Incidence of Adverse Events Using Flumazenil in Patients With Iatrogenic Benzodiazepine Delirium: A Retrospective Study.

BACKGROUND: Flumazenil is a competitive benzodiazepine (BZD) antagonist most used for treating delirium in BZD overdoses. Since its introduction, many have expressed concerns about its safety secondary to the risk of inducing BZD withdrawal and refractory seizures. STUDY QUESTION: What is the incidence of adverse drug events after the administration of flumazenil in patients with suspected iatrogenic BZD delirium? STUDY DESIGN: This is a retrospective cross-sectional study of patients from a single center from 2010 to 2013. Patients experiencing delirium after receiving BZDs in the hospital were included if they had a bedside toxicology consult and were administered flumazenil. Patients were excluded if they were given BZDs for ethanol withdrawal or if they did not have mental status documentation before and after flumazenil administration. Descriptive statistics were calculated. MEASURES AND OUTCOMES: The primary outcome was the incidence of adverse drug events after flumazenil administration. The secondary outcome was the efficacy of flumazenil determined by the patient's mental status. RESULTS: A total of 501 patient records were reviewed, and 206 patients were included in the final analysis. Of those patients, 172 (83.5%) experienced an objective improvement in their mental status within 1 hour after flumazenil administration. A total of 5 patients experienced adverse events (2.4%), 95% confidence interval (0.78, 5.54). Of these, 3 patients experienced minor agitation or restlessness without pharmacologic intervention. Two patients experienced moderate agitation or restlessness that resolved with haloperidol or physostigmine administration. No patients had a reported seizure, 95% confidence interval (0.0, 1.77). CONCLUSIONS: Flumazenil seems to be a safe and effective intervention for the reversal of delirium secondary to iatrogenic BZD administration.

From Traditional Typing to Intelligent Insights: A Narrative Review of Directions Toward Targeted Therapies in Delirium.

Delirium is a heterogeneous syndrome characterized by an acute change in level of consciousness that is associated with inattention and disorganized thinking. Delirium affects most critically ill patients and is associated with poor patient-oriented outcomes such as increased mortality, longer ICU and hospital length of stay, and worse long-term cognitive outcomes. The concept of delirium and its subtypes has existed since nearly the beginning of recorded medical literature, yet robust therapies have yet to be identified. Analogous to other critical illness syndromes, we suspect the lack of identified therapies stems from patient heterogeneity and prior subtyping efforts that do not capture the underlying etiology of delirium. The time has come to leverage machine learning approaches, such as supervised and unsupervised clustering, to identify clinical and pathophysiological distinct clusters of delirium that will likely respond differently to various interventions. We use sedation in the ICU as an example of how precision therapies can be applied to critically ill patients, highlighting the fact that while for some patients a sedative drug may cause delirium, in another cohort sedation is the specific treatment. Finally, we conclude with a proposition to move away from the term delirium, and rather focus on the treatable traits that may allow precision therapies to be tested.

Exploring Antipsychotic Use for Delirium Management in Adults in Hospital, Sub-Acute Rehabilitation and Aged Care Settings: A Systematic Literature Review.

