Compatible Effect of Remimazolam Besylate Combined With Afentanil for ATI

Study Overview
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Brief Summary
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To study the pharmacokinetics between remimazolam besylate and alfentanil; To determine the optimal dosage of the two drugs in awake endotracheal intubation; To provide clinical guidance for awake endotracheal intubation.

Detailed Description
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Tracheal intubation is the most effective and reliable method to establish artificial airway, which provides the best conditions for relieving airway obstruction, ensuring airway patency, removing respiratory secretions, preventing aspiration, assisting or controlling breathing, etc. Difficult airway management strategies must be adopted when patients are predicted to have difficulties in mask ventilation, supraglottic airway device (SAD) placement, or endotracheal intubation and front-of-neck airway (FONA) establishment. Awake tracheal intubation (ATI) is one of the important methods. ATI refers to tracheal intubation while the patient is awake and breathing spontaneously, most commonly by flexible bronchoscopy (FB) or video laryngoscopy (VL), which allows for airway control prior to induction of general anesthesia. Thus, the potential risks and consequences of difficulty in establishing the airway after anesthesia induction are avoided. The safety of ATI is reflected in the guarantee of spontaneous breathing and intrinsic airway tension of patients before tracheal tube insertion. The failure rate of ATI is only 1-2%, and it rarely requires airway first aid or causes patient death. ATI is currently the safest technique for dealing with difficult airways, but it accounts for only 0.2% of all tracheal intubation types in the UK. The reason is that ATI operators may be under great physical, mental, and psychological stress, which may lead to poor performance and increase the risk of complications, including failure. In addition, mechanical stimulation of the airway in the awake state can cause coughing, nausea, restlessness and other reactions to tracheal intubation, resulting in adverse consequences. Therefore, before the effective implementation of ATI, anesthesiologists often choose to combine small doses of analgesic and sedative drugs to achieve the minimum degree of sedation effect, so as to reduce the anxiety and discomfort of patients and improve the tolerance of patients. Studies have shown that drugs such as fentanyl, remifentanil, midazolam, propofol and dexmedetomidine can be used to assist ATI to improve patient satisfaction and reduce the risk of excessive sedation and airway obstruction. However, these drugs have different degrees of cardiovascular or respiratory adverse reactions, especially when used in large doses, which increases the risk of hypoxemia, hypotension or bradycardia. ATI guidelines suggest that excessive sedation is very dangerous for some patients, and it is recommended to use it with caution, and a minimum degree of reversible sedation is preferred. Therefore, how to ensure good sedation and analgesia and maintain normal spontaneous breathing is worthy of further study. Remimazolam besylate is a new type of benzodiazepine, which is an ultra-short-acting sedative/anesthetic drug. The mechanism is that by binding to benzodiazepine receptors, it specifically acts on GABAA receptors, enhances GABAA receptor activity, and selectively promotes extracellular chloride ions into cells, leading to hyperpolarization of cell membrane resting potential and decreased excitability, thus inhibiting neuronal electrical activity and producing sedative effect. And this effect can be specifically antagonized by flumazenil. As an important member of opioid receptor agonist, 30s of alfentanil exerts its drug effect, and its safety is far better than that of morphine. Alfentanil does not cause severe respiratory depression in the therapeutic dose range, and can reduce the use of sedative drugs when used in combination. In gastrointestinal endoscopy, hysteroscopy, fiberoptic bronchoscopy and other procedures with spontaneous breathing, alfentanil alone or in combination with benzodiazepines shows mild respiratory depression and high safety. The purpose of this study is to study the pharmacokinetics between remimazolam besylate and alfentanil hydrochloride by response surface analysis, to determine the standard drug concentration under spontaneous breathing, and to observe the clinical effect of awake tracheal intubation under this concentration dose, to explore the best compatible dose range of the two drugs, in order to provide a reference for clinical application in patients with difficult airway.

