A Lithium-Based Medication to Improve Neurological Outcomes After Surgical Carotid Reconstruction

Study Overview
=================
Brief Summary
-----------------
There are 10.3 million cases of stroke registered in the world every year; 63% of them lead to death. According to World Health Organization, stroke is one of the most important risk factors of death and early disability. Carotid artery surgery is a gold standard of hemodynamically significant carotid artery disease treatment. According to some trials, carotid artery surgery decreases the 2-years mortality. The most important part of carotid artery surgery is a temporary absence of blood flow in the carotid artery. The duration of this period is a crucial characteristic of this type of surgery. The absence of blood flow leads to brain ischemia which is the risk factor of postoperative neurocognitive disorders such as emergence delirium, postoperative delirium and postoperative cognitive dysfunction. Some surgical and non-surgical methods for brain protection were evaluated. According to recent data, there is no evidence of effective pharmacological protective methods that can decrease brain damage during carotid artery surgery. Nevertheless, some trials demonstrated that using lithium-based medications for patients with a stroke can reduce the volume of the stroke. Therefore, the investigators want to check the hypothesis that using lithium-based medication in the preoperative period can reduce brain damage during carotid artery surgery. The objectives of this trial: To determine if Lithium carbonate is superior to placebo for the occurrence of emergence delirium, agitation, postoperative delirium and postoperative cognitive dysfunction. To determine if Lithium carbonate is non-inferior to placebo for the occurrence of a new arrhythmia, leukocytosis, acute kidney injury, seizure disorders, diarrhea, nausea, and vomit.

Detailed Description
-----------------
There are 10.3 million cases of stroke registered in the world every year; 63% of them lead to death. According to World Health Organization, stroke is one of the most important risk factors of death and early disability. Carotid artery surgery is a gold standard of hemodynamically significant carotid artery disease treatment. According to some trials, carotid artery surgery decreases the 2-years mortality. The most important part of carotid artery surgery is a temporary absence of blood flow in the carotid artery. The duration of this period is a crucial characteristic of this type of surgery. The absence of blood flow leads to brain ischemia which is the risk factor of postoperative neurocognitive disorders such as emergence delirium, postoperative delirium and postoperative cognitive dysfunction. Some surgical and non-surgical methods for brain protection were evaluated. According to recent data, there is no evidence of effective pharmacological protective methods that can decrease brain damage during carotid artery surgery. Nevertheless, some trials demonstrated that using lithium-based medications for patients with a stroke can reduce the volume of the stroke. Therefore, the investigators want to check the hypothesis that using lithium-based medication in the preoperative period can reduce brain damage during carotid artery surgery. The objectives of this trial: To determine if Lithium carbonate is superior to placebo for the occurrence of emergence delirium, agitation, postoperative delirium and postoperative cognitive dysfunction. To determine if Lithium carbonate is non-inferior to placebo for the occurrence of a new arrhythmia, leukocytosis, acute kidney injury, seizure disorders, diarrhea, nausea, and vomit.

Official Title
-----------------
A Lithium-Based Medication to Improve Neurological Outcomes After Surgical Carotid Reconstruction: A Double-Blind, Placebo Control Randomized Trial (BINOS)

Conditions
-----------------
Carotid Artery Diseases, Carotid Artery Stenosis

Intervention / Treatment
-----------------
* Drug: Lithium Carbonate
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: age > 18 years elective carotid artery surgery general anesthesia written informed consent Exclusion Criteria: urgent surgery recent ( < 1 month) overt stroke Mini-mental State Examination < 20 points The presence of any mental disorder according to the International Classification of Diseases 11th Revision which is confirmed by a psychiatrist. The presence of any neuromuscular disease according to the International Classification of Diseases 11th Revision Hypersensitivity or known allergy to lithium carbonate History of seizure disorder History of leukemia Estimated glomerular filtration rate < 30 ml/min/1.73 m2 Left ventricular ejection fraction < 30% Heart failure equal 3 or 4 class according to the New York Heart Association Functional Classification Pregnant or breast-feeding women Inability to undergo a preoperative assessment for any reason Previously enrolled in this trial

