge of delirium and a set of interventions they could implement on patients to prevent the development of delirium. The methods of delivering nursing education on delirium prevention and early recognition were a strength of this project. Along with the education presented, nurses observed and practiced CAM-ICU assessments, which yielded a statistically significant improvement in nurses’ knowledge of delirium and comfort with the CAM-ICU. Nurses maintain a consistent presence at the bedside, ideal for preventing and ensuring prompt recognition of ICU delirium. The brisk improvement in nurses’ knowledge and comfort scores following the educational intervention ex- emplifies the importance of in-person nursing education on delirium, including the opportunity to ask questions and practice delirium assessment skills. This project’s outcomes were limited by a 70% nurse ed- ucation rate, as travel nurses, new hires, and nurses who floated to the NSICU from other units did not receive in- 85 105 60.3 3.15 68.22 5.79 0.0666 0.1315 0.032 person education on the EDI Protocol. All NSICU nurses received a follow-up email with a summary of educational points, but there was no method to ensure that the nurses read and understood the information. Gaps in the reach of nursing education may have adversely impacted nurse adoption and the protocol’s fidelity. Additionally, the lack of consistency in charge nurse audits of the delirium pre- vention measures may have adversely affected the report- ing and reinforcement of the delirium prevention measures delineated in the EDI Protocol. CONCLUSION This quality improvement project demonstrated the feasi- bility of nurse-led delirium prevention measures in the ICU. The project’s educational intervention included demon- strating the CAM-ICU assessment and dedicated time for nurses to practice this assessment skill. Project outcomes showed a statistically significant improvement in CAM-ICU documentation, nurses’ knowledge of delirium, and nurses’ comfort with the CAM-ICU assessment. Implementing nurse-driven delirium prevention and early identification strategies empowers nurses to play a crucial role in promot- ing positive outcomes for critically ill patients. AUTHOR CONTRIBUTIONS Megan Schoepke, DNP, AGACNP-BC, was responsible for conceptualization, investigation, and writing the original draft. Theresa A. Jizba, DNP, AGACNP-BC, ACHPN, was re- sponsible for supervision, writing, review, and editing. Jack Taylor, PhD was responsible for data curation and formal analysis. DISCLOSURE/CONFLICT OF INTEREST The authors have no financial relationships relevant to this article and no conflicts of interest to disclose. FUNDING SOURCES This research received no specific grant from public, com- mercial, or not-for-profit funding agencies.

  Nurse-Led Prevention and Early Identification of ICU Delirium: A Quality Improvement Project · 2026 · DOI

• Future delirium-directed cognition trials should be explicitly cognition-powered, employ harmonized and clinically meaningful endpoints (global cognition plus executive function plus functional cognition), and incorporate repeat follow-up beyond 3 months to dis- tinguish delayed recovery trajectories. Pragmatic bundle-based inter- ventions (e.g., comprehensive delirium prevention bundles), combined with structured post-ICU rehabilitation and survivorship clinic follow-up, may offer the most scalable pathway to detect durable cognitive benefit. Enrichment strategies targeting high-risk pheno- types (older age, prolonged delirium, shock burden, high sedative exposure) and the inclusion of neuro-ICU populations will be essen- tial to extend findings to broader critical care practice. Finally, mecha- nistic sub-studies incorporating biomarkers of neuroinflammation, endothelial injury, and sleep/circadian disruption may clarify which pathways are modifiable and identify responders to targeted interventions.

  Delirium-directed interventions and long-term cognitive outcomes in critically ill adults: a systematic review of randomized clinical trials · 2026 · DOI

• The findings of the CONFUSED study may provide the basis for future research aimed at validating identified biomarkers and predictive models in independent multicenter cohorts. In addition, the identified molecular pathways may represent potential targets for preventive or therapeutic interventions. In the long term, the integration of molecular biomarkers with clinical risk factors could enable the development of personalized perioperative risk assessment tools and targeted prevention strategies for POD. The authors declare that generative artificial intelligence (AI) was used in the research and writing processes. According to the GAIDeT taxonomy (2025), the following tasks were delegated to AI tools under full human supervision: The AI tool used was ChatGPT 4.5. Responsibility for the final content of the manuscript lies entirely with the authors. AI tools are not listed as authors and do not bear responsibility for the final outcomes. Declaration submitted by: Collective Responsibility.

