The Regional Anesthesia versus General Anesthesia (RAGA) randomised trial¹ tested the primary hypothesis that regional anaesthesia would reduce the incidence of postoperative delirium in older adults undergoing surgical repair for hip fracture. The trial had an allocation-concealed, open-label, multi-centre design. Patients were randomised to receive regional anaesthesia without sedation, or general anaesthesia followed by daily clinical delirium assessments via the Confusion Assessment Method (CAM)² the first week after surgery. Patients aged ≥ 65 years, with or without preexisting dementia, and a fragility hip fracture requiring surgical repair, were recruited from nine university teaching hospitals in Southeastern China.

Among the 950 patients enrolled and randomised, 941 were evaluable for the primary outcome of postoperative delirium incidence. Postoperative delirium occurred in 29 (6.2%) in the regional anaesthesia group versus 24 (5.1%) in the general anaesthesia group (unadjusted risk difference [RD], 1.1%; 95%CI, -1.7% to 3.8%; p = 0.48; unadjusted relative risk [RR], 1.2 [95%CI, 0.7 to 2.0]; p = 0.57]). Secondary outcomes, including mean delirium severity score, motoric subtypes of postoperative delirium, median pain score, median length of hospitalisation, and 30-day all-cause mortality were not different between groups.

The RAGA randomised trial concluded that regional anaesthesia without sedation does not significantly reduce the incidence of postoperative delirium during the first week after surgery in older patients with hip fracture. The rates of delirium were much lower than reported in other studies of hip fracture; this may have been due to the lower levels of frailty in the study population and low sensitivity of the delirium detection process as operationalised in the study. These findings add to a growing body of evidence suggesting that general anaesthetics alone do not cause postoperative delirium in older adults.

The primary hypothesis of the Regional versus General Anesthesia for Promoting Independence after Hip Fracture (REGAIN) trial^3,4 was that patients assigned to receive spinal, as compared with general, anaesthesia would be more likely to be alive and walking independently 60 days after surgery. REGAIN was a multi-centre, pragmatic, randomised superiority trial in which patients aged ≥ 50 years were randomised in a 1:1 ratio at 46 North American hospitals. The primary outcome was a composite of death or an inability to walk independently or with a cane or walker 60 days after randomisation. Secondary outcomes included postoperative delirium incidence, death within 60 days, time to discharge, and ambulation at 60 days after surgery. Postoperative delirium was assessed daily via the 3-Minute Diagnostic Interview for CAM (3D-CAM) for the first three days after surgery.⁵

Of the 1600 enrolled patients, 666 randomised to the spinal anaesthesia group and 769 randomised to the general anaesthesia group received their intended treatment. The primary outcome occurred similarly in each group: 18.5% with spinal anaesthesia and 18% with general anaesthesia (RR 1.03; 95% CI, 0.84 to 1.27; p = 0.83). No differences were found in secondary outcomes. Postoperative delirium occurred in 20.5% with spinal anaesthesia versus 19.7% with general anaesthesia.

REGAIN addressed the pragmatic question of whether anaesthesia type affected patient-centred outcomes in a hip fracture surgery cohort. For postoperative delirium, both groups received anaesthetic or sedative agents (albeit to a lesser extent with spinal anaesthesia), which is common practice in the U.S. and Canada. Nevertheless, the REGAIN findings for postoperative delirium are consistent with the RAGA trial.¹

In the Pro-MEDIC trial,⁶ the hypothesis was that evening melatonin would reduce delriium prevalence in critically ill patients if administered early in their hospital course. This multi-centre, randomised, placebo-controlled, double-blind trial was conducted across 12 Australian ICUs over three years. 847 patients, aged ≥ 18 years and with an expected ICU LOS > 72 hours, were enrolled within 48 hours of ICU admission. Patients were randomised to melatonin 4 mg or placebo at 21:00. Delirium was assessed twice daily using the CAM-ICU⁷ for 14 consecutive days or until ICU discharge. The primary outcome was the proportion of delirium-free assessments as a measure of delirium prevalence within 14 days or before ICU discharge.

There was no difference in the average proportion of delirium-free assessments per patient between the melatonin and placebo groups (79.2% versus 80% respectively, p = 0.55). This finding was consistent across subgroups, including diagnostic category, age, delirium risk, and secondary outcomes, including delirium severity, length of stay, mechanical ventilation, and mortality. This trial does not support the routine use of melatonin in the critically ill to prevent or treat delirium.

