Minimizing ICU Neurological Dysfunction with Dexmedetomidine-induced Sleep (MINDDS): protocol for a randomised, double-blind, parallel-arm, placebo-controlled trial.

Delirium, which is prevalent in postcardiac surgical patients, is an acute brain dysfunction characterised by disturbances in attention, awareness and cognition not explained by a pre-existing neurocognitive disorder. The pathophysiology of delirium remains poorly understood. However, basic science and clinical studies suggest that sleep disturbance may be a modifiable risk factor for the development of delirium. Dexmedetomidine is a α-2A adrenergic receptor agonist medication that patterns the activity of various arousal nuclei similar to sleep. A single night-time loading dose of dexmedetomidine promotes non-rapid eye movement sleep stages N2 and N3 sleep. This trial hypothesises dexmedetomidine-induced sleep as pre-emptive therapy for postoperative delirium. The MINDDS (Minimizing ICU Neurological Dysfunction with Dexmedetomidine-induced Sleep) trial is a 370-patient block-randomised, placebo-controlled, double-blinded, single-site, parallel-arm superiority trial. Patients over 60 years old, undergoing cardiac surgery with planned cardiopulmonary bypass, will be randomised to receive a sleep-inducing dose of dexmedetomidine or placebo. The primary outcome is the incidence of delirium on postoperative day 1, assessed with the Confusion Assessment Method by staff blinded to the treatment assignment. To ensure that the study is appropriately powered for the primary outcome measure, patients will be recruited and randomised into the study until 370 patients receive the study intervention on postoperative day 0. Secondary outcomes will be evaluated by in-person assessments and medical record review for in-hospital end points, and by telephone interview for 30-day, 90-day and 180-day end points. All trial outcomes will be evaluated using an intention-to-treat analysis plan. Hypothesis testing will be performed using a two-sided significance level (type I error) of α=0.05. Sensitivity analyses using the actual treatment received will be performed and compared with the intention-to-treat analysis results. Additional sensitivity analyses will assess the potential impact of missing data due to loss of follow-up. The Partners Human Research Committee approved the MINDDS trial. Recruitment began in March 2017. Dissemination plans include presentations at scientific conferences, scientific publications and popular media. NCT02856594.

Shelton KT ，Qu J ，Bilotta F ，Brown EN ，Cudemus G ，D'Alessandro DA ，Deng H ，DiBiasio A ，Gitlin JA ，Hahm EY ，Hobbs LE ，Houle TT ，Ibala R ，Loggia ML ，Pavone KJ ，Shaefi S ，Tolis G ，Westover MB ，Akeju O ... -  《BMJ Open》

Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial.

Delirium is a postoperative complication that occurs frequently in patients older than 65 years, and presages adverse outcomes. We investigated whether prophylactic low-dose dexmedetomidine, a highly selective α2 adrenoceptor agonist, could safely decrease the incidence of delirium in elderly patients after non-cardiac surgery. We did this randomised, double-blind, placebo-controlled trial in two tertiary-care hospitals in Beijing, China. We enrolled patients aged 65 years or older, who were admitted to intensive care units after non-cardiac surgery, with informed consent. We used a computer-generated randomisation sequence (in a 1:1 ratio) to randomly assign patients to receive either intravenous dexmedetomidine (0·1 μg/kg per h, from intensive care unit admission on the day of surgery until 0800 h on postoperative day 1), or placebo (intravenous normal saline). Participants, care providers, and investigators were all masked to group assignment. The primary endpoint was the incidence of delirium, assessed twice daily with the Confusion Assessment Method for intensive care units during the first 7 postoperative days. Analyses were done by intention-to-treat and safety populations. This study is registered with Chinese Clinical Trial Registry, www.chictr.org.cn, number ChiCTR-TRC-10000802. Between Aug 17, 2011, and Nov 20, 2013, of 2016 patients assessed, 700 were randomly assigned to receive either placebo (n=350) or dexmedetomidine (n=350). The incidence of postoperative delirium was significantly lower in the dexmedetomidine group (32 [9%] of 350 patients) than in the placebo group (79 [23%] of 350 patients; odds ratio [OR] 0·35, 95% CI 0·22-0·54; p<0·0001). Regarding safety, the incidence of hypertension was higher with placebo (62 [18%] of 350 patients) than with dexmedetomidine (34 [10%] of 350 patients; 0·50, 0·32-0·78; p=0·002). Tachycardia was also higher in patients given placebo (48 [14%] of 350 patients) than in patients given dexmedetomidine (23 [7%] of 350 patients; 0·44, 0·26-0·75; p=0·002). Occurrence of hypotension and bradycardia did not differ between groups. For patients aged over 65 years who are admitted to the intensive care unit after non-cardiac surgery, prophylactic low-dose dexmedetomidine significantly decreases the occurrence of delirium during the first 7 days after surgery. The therapy is safe. Braun Anaesthesia Scientific Research Fund and Wu Jieping Medical Foundation, Beijing, China. Study drugs were manufactured and supplied by Jiangsu Hengrui Medicine Co, Ltd, Jiangsu, China.