Official Title
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Compatible Dose Study and Effect Observation of Remimazolam Besylate Combined With Afentanil for Awake Endotracheal Intubation

Conditions
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Remimazolam, Awake Endotracheal Intubation

Intervention / Treatment
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* Drug: Dos of Afentanil 20
* Drug: Dos of Afentanil 30
* Drug: Dos of Afentanil 40
* Drug: Dos of Afentanil 50
* Drug: Dos of Afentanil 60
* Drug: Dos of Afentanil 70
* Drug: Dos of Afentanil 80
* Drug: Dos of Afentanil 90
* Drug: Dos of Afentanil 100


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: no predictable difficult airway, Mallampati grade Ⅰ-II; deviation from ideal body weight ≤25%; [Ideal weight (kg) = height (cm) -100 (male) or 105 (female)] American Society of Anesthesiologists grade Ⅰ-II; Informed consent: voluntarily participate in the trial and sign the informed consent. Exclusion Criteria: patients with head and neck lesions (including malignant tumors, previous surgery or radiotherapy), limited mouth opening, limited neck extension, obstructive sleep apnea, morbid obesity, and progressive airway injury; Relative contraindications: patients with respiratory diseases, allergy to local anesthetics, airway bleeding, and non-cooperation; patients known to be allergic to remimazolam besylate or benzodiazepines; patients with known allergy to alfentanil or opioids; body weight exceeding ±25% of ideal body weight; patients with coagulation dysfunction, endocrine diseases or other hemodynamic conditions; patients with a history of drug or alcohol dependence; Subjects who were deemed unsuitable for the study by the investigators.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: crisscross
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dos of R 0.1<br>The dosage of Remimazolam Besylate is 0.1 mg/kg | Drug: Dos of Afentanil 50<br>* the dosage of Afentanil is 50 ng/ml for TCI<br>* Other names: Afentanil 50;Drug: Dos of Afentanil 60<br>* the dosage of Afentanil is 60 ng/ml for TCI<br>* Other names: Afentanil 60;Drug: Dos of Afentanil 70<br>* the dosage of Afentanil is 70 ng/ml for TCI<br>* Other names: Afentanil 70;Drug: Dos of Afentanil 80<br>* the dosage of Afentanil is 80 ng/ml for TCI<br>* Other names: Afentanil 80;Drug: Dos of Afentanil 90<br>* the dosage of Afentanil is 90 ng/ml for TCI<br>* Other names: Afentanil 90;Drug: Dos of Afentanil 100<br>* the dosage of Afentanil is 100 ng/ml for TCI<br>* Other names: Afentanil 100;|
| Experimental: Dos of R 0.15<br>The dosage of Remimazolam Besylate is 0.15 mg/kg | Drug: Dos of Afentanil 40<br>* the dosage of Afentanil is 40 ng/ml for TCI<br>* Other names: Afentanil 40;Drug: Dos of Afentanil 50<br>* the dosage of Afentanil is 50 ng/ml for TCI<br>* Other names: Afentanil 50;Drug: Dos of Afentanil 60<br>* the dosage of Afentanil is 60 ng/ml for TCI<br>* Other names: Afentanil 60;Drug: Dos of Afentanil 70<br>* the dosage of Afentanil is 70 ng/ml for TCI<br>* Other names: Afentanil 70;Drug: Dos of Afentanil 80<br>* the dosage of Afentanil is 80 ng/ml for TCI<br>* Other names: Afentanil 80;Drug: Dos of Afentanil 90<br>* the dosage of Afentanil is 90 ng/ml for TCI<br>* Other names: Afentanil 90;|
| Experimental: Dos of R 0.2<br>The dosage of Remimazolam Besylate is 0.2 mg/kg | Drug: Dos of Afentanil 30<br>* the dosage of Afentanil is 30 ng/ml for TCI<br>* Other names: Afentanil 30;Drug: Dos of Afentanil 40<br>* the dosage of Afentanil is 40 ng/ml for TCI<br>* Other names: Afentanil 40;Drug: Dos of Afentanil 50<br>* the dosage of Afentanil is 50 ng/ml for TCI<br>* Other names: Afentanil 50;Drug: Dos of Afentanil 60<br>* the dosage of Afentanil is 60 ng/ml for TCI<br>* Other names: Afentanil 60;Drug: Dos of Afentanil 70<br>* the dosage of Afentanil is 70 ng/ml for TCI<br>* Other names: Afentanil 70;Drug: Dos of Afentanil 80<br>* the dosage of Afentanil is 80 ng/ml for TCI<br>* Other names: Afentanil 80;|