PAWEL (German acronym for “patient safety, cost-effectiveness, and quality of life”)⁸ was a stepped-wedge, cluster randomised trial comparing a tailored, multifaceted intervention to standard care across 5 German tertiary medical centres. The aim was to reduce postoperative delirium incidence and duration. The AKTIVER (German acronym for “everyday skills and cognition training and interdisciplinarity improves outcome and mitigates risk”) intervention included cognitive, motor, and sensory stimulation, meal companionship, stress relaxation, sleep promotion, and diagnostic test and operation room accompaniment. Patients aged ≥ 70 years undergoing elective orthopaedic, general, or cardiac surgery were eligible. The primary outcome was delirium incidence, as assessed with the I-CAM (short-form CAM plus an additional item for psychomotor activity as required per ICD-10 criteria),⁹ performed daily through postoperative day 7 by psychogeriatric research nurses. Delirium was assessed after discharge using a validated medical record review method.

Of the 1470 enrolled participants, postoperative delirium occurred in 147 (19.9%) of the intervention group and 171 (23.4%) of controls (RR, 0.85; 95% CI, 0.70–1.03; p = 0.10). Among cardiac surgery patients, there was no difference in delirium incidence between groups (intervention 35.2% vs control 36.5%; RR, 0.97; 95% CI, 0.77–1.22; p = 0.79). However, among non-cardiac surgery patients, delirium incidence was significantly lower in the intervention group (intervention 10.9% vs control 16.3%; RR, 0.67; 95% CI, 0.48–0.93; p = 0.008).

Adding to evidence for the efficacy of non-pharmacological interventions to prevent delirium, the AKTIVER intervention significantly reduced postoperative delirium risk in patients ≥ 70 years undergoing elective general and orthopaedic but not cardiac surgery. This was an effective intervention, but its reliance on volunteers may be challenging to implement in some centres.

This retrospective case-control study of electronic health records of patients admitted to a single level-one trauma centre¹⁰ compared cohorts before and after implementation of the Stanford Geriatric Trauma Care Pathway. This programme is based on geriatric best practices, which include order sets, guidelines, automated consultations, and escalation pathways delivered by a multidisciplinary team. The intervention was hypothesised to reduce delirium incidence (primary outcome) and hospital length of stay (secondary outcome). Delirium was measured using the CAM as performed by nurses each shift during routine care for the duration of hospitalisation and also if there was a diagnosis by the clinical team.

This study included 712 patients aged ≥ 65 treated for traumatic injury not undergoing operation. Delirium incidence was significantly lower in the post-implementation group compared with the baseline group (18.5% vs 28.3%; p = 0.002), even after accounting for patient demographics and injury characteristics (OR, 0.54; 95% CI 0.37–0.80; p < .001). Notably, the primary analysis did not adjust for frailty or dementia. Hospital length of stay was not different between post-implementation and baseline (mean [SD], 4.3 [2.9] days vs 4.3 [3.8] days; p = 0.20). The study provides evidence for the effectiveness of formalised, integrated, multidisciplinary systems to prevent delirium in trauma centres and warrants replication in randomised trials.

This was a single-centre, double-blinded, randomised control trial to determine whether breathing training could reduce the incidence of emergence delirium in preschool children after otorhinolaryngologic surgery performed with general anaesthesia.¹¹ The sample was 154 children aged 3 to 7 years with an ASA physical status I or II undergoing elective tonsillectomy and/or adenoidectomy under general anesthesia. The intervention involved practising controlled breathing through a straw to simulate conditions during anaesthesia emergence. Participants watched a standardised training video the day before surgery and performed breathing training sessions 5 minutes and 30 minutes after watching the video, then again before bed. The primary outcome was emergence delirium incidence, including hypoactive and hyperactive subtypes. Delirium incidence and severity were assessed with the Pediatric Emergence Delirium (PAED) scale¹² administered by post-anaesthesia care unit (PACU) nurses at 0, 5, 15, and 25 minutes after awakening.

For the primary outcome, emergence delirium was lower in the group receiving breathing training than the control group (10.4% vs. 35.1%, p < 0.001). The maximum PAED score (delirium severity) was lower in the training group (5.0 ± 5.0) compared with the control group (7.0 ± 7.0) (p = 0.001). There was no difference between groups in extubation time (intervention 35.0 ± 16.0 min vs control 30 ± 20.0 min, p = 0.8) or PACU stay time (65.0 ± 20.0 min vs 65.0 ± 20.0 min, p = 0.6).

Video-based breathing training during the preoperative visit in children aged 3 to 7 undergoing otorhinolaryngologic surgery led to reduced incidence and severity of emergence delirium, deserving further investigation other settings.

