Rate, Rhythm or Risk Control for New-onset Supraventricular Arrhythmia During Septic Shock: a Randomized Controlled Trial

Study Overview
=================
Brief Summary
-----------------
New-onset supraventricular arrhythmia (NOSVA) is reported in 40 % of patients with septic shock and is associated with hemodynamic alterations and mortality. The lack of consensus regarding best practices for the management of NOSVA in this setting has led to major variations in practice patterns. Observational studies reported three usual strategies: (i) heart rate control (hereafter rate control) with the use of antiarrhythmic drugs, essentially based on low dose of amiodarone, (ii) rhythm control with the use of antiarrhythmic drugs, essentially based on high dose of amiodarone, and electrical cardioversionand (iii) modifiable NOSVA risk factors control (hereafter risk control) without using antiarrhythmic drugs. Risk control would minimize adverse events of antiarrhythmic drugs. Rhythm control would rapidly improve haemodynamics via restoring diastole and decreasing cardiac metabolic demand, while minimizing exposure to anticoagulation. Rate control, would limit potential adverse events of high dose of amiodarone and of electrical cardioversion (only in patients intubated on mechanical ventilation), while controlling haemodynamics. Therefore, it seems important to compare these three strategies. Our hypothesis is dual: first, that rate control and rhythm control each improve hemodynamics with in fine a decreased mortality, as compared to a risk control; second, that rhythm control outperforms rate control in this setting. This is a multicenter, parallel-group, open-label, randomized controlled superiority trial to compare the effectiveness and safety of these three strategies (risk control, rate control and rhythm control) for NOSVA during septic shock.

Detailed Description
-----------------
All consecutive adult patients admitted to the intensive care unit with NOSVA during septic shock will be included in the presence of inclusion criteria and in the absence of exclusion criteria. Randomization, performed immediately after the inclusion (Day-1), in 1:1:1 ratio will be stratified on center. Then the patient will receive the randomized strategy: risk control, rate control or rhythm control. Before inclusion, the informed consent will be proposed to the patient. If the patient is unable to give his/her consent, the informed consent of the next-of-kin will be sought by study investigator. In the case the next-of-kins are unidentified and/or unreachable, an emergency procedure will be applied. Patient consent will be sought as soon as their state of health allows it. According to clinical guidelines, patients in all groups will receive therapeutic anticoagulation if NOSVA > 48 hours and in the absence of contraindication. In all groups, recommendations for the management of septic shock will be followed. After day-7 (or hospital discharge if before J7), NOSVA treatment will be left at the discretion of attending physicians. Evaluation criteria will be collected at day-2, day-3, day-7 (or at hospital discharge if before day-7), at the day of ICU discharge and at Day-28. If the patient has been discharged before Day-28, the vital status may be obtained by phone call at Day-28.

Official Title
-----------------
Comparison of Three Care Strategies in Cases of New-onset Supraventricular Arrhythmia During Septic Shock : a Randomized Controlled Trial

Conditions
-----------------
Supraventricular Arrhythmia, Septic Shock

Intervention / Treatment
-----------------
* Procedure: Risk control strategy
* Procedure: Rate control strategy:
* Procedure: Rhythm control strategy:


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age >= 18 years Septic shock, defined by the association of the following criteria: Documented or suspected infection, with initiation of antibiotic therapy Initiation of vasopressors (norepinephrine, epinephrine) for at least 1 hour to maintain the MAP > 65 mmHg NOSVA with heart rate ≥ 110 bpm lasting 5 minutes or more Written informed consent (patient, next of skin or emergency situation) Affiliation to a social security system Exclusion Criteria : Refractory shock defined by a dose of noradrenaline BASE or adrenaline BASE > 1.2 µg/kg/min Cardiac surgery or cardiac transplant in the previous month Aortic or mitral mechanical prosthesis, significant mitral stenosis (mitral surface < 1.5 cm2) Congenital heart disease other than bicuspid aortic valve, atrial defect or patent foramen ovale. History of supraventricular arrhythmia before septic shock NOSVA lasting at most 36 hrs (or 24 hrs with vasopressors) Electrical cardioversion or use of amiodarone, other antiarrhythmic, or drug inducing bradycardia (beta-blockers, bradycardic calcium channel blocker, digitalis, flécaïnamide) in the previous 6 hours before inclusion Contraindication to amiodarone: history of serious adverse event related to amiodarone, history of lung disease related to amiodarone, history of hyperthyroidism related to amiodarone, PR interval > 240 ms, severe sinus node dysfunction with no pacemaker, 2°/ 3° atrioventricular block with no pacemaker, QTc>480 ms, known or treated hyperthyroidism, hypersensitivity to iodine, amiodarone or to any of the excipients, severe hepatocellular insufficiency (prothrombin rate <20%), diffuse Interstitial Lung Disease. Kalemia < 3 mmol/L Pregnant or breast feeding women Moribund patient or death expected from underlying disease during the current admission; Patient deprived of liberty and persons subject to institutional psychiatric care Participation to another interventional trial on septic shock and/or arrhythmic disease