Su X ，Meng ZT ，Wu XH ，Cui F ，Li HL ，Wang DX ，Zhu X ，Zhu SN ，Maze M ，Ma D ... -  《-》

Dexmedetomidine and intravenous acetaminophen for the prevention of postoperative delirium following cardiac surgery (DEXACET trial): protocol for a prospective randomized controlled trial.

Shankar P ，Mueller A ，Packiasabapathy S ，Gasangwa D ，Patxot M ，O'Gara B ，Shaefi S ，Marcantonio ER ，Subramaniam B ... -  《Trials》

Alpha-2-adrenergic receptor agonists for the prevention of delirium and cognitive decline after open heart surgery (ALPHA2PREVENT): protocol for a multicentre randomised controlled trial.

Postoperative delirium is common in older cardiac surgery patients and associated with negative short-term and long-term outcomes. The alpha-2-adrenergic receptor agonist dexmedetomidine shows promise as prophylaxis and treatment for delirium in intensive care units (ICU) and postoperative settings. Clonidine has similar pharmacological properties and can be administered both parenterally and orally. We aim to study whether repurposing of clonidine can represent a novel treatment option for delirium, and the possible effects of dexmedetomidine and clonidine on long-term cognitive trajectories, motor activity patterns and biomarkers of neuronal injury, and whether these effects are associated with frailty status. This five-centre, double-blind randomised controlled trial will include 900 cardiac surgery patients aged 70+ years. Participants will be randomised 1:1:1 to dexmedetomidine or clonidine or placebo. The study drug will be given as a continuous intravenous infusion from the start of cardiopulmonary bypass, at a rate of 0.4 µg/kg/hour. The infusion rate will be decreased to 0.2 µg/kg/hour postoperatively and be continued until discharge from the ICU or 24 hours postoperatively, whichever happens first.Primary end point is the 7-day cumulative incidence of postoperative delirium (Diagnostic and Statistical Manual of Mental Disorders, fifth edition). Secondary end points include the composite end point of coma, delirium or death, in addition to delirium severity and motor activity patterns, levels of circulating biomarkers of neuronal injury, cognitive function and frailty status 1 and 6 months after surgery. This trial is approved by the Regional Committee for Ethics in Medical Research in Norway (South-East Norway) and by the Norwegian Medicines Agency. Dissemination plans include publication in peer-reviewed medical journals and presentation at scientific meetings. NCT05029050.

Neerland BE ，Busund R ，Haaverstad R ，Helbostad JL ，Landsverk SA ，Martinaityte I ，Norum HM ，Ræder J ，Selbaek G ，Simpson MR ，Skaar E ，Skjærvold NK ，Skovlund E ，Slooter AJ ，Svendsen ØS ，Tønnessen T ，Wahba A ，Zetterberg H ，Wyller TB ... -  《BMJ Open》

Dexmedetomidine for the prevention of postoperative delirium in patients after intracranial operation for brain tumours (DEPOD study): a study protocol and statistical plan for a multicentre randomised controlled trial.

Postoperative delirium (POD) is prevalent in patients after major surgery and is associated with adverse outcomes. Several studies have reported that dexmedetomidine, a highly selective α2-adrenergic receptor agonist, can decrease the incidence of POD. However, neurosurgical patients are usually excluded from previous studies. The present study was designed to investigate the impact of prophylactic use of low-dose dexmedetomidine on the incidence of POD in patients after intracranial operation. This is a multicentre, randomised, double-blinded and placebo-controlled trial. Seven hundred intensive care unit admitted patients after elective intracranial operation for brain tumours under general anaesthesia are randomly assigned to the dexmedetomidine group or the placebo group with a 1:1 ratio. For patients in the dexmedetomidine group, a continuous infusion of dexmedetomidine will be started at a rate of 0.1 μg/kg/hour immediately after enrolment on the day of operation and continued until 08:00 on postoperative day 1. For patients in the placebo group, normal saline will be administered at the same rate as in the dexmedetomidine group. The patients will be followed up for 28 days after enrolment. The primary endpoint is the incidence of POD, which is assessed two times per day using the Confusion Assessment Method for the intensive care unit (ICU), during the first 5 postoperative days. The secondary endpoints include the incidence of dexmedetomidine-related adverse events and non-delirium complications, the length of stay in the ICU and hospital and all-cause 28-day mortality after the operation. The study protocol was approved by the Institutional Review Board of Beijing Tiantan Hospital Affiliated to Capital Medical University (No KY2019-091-02) and registered at ClinicalTrials.gov. The results of the trial will be presented at national and international conferences relevant to subject fields and submitted to international peer-reviewed journals. Trial registration number: NCT04399343; Pre-results.

He X ，Cheng KM ，Zhang L ，Gu H ，Qu X ，Xu Y ，Ma P ，Zhou JX ... -  《BMJ Open》