BACKGROUND: International guidelines discourage antipsychotic use for delirium; however, concerns persist about their continued use in clinical practice. OBJECTIVES: We aimed to describe the prevalence and patterns of antipsychotic use in delirium management with regard to best-practice recommendations. Primary outcomes investigated were prevalence of use, antipsychotic type, dosage and clinical indication. METHODS: Eligibility criteria: studies of any design that examined antipsychotic use to manage delirium in adults in critical care, acute care, palliative care, rehabilitation, and aged care were included. Studies of patients in acute psychiatric care, with psychiatric illness or pre-existing antipsychotic use were excluded. INFORMATION SOURCES: we searched five health databases on 16 August, 2023 (PubMed, CINAHL, Embase, APA PsycInfo, ProQuest Health and Medical Collection) using MeSH terms and relevant keywords, including 'delirium' and 'antipsychotic'. Risk of bias: as no included studies were randomised controlled trials, all studies were assessed for methodological quality using the Mixed Methods Appraisal Tool. SYNTHESIS OF RESULTS: descriptive data were extracted in Covidence and synthesised in Microsoft Excel. RESULTS: Included studies: 39 studies published between March 2004 and August 2023 from 13 countries (n = 1,359,519 patients). Most study designs were retrospective medical record audits (n = 16). SYNTHESIS OF RESULTS: in 18 studies, participants' mean age was ≥65 years (77.79, ±5.20). Palliative care had the highest average proportion of patients with delirium managed with antipsychotics (70.87%, ±33.81%); it was lower and varied little between intensive care unit (53.53%, ±19.73%) and non-intensive care unit settings [medical, surgical and any acute care wards] (56.93%, ±26.44%) and was lowest in in-patient rehabilitation (17.8%). Seventeen different antipsychotics were reported on. In patients aged ≥65 years, haloperidol was the most frequently used and at higher than recommended mean daily doses (2.75 mg, ±2.21 mg). Other antipsychotics commonly administered were olanzapine (mean 11 mg, ±8.54 mg), quetiapine (mean 64.23 mg, ±43.20 mg) and risperidone (mean 0.97 mg, ±0.64 mg). CONCLUSIONS: The use of antipsychotics to manage delirium is strongly discouraged in international guidelines. Antipsychotic use in delirium care is a risk for adverse health outcomes and a longer duration of delirium, especially in older people. However, this study has provided evidence that clinicians continue to use antipsychotics for delirium management, the dose, frequency and duration of which are often outside evidence-based guideline recommendations. Clinicians continue to choose antipsychotics to manage delirium symptoms to settle agitation and maintain patient and staff safety, particularly in situations where workload pressures are high. Sustained efforts are needed at the individual, team and organisational levels to educate, train and support clinicians to prioritise non-pharmacological interventions early before deciding to use antipsychotics. This could prevent delirium and avert escalation in behavioural symptoms that often lead to antipsychotic use.

Impact of intraoperative dexmedetomidine on postoperative delirium and pro-inflammatory cytokine levels in elderly patients undergoing thoracolumbar compression fracture surgery: A prospective, randomized, placebo-controlled clinical trial.

BACKGROUND: This study evaluates the efficacy of dexmedetomidine (DEX) in reducing postoperative delirium (POD) and modulating pro-inflammatory cytokines in elderly patients undergoing thoracolumbar compression fracture surgery. METHODS: In this randomized, double-blind, placebo-controlled trial conducted from October 2022 to January 2023 at Anting Hospital in Shanghai, 218 elderly patients were randomized into DEX (n = 110) and normal saline (NS, n = 108) groups. The DEX group received 0.5 µg/kg/h DEX, and delirium incidence was assessed using the Confusion Assessment Method (CAM) on days 1 to 3 post-surgery. Levels of interleukins IL-1ß, IL-6, and tumor necrosis factor-α (TNF-α) were measured pre-operation (T0) and on postoperative days 1 (T1) and 3 (T3). Preoperative (T0) and postoperative day 1 (T1) cerebrospinal fluid (CSF) samples were treated with varying concentrations of olanzapine or DEX to observe their regulatory effects on the expression of Phospho-ERK1/2 and Phospho-JNK. RESULTS: Dexmedetomidine significantly lowered the incidence of POD to 18.2%, compared to 30.6% in the NS group (P = .033). While all patients showed an initial increase in cytokine levels after surgery, by T3, IL-6 and TNF-α levels notably decreased in the DEX group, with no significant change in IL-1ß levels across groups. The adverse events rate was similar between groups, demonstrating the safety of DEX in this population. In postoperative CSF samples, treatment with 0.5 mM DEX significantly downregulated Phospho-JNK and upregulated Phospho-ERK1/2 expression, demonstrating a dose-dependent modulation of inflammatory responses. CONCLUSION: Dexmedetomidine is effective in reducing early POD in elderly patients post-thoracolumbar compression fracture surgery. It also decreases IL-6 and TNF-α levels, indicating its potential in managing postoperative inflammatory responses. Treatment with 0.5 mM DEX significantly modulated Phospho-ERK1/2 and Phospho-JNK expressions in postoperative CSF samples, indicating a dose-dependent effect on reducing inflammation. This study contributes to understanding DEX's role in improving postoperative outcomes in elderly patients.