| Experimental: Dos of R 0.25<br>The dosage of Remimazolam Besylate is 0.25 mg/kg | Drug: Dos of Afentanil 30<br>* the dosage of Afentanil is 30 ng/ml for TCI<br>* Other names: Afentanil 30;Drug: Dos of Afentanil 40<br>* the dosage of Afentanil is 40 ng/ml for TCI<br>* Other names: Afentanil 40;Drug: Dos of Afentanil 50<br>* the dosage of Afentanil is 50 ng/ml for TCI<br>* Other names: Afentanil 50;Drug: Dos of Afentanil 60<br>* the dosage of Afentanil is 60 ng/ml for TCI<br>* Other names: Afentanil 60;Drug: Dos of Afentanil 70<br>* the dosage of Afentanil is 70 ng/ml for TCI<br>* Other names: Afentanil 70;Drug: Dos of Afentanil 80<br>* the dosage of Afentanil is 80 ng/ml for TCI<br>* Other names: Afentanil 80;|
| Experimental: Dos of R 0.3<br>The dosage of Remimazolam Besylate is 0.3 mg/kg | Drug: Dos of Afentanil 20<br>* the dosage of Afentanil is 20 ng/ml for TCI<br>* Other names: Afentanil 20;Drug: Dos of Afentanil 30<br>* the dosage of Afentanil is 30 ng/ml for TCI<br>* Other names: Afentanil 30;Drug: Dos of Afentanil 40<br>* the dosage of Afentanil is 40 ng/ml for TCI<br>* Other names: Afentanil 40;Drug: Dos of Afentanil 50<br>* the dosage of Afentanil is 50 ng/ml for TCI<br>* Other names: Afentanil 50;Drug: Dos of Afentanil 60<br>* the dosage of Afentanil is 60 ng/ml for TCI<br>* Other names: Afentanil 60;Drug: Dos of Afentanil 70<br>* the dosage of Afentanil is 70 ng/ml for TCI<br>* Other names: Afentanil 70;|
| Experimental: Dos of R 0.35<br>The dosage of Remimazolam Besylate is 0.25 mg/kg | Drug: Dos of Afentanil 20<br>* the dosage of Afentanil is 20 ng/ml for TCI<br>* Other names: Afentanil 20;Drug: Dos of Afentanil 30<br>* the dosage of Afentanil is 30 ng/ml for TCI<br>* Other names: Afentanil 30;Drug: Dos of Afentanil 40<br>* the dosage of Afentanil is 40 ng/ml for TCI<br>* Other names: Afentanil 40;Drug: Dos of Afentanil 50<br>* the dosage of Afentanil is 50 ng/ml for TCI<br>* Other names: Afentanil 50;Drug: Dos of Afentanil 60<br>* the dosage of Afentanil is 60 ng/ml for TCI<br>* Other names: Afentanil 60;Drug: Dos of Afentanil 70<br>* the dosage of Afentanil is 70 ng/ml for TCI<br>* Other names: Afentanil 70;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Respiratory Rate | RR≤8bpm means respiratory rate decreased after the use of Remimazolam Besylate and Afentanil. | During surgery | 
| Tidal volume | Vt≤5ml/kg means tidal volume decreased after the use of Remimazolam Besylate and Afentanil. | During surgery | 
| Deep breathing | Breathing hard and deep, and then PetCO2≥55mmHg mean deep breathing after the use of Remimazolam Besylate and Afentanil. | During surgery | 
| Airway obstruction | Difficulty in ventilation means airway obstruction after the use of Remimazolam Besylate and Afentanil. | During surgery | 
| Oxygen saturation decreased | SpO2≤94% means oxyfen saturation decreased after the use of Remimazolam Besylate and Afentanil. | During surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Airway status | Airway status evaluation during intubation | During surgery | 
| Intubation response | Body movement response during intubation | During surgery | 
| RASS score | Rass score evaluation during anesthesia induction (+4: Combative; +3: Very agitated; +2: Agitated; +1: Restless; 0: Alert and Calm; -1: Drowsy; -2: Light Sedation; -3: Moderate Sedation; -3: Moderate Sedation; -4: Deep Sedation; -5: Unarousable) | During surgery | 
| Hemodynamic assessments | Mean arterial blood pressure (MAP) ≤50mmHg or heart rate (HR) ≤45bpm indicates that this combination of anesthetic concentrations causes circulatory depression side effects and is recorded by 1; otherwise, it is recorded by 0. | During surgery | 
| The satisfaction of patients and anesthesiologists | The satisfaction of patients and anesthesiologists with the anesthesia regimen was evaluated (very satisfied, satisfied, fair, dissatisfied, very dissatisfied). | Up to 2 hours after surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Remimazolam, Awake Endotracheal Intubation