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Risk control strategy<br>Magnesium sulfate + control of the modifiable NOSVA risk factors | Procedure: Risk control strategy<br>* Magnesium sulfate 2g intravenous bolus over 20 mn (if creatinine clearance >30 mL/min) Control of the modifiable NOSVA risk factors: hypovolemia, sepsis, metabolic disorders (e.g., hypokalemia, hyponatremia), acidosis, hypoxia, excess cardiac inotropism of vasopressors, central venous catheter malposition, hyperthermia.<br>|
| Active Comparator: Rate control strategy<br>Risk-control + low-dose amiodarone | Procedure: Rate control strategy:<br>* Risk-control as described above Low dose amiodarone: Intravenous bolus (day-1): 4 mg/kg over 1hr (maximum 300 mg i.e. 2 IVL vials over 1 hour ) Enteral dose maintenance (day-1 to day-7): 200mg once a day (150 mg intravenous over 1hr if enteral route is unavailable)<br>|
| Active Comparator: Rhythm control strategy<br>Risk-control + high-dose amiodarone +/- electrical cardioversion | Procedure: Rhythm control strategy:<br>* Risk control as described above High dose amiodarone: Intravenous bolus (day-1): 7 mg/kg over 1hr 1 hour (maximum 600 mg i.e. 4 IVL vials over 1 hour); followed by continuous intravenous maintenance: for a total of 1200 mg over the first 24 hrs (infusion pump) Enteral dose maintenance Day-2 and day-3: 400 mg three times a day (720 mg continuous intravenous over 24 hrs if enteral route is unavailable). Day-4 to day-7: 200 mg once a day (150 mg intravenous over 1hr if enteral route is unavailable) - Electrical cardioversion (only in patients intubated on mechanical ventilation) if: NOSVA persists after initial bolus of amiodarone AND norepinephrine base (or epinephrine base) doses > 0.3 µg/kg/min; NOSVA persists more than 6 hrs after initial amiodarone bolus.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| all-cause mortality (a hierarchical criterion) | The duration of septic shock is defined as the time (number of days) from randomization to successful weaning of vasopressors The Finkelstein-Schoenfeld method is based on the principle that each patient in the clinical trial is compared with every other patient within each stratum in a pairwise manner. The pairwise comparison proceeds in hierarchical fashion, using all-cause mortality, followed by the duration of septic shock when patients cannot be differentiated on the basis of mortality. This method gives a higher importance to all-cause mortality. | 28 days | 
| the duration of septic shock according to the Finkelstein-Schoenfeld method (a hierarchical criterion). | The duration of septic shock is defined as the time (number of days) from randomization to successful weaning of vasopressors The Finkelstein-Schoenfeld method is based on the principle that each patient in the clinical trial is compared with every other patient within each stratum in a pairwise manner. The pairwise comparison proceeds in hierarchical fashion, using all-cause mortality, followed by the duration of septic shock when patients cannot be differentiated on the basis of mortality. This method gives a higher importance to all-cause mortality. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rhythm efficacy at day-7 (or at discharge or death if before day-7) | Number of patients with sinus rhythm Number of days alive with sinus rhythm Number of days alive with NOSVA and heart rate < 110 bpm Proportion of patients receiving therapeutic anticoagulation after randomisation | up to 7 days | 
| Morbimortality | Duration of septic shock and Length of stay in intensive care unit and in hospital at day-28 Proportion of patients alive free from vasopressors at day-7 (or at discharge or death if before day-7) Arterial lactate clearance at day-3 defined as the percentage of arterial lactate decrease between lactate at randomisation (day-1) and at day-3. Proportion of patients alive free from organ dysfunction at day-7 (or at discharge or death if before day-7) All-cause deaths at day-28. | Day 28 | 
| Tolerance at day-7 and day-28 | Proportion of patients with at least one arterial thrombotic event including ischemic stroke and non-cerebrovascular arterial thrombotic event Proportion of patients with at least one major bleeding event according to the International Society of Thrombosis and Haemostasis definition at Day-28; Proportion of patients with at least one serious adverse event related to amiodarone or to magnesium sulfate; and proportion of each type of event Proportion of patients presenting at least one serious adverse event associated with electrical cardioversion (for patients receiving electrical cardioversion). | Day 7 and day 28 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
New-onset supraventricular arrhythmia, Atrial fibrillation, Septic shock, Critically ill patient, Strategies, Antiarrhythmic drugs