Usefulness of Gabapentin as an Alternative/Adjunct Therapy for Delirium: A Retrospective Observational Study.

BACKGROUND: Antipsychotics are commonly used to treat delirium but can adversely affect the extrapyramidal and cardiac conduction systems. Antipsychotic use has also been reported to be associated with increased mortality in older adults. Therefore, alternative and adjunct medications for delirium are necessary. We retrospectively assessed the efficacy and safety of gabapentin (GBP) as an alternative and adjunct medication for delirium. METHODS: We retrospectively investigated the records of patients with delirium treated with GBP (71 patients; median age, 81 years; interquartile range, 76-87.5 years; 54.9% males) at a general hospital. We examined duration to delirium improvement, as assessed by the Intensive Care Delirium Screening Checklist (ICDSC) and DSM-5 criteria, as well as adverse events. RESULTS: The median (interquartile range) GBP dose was 200 mg (150-350 mg) /day. A total of 71.8% and 85.9% of the patients failed to meet the diagnostic criteria for delirium at 2 days and 5 days after initial administration, respectively (p<0.05). In subgroup analysis, patients with a history of epilepsy or cerebrovascular disease responded better to GBP than did those without such histories, suggesting that patients with abnormal/borderline neuronal activity respond to GBP even though they do not exhibit seizures. GBP did not induce extrapyramidal symptoms, cardiac conduction disturbances, hyperglycemia, or epilepsy but caused sleepiness and myoclonus. CONCLUSIONS: GBP may improve delirium with fewer adverse effects and may be a safe alternative or adjunct treatment for delirium. Dosage adjustment may be necessary to prevent sleepiness.

Preventive Effects of Ramelteon, Suvorexant, and Lemborexant on Delirium in Hospitalized Patients With Physical Disease: A Retrospective Cohort Study.

BACKGROUND: New sleep-inducing drugs (eg, ramelteon, suvorexant, and lemborexant) have been shown to prevent delirium in high-risk groups. However, no single study has simultaneously evaluated the delirium-preventing effects of all novel sleep-inducing drugs in hospitalized patients. Therefore, this study aimed to clarify the relationship between sleep-inducing drugs and delirium prevention in patients hospitalized in general medical-surgical settings for nonpsychiatric conditions who underwent liaison interventions for insomnia. METHODS: This retrospective cohort study included patients treated in general medical-surgical settings for nonpsychiatric conditions with consultation-liaison psychiatry consult for insomnia. Delirium was diagnosed by fully certified psychiatrists using the Diagnostic and Statistical Manual of Mental Disorders 5 th edition. The following items were retrospectively examined from medical records as factors related to delirium development: type of sleep-inducing drugs, age, sex, and delirium risk factors. The risk factors of delirium development were calculated using adjusted odds ratios (aORs) via multivariate logistic regression analysis. RESULTS: Among the 710 patients analyzed, 257 (36.2%) developed delirium. Suvorexant (aOR, 0.61; 95% confidence interval [CI], 0.40-0.94; P = 0.02) and lemborexant (aOR, 0.23; 95% CI, 0.14-0.39; P < 0.0001) significantly reduced the risk of developing delirium. Benzodiazepines (aOR, 1.90; 95% CI, 1.15-3.13; P = 0.01) significantly increased this risk. Ramelteon (aOR, 1.30; 95% CI, 0.84-2.01; P = 0.24) and Z-drugs (aOR, 1.27; 95% CI, 0.81-1.98; P = 0.30) were not significantly associated with delirium development. CONCLUSIONS: The use of suvorexant and lemborexant may prevent delirium in patients with a wide range of medical conditions.

Tocilizumab is associated with reduced delirium and coma in critically ill patients with COVID-19.