  AI-Supported, Integrative Prediction of Postoperative Delirium: Protocol for the CONFUSED Study. · 2026 · DOI

• This review adhered to the PRISMA 2020 recommen- dations and applied the Cochrane RoB 2.0. The use of a frequentist network meta-analysis allowed for the simul- taneous comparison of multiple IMT strategies and rep- resents a key methodological strength. However, this study has several limitations. First, substantial heterogeneity in IMT protocols (intensity, device, duration, and timing) likely influenced the pooled estimates. Second, the definitions and timing of weaning success varied across studies. Third, sev- eral trials were small, limiting the statistical power. Fourth, although formal tests for publication bias were not significant, funnel plot asymmetry suggested that publication bias cannot be fully excluded, particularly given the small number of studies that contributed to some comparisons. Finally, the absence of a GRADE assessment limits the formal certainty grading of the evidence. Additionally, the relatively small number of studies contributing to network comparisons may limit the pre- cision of the indirect estimates. The inclusion of tracheostomized patients reflects real-world IMT application but may have contributed to clinical heterogeneity across studies.

  Efficacy of inspiratory muscle training on weaning success in mechanically ventilated ICU patients: a systematic review and network meta-analysis of randomized controlled trials · 2026 · DOI

• This pilot study is among the first in Germany to address the phenomenon of delirium in nursing homes and takes a first step towards raising awareness with a target group-specific e-learning program. As an exploratory pilot study, the sample size of 80 nursing professionals provided initial insights to inform further refinement of the e-learning program. The sample is characterised by self-selection of participants i.e., nursing professionals who were particularly interested in the topic were more likely to complete the e-learning program. Financial incentives must also be considered, as they influenced participation in the study and likely led to nurses completing the e-learning program who otherwise might not have done so. This may have led to an overestimation of the observed effects, as participants with higher intrinsic motivation or prior interest in delirium may have been more engaged with the learning material and Molitor et al. BMC Medical Education (2026) 26:680 more receptive to knowledge acquisition. Consequently, the results may not fully reflect the impact of the intervention in a less motivated or more heterogeneous population. Furthermore, the interpretation of data at the subgroup level must be performed with caution, as the sample size was very small. The small subgroup sizes reduce statistical precision and increase the likelihood of unstable effect estimates. As no formal a priori power calculation or predefined target sample size was established, the final sample depended on participation within the recruitment period, and the study was not statistically powered to detect small effects or subgroup differences with high precision. Therefore, subgroup findings should be interpreted as exploratory rather than confirmatory and cannot be generalised to specific professional groups without further validation in adequately powered studies. Although significant improvements with large effect sizes were observed in the overall sample, the robustness of subgroup analyses remains limited. Future controlled studies should perform formal sample size calculations based on the effect sizes observed in the present study. In addition, the nursing homes differed considerably in terms of size and clientele. With respect to recruitment, it must be taken into account that the email addresses did not directly reach the nursing professionals instead, the messages always had to be forwarded to the interested parties through the management of the nursing home, which must be considered a barrier. Another limitation is that pre- and posttests almost always lead to improvements in the intervention group, especially when the measurement is taken immediately after the intervention. Given that this is a pilot study, future studies on the impact of delirium training should include more time points for data collection. Moreover, the immediate post-intervention assessment does not allow conclusions about the sustainability of knowledge and confidence gains. It remains unclear whether the observed improvements persist over time or translate into sustained behavioural changes in clinical practice. Long-term follow-up assessments are therefore essential to evaluate retention effects and practical implementation. Although the “Knowledge about delirium in nursing homes” questionnaire showed good content validity, some items contained negative wording and formal stumbling blocks. It is striking that all items that were rated worse in the comparison between the pre- and posttests were negatively worded. The incorrect answers may partly be due to misunderstandings related to the negatively worded items. However, it cannot be ruled out that certain content areas require clearer emphasis within the e-learning modules.

  Improving delirium knowledge and recognition confidence in nursing homes through an e-learning program: a pre–post study · 2026 · DOI

• This study has several strengths, including a structured systematic review process, PROSPERO registration, PRISMA- the currently based reporting, and quantitative synthesis of available evidence. However, should be considered. First, only seven studies were included, and some pooled analyses were based on only a small number of studies. Second, substantial heterogeneity was observed for certain outcomes. Third, all included studies were observational in design, so the pooled findings should be interpreted as associations rather than causal relationships. Fourth, although the eligibility criteria covered OMFS broadly, most included studies focused on major oral cancer surgery, head and neck oncologic procedures, and reconstructive surgery, which may limit the applicability of the findings to the full range of OMFS procedures. Therefore, caution is warranted when generalizing these results to lower-complexity or non-oncologic OMFS populations.

  Factors associated with postoperative delirium in patients undergoing oral and maxillofacial surgery: a meta-analysis of observational study · 2026 · DOI

• The study demonstrated that cognitive rehabilitation reduced post-traumatic amnesia (PTA) duration, but the mechanism linking PTA recovery to earlier mechanical ventilation weaning remains unexplored. Future research must examine the causal pathway between improved cognitive function (measured by PTA duration and GCS scores) and successful extubation outcomes in moderate traumatic brain injury patients.

