Delirium Reduction by Volatile Anesthesia in Cardiac Surgery

Study Overview
=================
Brief Summary
-----------------
Parallel group, prospective, randomized, controlled, single-blinded trial. The aim of our study is to test the hypothesis that volatile anesthesia would reduce the incidence of early postoperative delirium in patients undergoing cardiac surgery with CPB as compared to TIVA.

Detailed Description
-----------------
Delirium is a common neurologic complication after cardiac surgery. Up to 52% of postoperative cardiac surgery patients have delirium. The occurrence of postoperative delirium is associated with worse outcomes, including prolonged length of stay in the ICU and hospital, increased morbidity and mortality, compromised long-term cognitive function and physical ability, and elevated medical care costs. Morbidity of postoperative cognitive dysfunction and delirium mostly common in patients with age more than 60 years. Several factors including cerebral anoxia, embolism, excessive excitatory neurotransmitter release, systemic inflammatory response, electrolyte and metabolic disorders and hemodynamic changes have been demonstrated to contribute to postoperative neurological dysfunction and delirium. Previous studies have shown that inhalation anaesthesia and total intravenous anaesthesia (TIVA) may produce different degrees of cerebral protection in these patients. Effects of this two types of anaesthesia in cardiac surgery with CPB remain controversial and much debated. Inhalation agents depress glucose metabolism, decrease cerebral metabolic rate and oxygen consumption. They also partially uncouple the reactivity of cerebral blood flow to CO2. The changes in cerebral blood flow (CBF) depend on the changes in cerebral metabolism and on direct vasodilatory effects. Cerebral autoregulation is dose-dependently altered. Volatile anaesthetics have been shown to initiate early ischemic preconditioning in neurons, but models of focal brain ischemia suggest it can take 24 h for preconditioning to develop fully. Propofol is a well-known potentiator of GABAA receptors, it reduces cerebrovascular resistance, CBF and cerebral oxygen delivery during cardiopulmonary bypass. A neuroprotective effect of propofol has been shown to be present in many in vitro and in vivo established experimental models of mild/moderate acute cerebral ischemia. In recent meta-analysis of 13 randomized controlled studies Chen et al compared the neuroprotective effects of inhalational anesthesia and those of total intravenous anesthesia (TIVA) in cardiac surgery with cardiopulmonary bypass. They have shown that anesthesia with volatile agents appeared to provide better cerebral protection than TIVA. As this meta-analysis had several limitations (small sample size of included studies, high heterogenity, etc.), further studies with larger clinically relevant sample-sizes are needed to demonstrate which anesthetics are more beneficial in terms of brain protection in cardiac surgery.

Official Title
-----------------
Delirium Reduction by Volatile Anesthesia in Cardiac Surgery: Prospective, Randomized, Single-blinded Study

Conditions
-----------------
Delirium

Intervention / Treatment
-----------------
* Drug: Volatile agent
* Drug: Propofol


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males and females > 65 years Written informed consent Cardiac surgery with CPB Exclusion Criteria: Emergency surgery Surgery on aorta Known allergy to components of anaesthesia Pregnancy Hemodynamically significant stenosis of carotid arteries Parkinson's disease Liver cirrhosis (Child B or C) Current enrollment into another RCT (in the last 30 days) Previous enrollment and randomization into the DELICATE trial Poor language comprehension Preoperative Medications: Anticholinergics (dimedrol, atropine, dramina), antidepressants, antiepileptics, antiparkinson drugs, chemotherapeutic agents

Ages Eligible for Study
-----------------
Minimum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomly allocated to receive either inhalation anaesthesia or TIVA. Permuted-block randomization will be used to allocate subjects to one of the study groups. Sequentially numbered sealed opaque envelopes will contain the treatment code, to be opened in the morning of surgery. Patients will be unaware of group assignment. All the statistical analyses will be performed by the biostatistician not involved in treatment allocation.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Volatile anesthesia group<br> | Drug: Volatile agent<br>* Patients will receive volatile agent to provide general anaesthesia, including CPB period. Volatile agents will be administered from anesthesia induction to the end of surgery. Concentration (MAC) of volatile agent will be selected by anaesthesiologist according to clinical situation and patient features.<br>* Other names: Isoflurane;|
| Active Comparator: TIVA group<br> | Drug: Propofol<br>* Patients will receive propofol and no volatile agent. Propofol will be used for induction and maintenance of anesthesia.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postoperative delirium | Postoperative delirium detection will be managed with Confusion Assessment Method for the ICU (CAM-ICU) | 5 days after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early postoperative cognitive dysfunction | We will use Montreal Cognitive Assessment (MoCA) to detect cognitive dysfunction | 7 days after surgery | 
| Delirium duration | number of days | 10 days after surgery | 
| Duration of ICU stay | number of days | 30 days | 
| Duration of hospital stay | number of days | 60 days | 
| 30-day all-cause mortality | yes/no | 30 days | 
| One-year all-cause mortality | yes/no | 1 year | 
| Myocardial infarction (MI) | yes/no | 30 days | 
| Stroke | Stroke will be diagnosed by neurologist (yes/no) | 30 days | 
| Seizures | Presence of Seizures (yes/no) | 30 days | 
| Incidence of acute kidney injury (AKI) | According to KDIGO criteria | 30 days | 
| Renal replacement therapy | We will collect data about need of renal replacement therapy (yes/no) | 30 days | 
| Infectious complications | We will collect data about infectious complications: wound infection, mediastinitis, pneumonia, positive blood culture | 30 days | 
| Pain assessment with Behavioral Pain Scale (BPS) | The BPS is an observational pain scale. It has been validated for use in deeply sedated, mechanically ventilated patients. The BPS contains 3 subscales: facial expression, upper limb movements, and compliance with mechanical ventilation. Each subscale is scored from 1 (no response) to 4 (full response). Therefore, BPS scores range from 3 (no pain) to 12 (maximal pain). A BPS score of 6 or higher is considered to reflect unacceptable pain. | 5 days after surgery | 
| Pain assessment with Numerical Rating Scale (NRS) | A NRS involves asking the patient to rate his or her pain from 0 to 10 (11 point scale) or from 0 to 100 (101 point scale) with the understanding that 0 is equal to no pain and 10 or 100 is equal to worst possible pain. | 5 days after surgery | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
delirium, Cardiac surgery, Cardiopulmonary bypass, Cognitive dysfunction