Recent preclinical studies demonstrate a direct pathological role for the interleukin-6 (IL-6) pathway in mediating structural and functional delirium-like phenotypes in animal models of acute lung injury. Tocilizumab, an IL-6 pathway inhibitor, has shown reduced duration of ventilator dependency and mortality in critically ill patients with COVID-19. In this study, we test the hypothesis that tocilizumab is associated with reduced delirium/coma prevalence in critically ill patients with COVID-19. 253 patients were included in the study cohort, 69 in the tocilizumab group and 184 in the historical control group who did not receive tocilizumab. Delirium was assessed using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) with a positive score indicating delirium. Coma was defined as a Richmond Agitation-Sedation Scale score of - 4 or - 5. Tocilizumab was associated with significantly greater number of days alive without delirium/coma (tocilizumab [7 days (IQR: 3-9 days)] vs control [3 days (IQR: 1-8 days)]; p < 0.001). These results remained significant after adjusting for age, sex, sepsis, Charlson Comorbidity Index, Sequential Organ Failure Assessment score, and median daily dose of analgesics/sedatives ( ß ^ = 0.671, p = 0.010). There were no significant differences in mortality ( ß ^ = - 0.204, p = 0.561), ventilator duration ( ß ^ = 0.016, p = 0.956), and ICU or hospital length of stay ( ß ^ = - 0.134, p = 0.603; ß ^ = 0.003, p = 0.991, respectively). Tocilizumab use was associated with significantly increased number of days without delirium/coma. Confirmation of these findings in randomized prospective studies may inform a novel paradigm of pharmacological amelioration of delirium/coma during critical illness.

Efficacy and safety of perioperative melatonin for postoperative delirium in patients undergoing surgery: a systematic review and meta-analysis.

OBJECTIVE: To assess the efficacy and safety of perioperative melatonin and melatonin agonists in preventing postoperative delirium (POD). METHODS: We conducted a systematic search for randomized controlled trials (RCTs) published through December 2022. The primary outcome was efficacy based on the incidence of POD (POD-I). Secondary outcomes included efficacy and safety according to the length of hospital or intensive care unit stay, in-hospital mortality, and adverse events. Subgroup analyses of POD-I were based on the type and dose of drug (low- and high-dose melatonin, ramelteon), the postoperative period (early or late), and the type of surgery. RESULTS: In the analysis (16 RCTs, 1981 patients), POD-I was lower in the treatment group than in the control group (risk ratio [RR] = 0.57). POD-I was lower in the high-dose melatonin group than in the control group (RR = 0.41), whereas no benefit was observed in the low-dose melatonin and ramelteon groups. POD-I was lower in the melatonin group in the early postoperative period (RR = 0.35) and in patients undergoing cardiopulmonary surgery (RR = 0.54). CONCLUSION: Perioperative melatonin or melatonin agonist treatment suppressed POD without severe adverse events, particularly at higher doses, during the early postoperative period, and after cardiopulmonary surgery.

Listeria brain abscess: a therapeutically challenging rare presentation of listeriosis.

We report a very rare case of Listeria multiple brain abscesses manifested as delirium, which represented diagnostic and therapeutic challenges overcome only by the close cooperation between Infectious Diseases and Neuroradiology, without which a satisfactory outcome would not be achieved.An elderly man presented with confusion and drowsiness with a background of type-II diabetes mellitus. Although computed tomography of the brain only showed frontal lobe oedema, contrast magnetic resonance (MR) imaging showed numerous irregular rim-enhancing lesions containing central diffusion restriction, suggesting multiple pyogenic cerebral abscesses of unclear aetiology. Thereafter, Listeria monocytogenes was isolated from blood cultures, suggesting this as the causative organism. Deemed unsuitable for neurosurgical drainage, the patient received medical management with a protracted course of antibiotics. This case was extremely challenging, due to 1) the impossibility of source control, 2) the small number of effective antibiotics available to treat this condition, and 3) the inevitable antibiotic side-effects, derived from long-term exposure. A successful outcome was only possible thanks to strict close multidisciplinary follow up, requiring frequent MR imaging and a judicious antibiotic choice, including monitoring of their side-effects. Due to the rarity of this condition, there is lack of guidance on its management, hence the importance of multidisciplinary involvement with very close imaging and antibiotic monitoring.