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

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

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lithium<br>In preoperative period patients will take 300mg of lithium carbonate on 1-1-1 regimen during 2 days prior to surgery. On the day of surgery, they will take 300mg of lithium carbonate 2 hours before surgery. After the surgery, patients will take 300mg of lithium carbonate in the afternoon and 300mg of lithium carbonate in the evening. | Drug: Lithium Carbonate<br>* In preoperative period patients will take 300 mg of lithium carbonate on 1-1-1 regimen during 2 days prior to surgery. On the day of surgery they will take 300mg of lithium carbonate 2 hours before surgery.<br>|
| Placebo Comparator: Placebo<br>In preoperative period patients will take placebo on 1-1-1 regimen during 2 days prior to surgery. On the day of surgery, they will take placebo 2 hours before surgery. After the surgery, patients will take placebo in the afternoon and in the evening. | Drug: Placebo<br>* In preoperative period patients will take placebo on 1-1-1 regimen during 2 days prior to surgery. On the day of surgery they will placebo 2 hours before surgery.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of emergence delirium | Number of patients with positive the confusion assessment method for the intensive care unit as soon as they reach Aldrete score of 9 points | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of agitation | Richmond agitation-sedation scale more or equal +2 evaluated from the end of volatile anesthetic supply to the moment when a patient reaches Aldrete score of 9 points Richmond agitation-sedation scale: minimum value = -5 (Unarousable - no response to voice or physical stimulation) maximum value = +4 (Combative - overtly combative or violent; immediate danger to staff) Adequate patients have the results of Richmond agitation-sedation score equal 0 (Alert and calm; Spontaneously pays attention to caregiver) | 30 days | 
| Frequency of postoperative delirium | Number of patients with even one positive confusion assessment method for the intensive care unit or 3-minute confusion assessment method | 30 days | 
| Length of postoperative delirium | 30 days - number of days in which patient had positive confusion assessment method for the intensive care unit or 3-minute confusion assessment method | until 1 month after surgery | 
| Frequency of overt strokes | Number of overt strokes | 1 year | 
| Frequency of covert strokes | Number of covert strokes | 1 year | 
| Length of stay in intensive care unit | Number of days in intensive care unit | 1 month | 
| Length of hospitalization | Number of days in hospital | 1 month | 
| Frequency of cardiac death | Number of of cardiac deaths | 1 year | 
| Frequency of non-fatal cardiac arrest | Number of non-fatal cardiac arrests | 1 year | 
| Frequency of major adverse cardiac event | Number of major adverse cardiac events | 1 year | 
| Frequency of major adverse cardiac and cognitive event | Number of major adverse cardiac and cognitive events | 1 year | 
| 30-days mortality | Number of deaths in period of 30 days after surgery | 30 days | 
| 1-year mortality | Number of deaths in period of 1 year after surgery | 1 year | 
| Frequency of new postoperative arrhythmia | Number of new postoperative arrhythmias | 1 month | 
| Frequency of leukocytosis | Number of patients with leukocytosis | From 2 days before surgery to the day of surgery | 
| Frequency of acute diarrhea | Number of patients with acute diarrhea | From 2 days before surgery to the day of surgery | 
| Frequency of postoperative nausea and vomit | Number of patients with postoperative nausea and vomit | 1 month | 
| Frequency of preoperative nausea and vomit | Number of patients with preoperative nausea and vomit | From 2 days before surgery to the day of surgery | 
| Frequency of acute kidney injury | Number of patients with acute kidney injury | 1 month | 
| Frequency of myasthenia | Number of patients with myasthenia | From 2 days before surgery to the day of surgery | 
| Frequency of preoperative seizure | Number of patients with seizure | From 2 days before surgery to the day of surgery | 
| Frequency of postoperative seizure | Number of patients with seizure | 1 month | 
| Serum level of S100 beta protein | Serum level of S100 beta protein | 2 days after surgery | 
| Serum level of neuron-specific enolase | Serum level of neuron-specific enolase | 2 days after surgery | 
| Serum level of Tau-protein | Serum level of Tau-protein | 2 days after surgery | 
| Serum level of Neurofilament light polypeptide | Serum level of Neurofilament light polypeptide | 2 days after surgery | 
| Serum level of Glial fibrillary acidic protein | Serum level of Glial fibrillary acidic protein | 2 days after surgery | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Carotid artery diseases, Carotid artery stenosis, Carotid artery surgery, Lithium, Neurocognitive disorders, Postoperative cognitive disorders, Postoperative delirium, Emergence delirium, Agitation, Stroke, Neuroinflammation