Low-dose Dexmedetomidine and Postoperative Delirium After Cardiac Surgery

Study Overview
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Brief Summary
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Delirium is an acutely occurred and fluctuating cerebral dysfunction characterized with inattention, altered consciousness, cognitive decline and/or abnormal perception. It is common in the elderly after cardiac surgery and is associated with worse outcomes. Causes leading to delirium are multifactorial but sleep disturbances remains an important one. In previous studies, sedative-dose dexmedetomidine improves sleep quality in ICU patients with mechanical ventilation; and low-dose dexmedetomidine improves sleep quality in postoperative patients without mechanical ventilation. In recent studies of elderly after noncardiac surgery, night-time infusion of low-dose dexmedetomidine reduces delirium and improves 2-year survival. The investigators hypothesize that, for elderly patients after cardiac surgery, night-time infusion of dexmedetomidine may also improve sleep quality, reduce delirium development and improve 2-year survival.

Detailed Description
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Delirium is an acutely occurred and fluctuating cerebral dysfunction characterized with inattention, altered consciousness, cognitive decline and/or abnormal perception. It is common in the elderly after cardiac surgery and is associated with worse outcomes. The development of delirium is a consequence of multiple factors. For patients undergoing cardiac surgery, surgical stress and/or cardiopulmonary bypass can produce hyper-inflammatory and stress response, both of which are important factors leading to delirium. Meanwhile, patients in ICU after major surgery often develop sleep disturbances, which are also associated with increased risk of delirium. Dexmedetomidine is a highly selective α2-adrenoceptor agonist with sedative, analgesic and anxiolytic properties. In previous studies of elderly patients admitted to ICU after non-cardiac surgery, continuous infusion of low-dose dexmedetomidine during nighttime improves sleep quality, reduces delirium, and improves 2-year survival. The investigators hypothesize that, for patients admitted to ICU after cardiac surgery, nighttime infusion of low-dose dexmedetomidine can decrease the incidence of delirium and improve long-term survival. The purpose of this study is to investigate the effect of nighttime infusion of low-dose dexmedetomidine on postoperative sleep quality, delirium, and 2-year survival in elderly patients admitted to ICU after cardiac surgery.

Official Title
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Effect of Low-dose Dexmedetomidine on Postoperative Delirium in Patients After Cardiac Surgery: A Multicenter, Double-blinded, Randomized Controlled Trial

Conditions
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Cardiac Surgery, Cardiopulmonary Bypass, Dexmedetomidine, Delirium, Survival

Intervention / Treatment
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* Drug: Dexmedetomidine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥60 years but <90 years; Scheduled to undergo cardiac surgery with cardiopulmonary bypass under general anesthesia; Expected to stay in the intensive care unit (ICU) for at least 1 night after surgery. Exclusion Criteria: Patients who meet any of the following criteria will be excluded. Refuse to participate in the study; Preoperative history of schizophrenia, epilepsy, Parkinsonism, or myasthenia gravis; Preoperative obstructive sleep apnea (previously diagnosed as obstructive sleep apnea, or the snoring, tiredness, observed apnea, high blood pressure-body mass index, age, neck circumference and gender [STOP-Bang] questionnaires ≥3); Inability to communicate during the preoperative period because of coma, profound dementia or language barrier; Preoperative sick sinus syndrome, severe sinus bradycardia (< 50 beats per minute), or second-degree atrioventricular block or above without pacemaker; Severe hepatic dysfunction (Child-Pugh class C); Severe renal dysfunction (requirement of renal replacement therapy) before surgery; Presence of delirium (diagnosed by the Confusion Assessment Method [CAM]/CAM for the Intensive Care Unit [CAM-ICU]); Current treatment with dexmedetomidine or clonidine.