Efficacy of melatonin in decreasing the incidence of delirium in critically ill adults: a randomized controlled trial.

OBJECTIVE: To determine whether enteral melatonin decreases the incidence of delirium in critically ill adults. METHODS: In this randomized controlled trial, adults were admitted to the intensive care unit and received either usual standard care alone (Control Group) or in combination with 3mg of enteral melatonin once a day at 9 PM (Melatonin Group). Concealment of allocation was done by serially numbered opaque sealed envelopes. The intensivist assessing delirium and the investigator performing the data analysis were blinded to the group allocation. The primary outcome was the incidence of delirium within 24 hours of the intensive care unit stay. The secondary outcomes were the incidence of delirium on Days 3 and 7, intensive care unit mortality, length of intensive care unit stay, duration of mechanical ventilation and Glasgow outcome score (at discharge). RESULTS: We included 108 patients in the final analysis, with 54 patients in each group. At 24 hours of intensive care unit stay, there was no difference in the incidence of delirium between Melatonin and Control Groups (29.6 versus 46.2%; RR = 0.6; 95%CI 0.38 - 1.05; p = 0.11). No secondary outcome showed a statistically significant difference. CONCLUSION: Enteral melatonin 3mg is not more effective at decreasing the incidence of delirium than standard care is in critically ill adults.

A joint frailty model for recurrent and competing terminal events: Application to delirium in the ICU.

Joint models linking longitudinal biomarkers or recurrent event processes with a terminal event, for example, mortality, have been studied extensively. Motivated by studies of recurrent delirium events in patients receiving care in an intensive care unit (ICU), we devise a joint model for a recurrent event process and multiple terminal events. Being discharged alive from the ICU or experiencing mortality may be associated with a patient's hazard of delirium, violating the assumption of independent censoring. Moreover, the direction of the association between the hazards of delirium and mortality may be opposite of the direction of association between the hazards of delirium and ICU discharge. Hence treating either terminal event as independent censoring may bias inferences. We propose a competing joint model that uses a latent frailty to link a patient's recurrent and competing terminal event processes. We fit our model to data from a completed placebo-controlled clinical trial, which studied whether Haloperidol could prevent death and delirium among ICU patients. The clinical trial served as a foundation for a simulation study, in which we evaluate the properties, for example, bias and confidence interval coverage, of the competing joint model. As part of the simulation study, we demonstrate the shortcomings of using a joint model with a recurrent delirium process and a single terminal event to study delirium in the ICU. Lastly, we discuss limitations and possible extensions for the competing joint model. The competing joint model has been added to frailtypack, an R package for fitting an assortment of joint models.

Aripiprazole for treating delirium: A systematic review-Is it a valid yet understudied treatment?

BACKGROUND: Delirium is a neuropsychiatric condition that commonly occurs in medical settings, especially among older individuals. Despite the lack of strong evidence in the literature, haloperidol is considered the first-line pharmacological intervention. Unfortunately, its adverse effects can be severe, and psychiatrists are considering the use of alternative drugs targeting dopamine and serotonin domains (atypical antipsychotics). Among them, aripiprazole is considered to have one of the safest pharmacological profiles. AIMS: The purpose of this study is to examine the studies on aripiprazole as a pharmacological treatment of delirium present in today's literature. METHODS: We carried out systematic research of MedLine, PubMed, Cochrane, Embase, and ScienceDirect examining articles written between January 2002 and September 2023, including experimental studies published in peer-reviewed journals. RESULTS: The 6 final included studies examined a total of 130 patients, showing a delirium resolution in a 7-day span of 73.8% of patients treated with aripiprazole. CONCLUSIONS: Considering the limited data currently available, we can assert that aripiprazole is at least as efficient as haloperidol, the true point is that it has a far better tolerability and safety profile. Nonetheless, further studies are necessary to provide more compelling data, together with a more precise indication regarding minimum efficient dose, as the main limitations of our review are the very small sample size, the small percentage of subjects with preexisting dementia, and the fact that most studies used scales with low specificity for the examined condition.