  Effect of Early Cognitive Rehabilitation Therapy on Mechanical Ventilation Weaning Time in Moderate Traumatic Brain Injury: A Randomized Controlled Trial · 2026 · DOI

• While extubation success criteria (cough presence, negative fluid balance, GCS ≥10) have been identified in previous cohort studies, no research has specifically examined how cognitive rehabilitation therapy status interacts with these traditional weaning criteria in moderate traumatic brain injury populations. Future studies should investigate whether cognitive rehabilitation-enhanced patients meet extubation criteria at different time points compared to control groups.

  Effect of Early Cognitive Rehabilitation Therapy on Mechanical Ventilation Weaning Time in Moderate Traumatic Brain Injury: A Randomized Controlled Trial · 2026 · DOI

• The paper documents physiological responses (tachycardia) triggered by specific auditory and visual stimuli during cognitive rehabilitation therapy but lacks systematic investigation of stimulus-response relationships. Future research must develop standardized stimulus selection protocols and characterize which visual and auditory stimulus parameters elicit adverse physiological responses in mechanically ventilated brain-injured patients.

  Effect of Early Cognitive Rehabilitation Therapy on Mechanical Ventilation Weaning Time in Moderate Traumatic Brain Injury: A Randomized Controlled Trial · 2026 · DOI

• The study was limited to a narrow age demographic; future investigations require extended study durations and enrollment of more heterogeneous aging populations to validate whether early cognitive rehabilitation therapy's benefits on mechanical ventilation weaning time generalize across younger and older moderate traumatic brain injury populations.

  Effect of Early Cognitive Rehabilitation Therapy on Mechanical Ventilation Weaning Time in Moderate Traumatic Brain Injury: A Randomized Controlled Trial · 2026 · DOI

Most-cited papers in Intensive Care Unit Cognitive Disorders

• Delirium in Mechanically Ventilated Patients · JAMA · 2001 · 2,708 citations
• Long-Term Cognitive Impairment after Critical Illness · New England Journal of Medicine · 2013 · 2,360 citations
• Paresis Acquired in the Intensive Care Unit<SUBTITLE>A Prospective Multicenter Study</SUBTITLE> · JAMA · 2002 · 1,255 citations
• Occurrence and outcome of delirium in medical in-patients: a systematic literature review · Age and Ageing · 2006 · 945 citations
• One-Year Health Care Costs Associated With Delirium in the Elderly Population · Archives of Internal Medicine · 2008 · 875 citations
• Postoperative Delirium · Archives of Internal Medicine · 1995 · 423 citations
• Use of Medications With Anticholinergic Effect Predicts Clinical Severity of Delirium Symptoms in Older Medical Inpatients · Archives of Internal Medicine · 2001 · 365 citations
• An Empirical Study of Delirium Subtypes · The British Journal of Psychiatry · 1992 · 320 citations
• A Nurse‐Led Interdisciplinary Intervention Program for Delirium in Elderly Hip‐Fracture Patients · Journal of the American Geriatrics Society · 2001 · 278 citations
• The consistent burden in published estimates of delirium occurrence in medical inpatients over four decades: a systematic review and meta-analysis study · Age and Ageing · 2020 · 263 citations

Most recent work

• Efficacy and Safety of Remimazolam Tosylate versus Propofol for Sedation of Postoperative Mechanically Ventilated Patients in Intensive Care Units: A Multicenter, Randomized, Single-blind, Noninferiority, Phase 3 Trial · Anesthesiology · 2026
• Efficacy of inspiratory muscle training on weaning success in mechanically ventilated ICU patients: a systematic review and network meta-analysis of randomized controlled trials · BMC Pulmonary Medicine · 2026
• Effects of the ABCDEF Bundle on Delirium, Function, and Quality of Life in Australian ICU Patients: A Pragmatic Randomized Controlled Trial · Critical Care Medicine · 2026
• Determinants of Delayed Recovery of Consciousness After Analgosedation Discontinuation in the ICU: Insights From Patients With COVID-19 Hypoxemic Respiratory Failure · Critical Care Medicine · 2026
• Effect of preoperative warming combined with dexmedetomidine on postoperative delirium in elderly patients undergoing hip fracture surgery: a randomized controlled trial · Frontiers in Medicine · 2026
• Hidden Burden of ICU: Patient-Perceived Stressors After Cardiothorasic Surgery · Journal of Clinical Medicine · 2026
• Risk factors associated with the development of delirium in hospitalized older adults with cardiopathy · The Journal of Latin American Geriatric Medicine · 2026
• Effect of multicomponent programs for prevention of delirium in surgical patients · The Journal of Latin American Geriatric Medicine · 2026
• Explainable deep-learning models to predict diaphragmatic dysfunction and cognitive stress in ICU patients under mechanical ventilation · Frontiers in Physiology · 2026
• Effect of Early Cognitive Rehabilitation Therapy on Mechanical Ventilation Weaning Time in Moderate Traumatic Brain Injury: A Randomized Controlled Trial · International Journal of Drug Delivery Technology · 2026

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