This prospective cohort study¹³ evaluated the real-world effectiveness of implementing a smart tablet app-based delirium identification protocol, based on clinician profession. Clinicians included hospitalists, nurses, and certified nursing assistants (CNAs). Patients were assessed daily for two consecutive days by: (1) trained research personnel using a rigorous research reference standard delirium assessment based on Mini-Mental Status Examination, long-form CAM, and supplemental items to assess attention and delirium symptom severity; (2) CNAs using an app-based ultra-brief 2-item screener (UB-2); and (3) physicians and nurses using an app-based 2-step protocol consisting of the UB-2, followed by the 3-Minute Diagnostic Interview for Confusion Assessment Method (3D-CAM) in UB-2 positive patients. The authors hypothesised that the app-based protocol would be feasible (≥ 95% completion); brief (< 1 min for the UB-2; < 2 min for the 2-step protocol); and achieve an accuracy > 85%, sensitivity > 80% and specificity > 90%.

The study enrolled 527 older adult inpatients and involved 399 clinicians from two hospitals. Of the 924 delirium assessments completed, 154 (17%) of 114 patients (22%) were positive for delirium. The overall completion rate of the app-based protocol exceeded 97%. On average, CNAs completed the UB-2 in 62 seconds, while nurses and physicians completed the 2-step protocol in 104 seconds and 106 seconds, respectively. When the UB-2 was administered by physicians, nurses, and CNAs, the corresponding sensitivities were 88%, 87%, and 82%; specificities, 64%, 70%, and 66%; and accuracy, 69%, 73%, and 70%. For physicians and nurses, the 2-step protocol had sensitivities of 65% and 63%; specificities of 93% and 91%; and accuracy of 89% and 87%, respectively.

These findings demonstrate that the app-based delirium detection protocol was feasible and quick when administered in real-world practice by hospitalists, nurses, and CNAs alike. Many patients were excluded due to inability to effectively communicate in English, necessating further study in other languages.

This was a retrospective cohort study¹⁴ that aimed to develop an automated, neurophysiologically derived measure of delirium and its severity: the Electroencephalographic Confusion Assessment Method Severity Score (E-CAM-S). The E-CAM-S was calculated by applying a learning-to-rank machine learning model to frontal electroencephalography (EEG) signals from 373 adult patients. The short-form Confusion Assessment Method Severity (CAM-S) was the clinical reference standard.

For the primary outcome, E-CAM-S correlated with CAM-S (r = 0.68; p < 0.0001); 53 EEG features were predictive of delirium severity in the whole sample and 23 in the non-comatose subsample. In terms of clinical outcomes, E-CAM-S and CAM-S had similar strengths of association with hospital length of stay (Spearman’s rho: 0.33 vs 0.41, p = 0.08) and in-hospital mortality (area under the curve: 0.77 vs 0.81; p = 0.3).

These findings suggest that the E-CAM-S derived from 4 frontal EEG leads objectively quantified delirium severity and predicted clinical outcomes similar to conventional interview-based clinical assessment. The E-CAM-S shows promise for automatic detection and routine screening of delirium severity. However, future research is needed to understand the wide range of EEG features associated with delirium severity and to prospectively assess the clinical application of the features selected by the machine learning model.

A microfluidic-assisted blood-brain barrier (BBB) device used primary human cells to examine the effect of omega-3 fatty acids on interleukin (IL)-1β-induced inflammation.¹⁵ Omega-3 fatty acids protected BBB homeostasis and inhibited IL-1β-induced inflammation in BBB-associated endothelial cells and pericytes, including vascular cell adhesion molecule 1 overexpression, intercellular gaps between human brain microvascular endothelial cells, and disruption of the human astrocytic network density.

There were effects of omega-3 fatty acid on postoperative BBB disruption, microglial activation, and delirium-like behaviour (inattention) in a mouse model. Male and female mice 12–16 weeks old were randomised to three groups: control, surgery, and surgery with application of omega-3 fatty acids. After surgery, the hippocampus was isolated to evaluate gene expression of neuroinflammatory markers; a five-choice serial reaction time task was used to assess inattention.

Omega-3 fatty acids contributed to the maintenance of BBB integrity and protected against surgery-induced microglial activation and attention deficits in mice. An additional novel finding was that surgery-induced pericyte loss and perivascular macrophage activation was effectively rescued by omega-3 fatty acid pretreatment.

This researcher-developed micro-physiological BBB device provides evidence in support of the BBB-protective effect of omega-3 fatty acids in a mouse model of delirium. It also identified pericytes and perivascular macrophages as potential new intervention targets to prevent postoperative delirium.