Fixed dose ketamine for prehospital management of hyperactive delirium with severe agitation.

INTRODUCTION: Patients exhibiting signs of hyperactive delirium with severe agitation (HDSA) may require sedating medications for stabilization and safe transport to the hospital. Determining the patient's weight and calculating the correct weight-based dose may be challenging in an emergency. A fixed dose ketamine protocol is an alternative to the traditional weight-based administration, which may also reduce dosing errors. The objective of this study was to evaluate the frequency and characteristics of adverse events following pre-hospital ketamine administration for HDSA. METHODS: Emergency Medical Services (EMS) records from four agencies were searched for prehospital ketamine administration. Cases were included if a 250 mg dose of ketamine was administered on standing order to an adult patient for clinical signs consistent with HDSA. Protocols allowed for a second 250 mg dose of ketamine if the first dose was not effective. Both the 250 mg initial dose and the total prehospital dose were analyzed for weight based dosing and adverse events. RESULTS: Review of 132 cases revealed 60 cases that met inclusion criteria. Patients' median weight was 80 kg (range: 50-176 kg). No patients were intubated by EMS, one only requiring suction, three required respiratory support via bag valve mask (BVM). Six (10%) patients were intubated in the emergency department (ED) including the three (5%) supported by EMS via BVM, three (5%) others who were sedated further in the ED prior to requiring intubation. All six patients who were intubated were discharged from the hospital with a Cerebral Performance Category (CPC) 1 score. The weight-based dosing equivalent for the 250 mg initial dose (OR: 2.62, CI: 0.67-10.22) and the total prehospital dose, inclusive of the 12 patients that were administered a second dose, (OR: 0.74, CI: 0.27, 2.03), were not associated with the need for intubation. CONCLUSION: The 250 mg fixed dose of ketamine was not >5 mg/kg weight-based dose equivalent for all patients in this study. Although a second 250 mg dose of ketamine was permitted under standing orders, only 12 (20%) of the patients were administered a second dose, none experienced an adverse event. This indicates that the 250 mg initial dose was effective for 80% of the patients. Four patients with prehospital adverse events likely related to the administration of ketamine were found. One required suction, three (5%) requiring BVM respiratory support by EMS were subsequently intubated upon arrival in the ED. All 60 patients were discharged from the hospital alive. Further research is needed to determine an optimal single administration dose for ketamine in patients exhibiting signs of HDSA, if employing a standardized fixed dose medication protocol streamlines administration, and if the fixed dose medication reduces the occurrence of dosage errors.

Recognition and Management of Delirium in the Neonatal Intensive Care Unit: Case Series From a Single-Center Level IV Intensive Care Unit.

Delirium often goes unrecognized in neonates and children because of lack of experience in evaluating behavior and cognition, insufficient awareness of the prevalence, and nondistinctive symptoms in this population. Although there are increasing reports of the presence of delirium in neonates, there are little data to guide the pharmacologic treatment in this population. In this retrospective single-center case series, we present our experience using quetiapine to treat delirium in 9 medically complex neonates. Based on an extensive literature review, expert opinion, and institutional experience, we propose an approach for monitoring and treating delirium in neonates and infants.

Comparison of Remimazolam and Propofol on Postoperative Delirium in Elderly Patients Undergoing Radical Resection of Colon Cancer: A Single-Center Prospective Randomized Controlled Study.