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dexmedetomidine group<br>Dexmedetomidine infusion is administered from 16:00 to 08:00 during the night of surgery; and will repeated for a maximum of 5 consecutive nights. For patients with mechanical ventilation, the infusion rate is 0.2-0.7 ug/kg/h; for those without mechanical ventilation, the infusion rate is 0.05-0.2 ug/kg/h. The target depth of sedation is Richmond Agitation-Sedation Scale (RASS) -1. | Drug: Dexmedetomidine<br>* Dexmedetomidine infusion is administered from 16:00 to 08:00 during the night of surgery in the intensive care unit; and will repeated for a maximum of 5 consecutive nights. For patients with mechanical ventilation, the infusion rate is 0.2-0.7 ug/kg/h; for those without mechanical ventilation, the infusion rate is 0.05-0.2 ug/kg/h. The target depth of sedation is Richmond Agitation-Sedation Scale (RASS) -1.<br>* Other names: Low-dose dexmedetomidine infusion;|
| Placebo Comparator: Placebo group<br>Placebo (normal saline) infusion is administered from 16:00 to 08:00 in the same speed for the same duration as in the dexmedetomidine group. The conventional sedation is provided when necessary with propofol and/or midazolam by intravenous infusion/injection. The target depth of sedation depth is RASS -1. | Drug: Placebo<br>* Placebo (normal saline) infusion is administered in the same rate for the same duration as in the dexmedetomidine group. The conventional sedation is provided when necessary with propofol and/or midazolam by intravenous infusion/injection. The target depth of sedation depth is RASS -1.<br>* Other names: Normal saline infusion;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of delirium within the first 5 days after surgery | Delirium is assessed twice daily (8:00-10:00 am, 18:00-20:00 pm) with the Confusion Assessment Method (CAM, for patients without mechanical ventilation) or CAM for the intensive care unit (CAM-ICU, for patients with mechanical ventilation) during postoperative days 1-5. | During the first 5 days after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of mechanical ventilation after surgery | Duration of mechanical ventilation after surgery | Up to 30 days after surgery | 
| Length of stay in ICU after surgery | Length of stay in ICU after surgery | Up to 30 days after surgery | 
| Length of stay in hospital after surgery | Length of stay in hospital after surgery | Up to 30 days after surgery | 
| Incidence of Major Adverse Cardiovascular Events (MACEs) within 30 days after surgery | Postoperative Major Adverse Cardiac Events (MACEs) include in-hospital death, myocardial infarction, second surgery, non-fetal cardiac arrest/ventricular fibrillation, and stroke. The occurrence of major postoperative events is followed up twice daily during postoperative days 1-5, then once a week until 30 days after surgery. | Up to 30 days after surgery | 
| Incidence of other complications | Incidence of other complications (including hospital re-admission) within 30 days after surgery. | Up to 30 days after surgery | 
| All-cause 30-day mortality | All-cause mortality within 30 days after surgery | At 30 days after surgery | 
| Subjective sleep quality at 30 days after surgery | Subjective sleep quality at 30 days after surgery is assessed with Pittsburgh sleep quality index (PSQI) | At 30 days after surgery | 
| 2 -year Major Adverse Cardiac and Cerebrovascular Events (MACCEs)-free survival after surgery | Major Adverse Cardiac and Cerebrovascular Events (MACCEs) include cardiac death, myocardial infarction, revascularization, and stroke. | Up to 2 years after surgery | 
| 2-year overall survival after surgery | 2-year survival overall after surgery | Up to 2 years after surgery | 
| Cognitive function in 1- and 2-year survivors | Cognitive function in 1- and 2-year survivors is assessed with the modified Telephone Interview for Cognitive Status (TICS-m, score ranges from 0 to 40, with higher score indicating better function). | At the end of the 1st and 2nd years after surgery | 
| Quality of life in 1- and 2- year survivors | Quality of life in 1- and 2-year survivors is assessed with the 36-Item Short Form Health Survey (SF-36). The SF-36 evaluates 8 different domains of quality of life, i.e., physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. The score of each domain ranges from 0 to 100, with high score indicating better function. | At the end of the 1st and 2nd years after surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiac Surgery, Cardiopulmonary Bypass, Dexmedetomidine, Delirium, Survival