COnventional vs. Optimised PERiprocedural Analgosedation vs. Total IntraVEnous Anaesthesia for Pulsed-Field Ablation (COOPERATIVE-PFA)

Study Overview
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Brief Summary
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A prospective single blinded (subject blinded) 1:1:1 randomised control trial with three parallel arms testing superiority of analgosedation regimen based on remimazolam and total intravenous anesthesia over propofol based analgosedation. The primary composite endpoint consists of hypoxaemia, hypotension, or hypertension requiring intervention.

Official Title
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Conventional vs. Optimised Periprocedural Analgosedation vs. Total Intravenous Anaesthesia for Pulsed-field Ablation: a Randomised Controlled Trial

Conditions
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Atrial Fibrillation

Intervention / Treatment
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* Drug: Remimazolam
* Drug: Propofol
* Drug: Propofol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Atrial fibrillation (AF) (paroxysmal, persistent or long standing persistent) with indication for catheter ablation Age above 18 years Capacity to give informed consent Exclusion Criteria: Heart failure (NYHA III-IV), irrespective of left ventricular ejection fraction Left ventricular ejection fraction < 20% Significant valvulopathy (moderate or severe aortic stenosis, severe mitral regurgitation, severe aortic regurgitation, moderate and severe mitral stenosis, severe tricuspid regurgitation) Obstructive sleep apnoea syndrome (AHI >30) Low oxygen saturation (<93%) at baseline High aspiration risk (hiatal hernia, gastroesophageal reflux disease on chronic pharmacotherapy) Hypersensitivity to the study drugs Chronic kidney disease (stage 4 and 5 of CKD), liver cirrhosis Anticipated difficult airways ASA (American Society of Anaesthesiologists) score > 4 Schizophrenia Epilepsy Other individual contraindications (will be reported in detail)

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Interventional Model Description: Study arms, analgosedation and TIVA protocols: Conventional propofol analgosedation (arm P): current standard practice in most centres, a combination of short-acting benzodiazepine (midazolam) at the beginning, short-acting opioid (sufentanil in this study) and propofol boluses before and during the application of ablation pulses with unsecured airway Optimised continuous intravenous analgosedation (arm R): ultrashort-acting benzodiazepine (remimazolam) and ketamine with unsecured airway Total intravenous anaesthesia with secured airway (arm TIVA): continuous propofol infusion using target controlled infusion (TCI) and short acting opioid boluses - sufentanil
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm P<br>Patients in arm P will be administered 2-3 mg midazolam IV before the beginning of the procedure, 5-10 mcg sufentanil IV and a loading dose of propofol 0,8-1,0 mg/kg in 2-5 minutes before the start of the ablation phase. During the procedure, boluses of 0,5 mg/kg propofol will be repeated as needed, in case of inappropriate analgosedation, boluses of midazolam and/or sufentanil can also 0be repeated. | Drug: Propofol<br>* analgosedation with secured airway<br>|
| Experimental: Arm R<br>Patients in arm R will be administered 2,5 mg loading dose of remimazolam followed by continuous infusion at 0,5 mg/h/kg of ideal body weight (IBW, calculated using the Miller formula) and a dose of ketamine 1 mg/kg IBW 2-5 minutes before the beginning of the ablation phase. In case of inadequate sedation depth, a bolus of 2,5 mg remimazolam can be repeated as needed. If the patient shows signs of pain or discomfort, a single dose of ketamine - 0,5 mg/kg IBW - will be administered, followed by a bolus of 5-10 mcg sufentanil if needed. The continuous infusion will be terminated as the last ablation pulses are delivered. | Drug: Remimazolam<br>* analgosedation without secured airway<br>|
| Active Comparator: Arm TIVA (Total Intravenous Anesthesia)<br>Patients randomised in arm TIVA will be administered light analgosedation with spontaneous ventilation for the first part of the procedure. The analgosedation will be induced and maintained with bolus of 5 mcg sufentanil IV and propofol infusion dosed by TCI system (the target plasma concentration for propofol 1-2 mcg/ml). Before the beginning of the ablation phase, general anesthesia will be induced with one bolus of 5-10 mcg sufentanil (the TCI target 3-7 mcg/ml for induction and 3-5 mcg/ml for the rest of the procedure), and a bolus of rocuronium 0,2-0,4 mg/kg IBW. Then, the airways will be secured with a laryngeal mask (LMA), the patient ventilated (0,4 - 0,45 FiO2, the target EtCO2 30 - 45 mmHg). After the last ablation pulse is delivered, infusion of propofol will be ceased and LMA extracted at the return of consciousness, muscle strength and sufficient spontaneous ventilation. If residual muscle relaxation occurs, sugammadex will be administered. | Drug: Propofol<br>* TIVA with secured airway<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary composite endpoint (rate of hypoxaemia, hypotension, or hypertension events) | Composite endpoint consisting of the rate of (1) hypoxaemia events requiring intervention, (2) hypotension events requiring intervention or leading to the procedure interruption, or (3) hypertension events requiring intervention | Procedure duration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total number of haemodynamic instability events (hypoxemia, hypotension, hypertension; defined above), each five minutes of a continuous instability counts as a new event, as well as an instability persisting despite an intervention |  | Procedure duration | 
| Total number of: a) hypoxemia events hypoxaemia <85% (more than 60s) b) hypotension events = systolic blood pressure (SBP) < 85 mmHg (more than 60s) c) hypertension event = SBP > 200 mmHg (more than 60s) |  | Procedure duration | 
| Total number of interventions a) jaw thrust b) nasopharyngeal airway administration c) LMA / orotracheal intubation d) increasing FiO2 (oxygen flow) e) hypotensive drugs administration f) vasoactive drugs administration (ephedrine, noradrenaline) |  | Procedure duration | 
| Total procedural time |  | Procedure duration | 
| Analgosedation depth by bispectral (BIS) monitoring: area under the curve of BIS index (measured every 3 minutes during the procedure) |  | Procedure duration | 
| Procedural sedation quality | PROcedural Sedation Assessment Survey - a previously validated form | 12-24 hours after the procedure | 
| Difficult sedation score | 1-10 scale (10 = the worst), reported by an anaesthesiologist | Procedure duration | 
| Operator's satisfaction score | 1-10 scale (10 = the worst), reported by the operating physician | Procedure duration | 
| Total number of serious adverse events | death, cardiopulmonary resuscitation (chest compression or adrenaline administration), an emergency intubation or prolonged stay in intensive care unit | From randomization until discharge | 
| carbon dioxide partial pressure after the procedure | partial pressure (kPa) of CO2 measured in an arterial blood sample | blood sample taken after the procedure (up to 10 minutes) | 
| 28-day serious adverese events | death, a condition related to the procedure requiring inpatient hospitalization | discharge to the day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Analgosedation, Remimazolam, Atrial Fibrillation, Pulsed field ablation