BACKGROUND We compared the effect of remimazolam and propofol intravenous anesthesia on postoperative delirium in elderly patients undergoing laparoscopic radical resection of colon cancer. MATERIAL AND METHODS One hundred patients undergoing elective radical operation of colon cancer under general anesthesia were divided into a remimazolam group (group R) and propofol group (group P) by a random number table method. During anesthesia induction and maintenance, group R was intravenously injected with remimazolam to exert sedation; however, in group P, propofol was injected instead of remimazolam. The occurrence of postoperative delirium was assessed with the Confusion Assessment Method for the Intensive Care Unit scale and postoperative pain was assessed with the visual analogue score (VAS). The primary outcome measures were the incidence and duration of delirium within 7 days following surgery. Secondary outcome measures included postoperative VAS scores, intraoperative anesthetic drug dosage, and adverse reactions, including nausea and vomiting, hypoxemia, and respiratory depression. RESULTS There was no significant difference in baseline data between the 2 groups (P>0.05). There was no statistically significant difference in the incidence and duration of postoperative delirium between the 2 groups (P>0.05). There were no significant differences in VAS scores, remifentanil consumption, and adverse reactions, including nausea and vomiting, hypoxemia, and respiratory depression between the 2 groups (P>0.05). CONCLUSIONS In elderly patients undergoing radical colon cancer surgery, remimazolam administration did not improve or aggravate the incidence and duration of delirium, compared with propofol.

Treatment of Anticholinergic Delirium with Oral Rivastigmine: A Case Report.

BACKGROUND: Anticholinergic toxicity is commonly encountered in the emergency department. However, the availability of physostigmine, a central acetylcholinesterase inhibitor used to reverse anticholinergic delirium, has been significantly limited due to national drug shortages in the United States. Several articles have explored the viability of rivastigmine as an alternative treatment in these patients. CASE REPORT: A 33-year-old man presented to the emergency department after a suspected suicide attempt. The patient was found with an empty bottle of diphenhydramine at the scene. On arrival, he was tachycardic and delirious, with dilated and nonreactive pupils and dry skin. As the clinical picture was highly suggestive of anticholinergic toxicity, the patient was treated with oral rivastigmine at a starting dose of 4.5 mg to reverse his anticholinergic delirium. Although a repeat dose was required, his delirium resolved without recurrence. Why Should an Emergency Physician Be Aware of This? Oral rivastigmine has been applied successfully here and in other case reports to reverse anticholinergic delirium with the benefit of prolonged agitation control. Emergency physicians may consider this medication in consultation with a specialist, with initial doses starting at 4.5-6 mg, if encountering anticholinergic delirium when physostigmine is not available.

Antipsychotics in the Treatment of Delirium in Critically Ill Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: To conduct a systematic review and meta-analysis assessing whether the use of antipsychotic medications in critically ill adult patients with delirium impacts patient-important outcomes. DATA SOURCES: A medical librarian searched Ovid MEDLINE, EMBASE, APA PsycInfo, and Wiley's Cochrane Library as well as clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform up to November 2023. STUDY SELECTION: Independently and in duplicate, reviewers screened abstracts and titles for eligibility, then full text of qualifying studies. We included parallel-group randomized controlled trials (RCTs) that included critically ill adult patients with delirium. The intervention group was required to receive antipsychotic medications at any dose, whereas the control group received usual care or placebo. DATA EXTRACTION: Reviewers extracted data independently and in duplicate using a piloted abstraction form. Statistical analyses were conducted using RevMan software (version 5.4). DATA SYNTHESIS: Five RCTs ( n = 1750) met eligibility criteria. The use of antipsychotic medications compared with placebo did not increase the number of delirium- or coma-free days (mean difference 0.90 d; 95% CI, -0.32 to 2.12; moderate certainty), nor did it result in a difference in mortality, duration of mechanical ventilation, ICU, or hospital length of stay. The use of antipsychotics did not result in an increased risk of adverse events (risk ratio 1.27; 95% CI, 0.71-2.30; high certainty). Subgroup analysis of typical versus atypical antipsychotics did not identify any subgroup effect for any outcome. CONCLUSIONS: In conclusion, our systematic review and meta-analysis demonstrated with moderate certainty that there is no difference in delirium- or coma-free days when delirious critically ill adults are treated with antipsychotic medications. Further studies in the subset of patients with hyperactive delirium may be of benefit.

Melatonin does not reduce delirium severity in hospitalized older adults: Results of a randomized placebo-controlled trial.

BACKGROUND: Delirium is common in older inpatients, causing distress, cognitive decline, and death. Current therapies are unsatisfactory, limited by lack of efficacy and adverse effects. There is an urgent need for effective delirium treatment. Sleep wake cycle is disturbed in delirium; endogenous Melatonin is perturbed, and exogenous Melatonin is a safe and effective medication for sleep disorders. This study aims to determine the effect of oral Melatonin 5 mg immediate release (IR) nightly for five nights on the severity of delirium in older (≥65 years) medical inpatients. METHODS: This was a double-blinded, randomized controlled trial in general internal medicine units of a tertiary teaching hospital. Older inpatients with Confusion Assessment Method positive, hyperactive or mixed delirium within 48 h of admission or onset of in-hospital delirium were included. The primary outcome was change in delirium severity measured with the Memorial Delirium Assessment Scale (MDAS). A previous pilot trial showed 120 participants randomized 1:1 to Melatonin or Placebo would provide 90% power to demonstrate a 3-point reduction in the MDAS. RESULTS: One hundred and twenty participants were randomized, 61 to Melatonin 5 mg and 59 to Placebo. The medication was well tolerated. The mean MDAS improvement was 4.9 (SD 7.6) in the Melatonin group and 5.4 (SD 7.2) in the Placebo group, p-value 0.42, a non-significant difference. A post-hoc analysis showed length of stay (LOS) was shorter in the intervention group (median 9 days [Interquartile Range (IQR) 4, 12] vs. Placebo group 10 [IQR 6, 16] p-value = 0.033, Wilcoxon Rank Sum test). CONCLUSIONS: This trial does not support the hypothesis that Melatonin reduces the severity of delirium. This may be due to no effect of Melatonin, a smaller effect than anticipated, an effect not captured on a multidimensional delirium assessment scale, or a type II statistical error. Melatonin may improve LOS; this hypothesis should be studied.

Rivastigmine for the management of anticholinergic delirium.

INTRODUCTION: Anticholinergic agents are commonly taken in overdose, often causing delirium. The spectrum of anticholinergic delirium ranges from mild agitation to severe behavioural disturbance. Physostigmine is an effective treatment for anticholinergic delirium, but its availability is limited. As rivastigmine is readily available, it has been used to manage anticholinergic delirium; however, there is limited research investigating its use. METHOD: This was a retrospective review of patients with anticholinergic delirium treated in two toxicology units with rivastigmine (oral capsule or transdermal patch) from January 2019 to June 2023. The primary outcome was the use of further parenteral treatment (sedation or physostigmine) for delirium post rivastigmine administration. RESULTS: Fifty patients were administered rivastigmine for the management of anticholinergic delirium. The median age was 36 years (interquartile range: 25-49 years) and 27 (54 per cent) were females. Features consistent with anticholinergic toxicity included tachycardia in 44 (88 per cent) and urinary retention requiring catheterisation in 40 (80 per cent). Forty-three patients (86 per cent) were treated with physostigmine before rivastigmine administration. Twenty-two were managed with transdermal rivastigmine (most commonly 9.5 mg/24 hour patch), and 28 with oral rivastigmine 6 mg. Further parenteral sedation and/or physostigmine treatment were required more often in patients given transdermal than oral rivastigmine [16/22 (73 per cent) versus 9/28 (32 per cent), P = 0.010)]. No patients had bradycardia or gastrointestinal symptoms following rivastigmine administration. One patient with a history of epilepsy had a seizure, 1.5 hours post physostigmine administration and 7 hours post transdermal rivastigmine. DISCUSSION: Rivastigmine has been increasingly used for the management of patients with anticholinergic delirium, due to the lack of availability of physostigmine. In this case series, rivastigmine transdermal patch appeared to be less effective than oral rivastigmine capsules, likely due to its slow onset of action and/or insufficient dose. CONCLUSION: Rivastigmine can be used to treat anticholinergic delirium. In our case series oral rivastigmine appeared more effective than transdermal rivastigmine.