Population and inclusion criteria
The “Intravenous beNzodiazepine Safety and Tolerability in Emergency Atrial fibrillation Direct-current cardioversion” (INSTEAD) is a single centre, prospective, open blinded, randomized study included consecutive patients admitted to the Emergency Department or the University Hospital “Ospedali Riuniti Umberto I - Lancisi - Salesi” requiring urgent or emergency DCC. The present study follows a pilot trial  that has already been performed in order to assess clinical feasibility.
Emergency DCC was defined as DCC performed in haemodynamically compromised patients with new-onset AF, according to European guidelines . Urgent DCC was defined as DCC performed within two hours from patient’s admission due to persistent invalidating symptoms such as chest pain, pre-syncope, or severe palpitations. No anti-arrhythmic drugs were given prior to DCC for pharmacological cardioversion.
The inclusion criteria consisted in age > 18 years old and admission for high rate AF or atrial flutter requiring urgent/emergency cardioversion. A documented or suspected allergy or intolerance to midazolam or propofol represented the only exclusion criterion. No patient was excluded based on comorbidities or concomitant diseases in order to reflect “real-life” population data.
The study conforms to the Declaration of Helsinki and was performed in accordance with the Consolidated Standards of Reporting Trials (CONSORT) standards and national recommendations by competent authorities (Supplementary Table 1). The protocol was approved by the internal review board of our institution (University Hospital “Ospedali Riuniti Umberto I - Lancisi - Salesi”). Written informed consent was gained from all patients.
An accurate medical history was recorded from all patients in order to assess cardiovascular risk factors such as hypertension, diabetes, dyslipidaemia, family history and smoking habit. In addition, we recorded the patients’ comorbidities and known cardiovascular diseases. We also took note of the drug history and the number of previous cardioversions, electrical or pharmacological, that the patients had undergone. We performed routine blood tests, a 12 lead ECG and an echocardiogram for each patient.
All enrolled patients were randomized in a 1:1 fashion into the propofol or midazolam group. The CONSORT flow diagram is showed in Fig. 1.
With regards to the propofol group, the procedure was carried out with the assistance of the anaesthesiologist who administered propofol 1 mg/kg followed by 0.5 mg/kg every three minutes until satisfactory sedation (Ramsay sedation scale > 4) . The cardiologist delivered the shock through a manual external defibrillator (Zoll M-Series, Zoll Medical Corporation, Chelmsford, MA, USA).
In the midazolam group, both procedural sedation and DCC were carried out by the cardiologist who administered a starting dose of midazolam 3 mg, followed by 2 mg every 2 minutes until satisfactory response ( Ramsay sedation scale > 4) . The anaesthesiologist was readily available during the whole procedure in order to intervene if deemed necessary.
A maximum of three shocks were delivered, following a step up published protocol : a first 150 J shock with the paddles in antero-apical position. If not effective, a second shock of 200 J was delivered keeping the paddles in the same position. If both shocks failed to restore sinus rhythm, a third 200 J shock was delivered with adhesive paddles in the anteroposterior position.
One-hundred percent oxygen supplementation and saline infusion were provided to each patient during the procedure.
At the end of the procedure, 1 mg of flumazenil was administered to the patients in the midazolam group in order to revert the effects of the benzodiazepine.
When awake, all patients were asked to rate the pain and distress on a scale going from no pain to the worst possible pain and distress according to a visual analogue scale (VAS).
A 12-lead ECG was performed at the beginning and at the end of the procedure in order to assess the restoration of sinus rhythm and all vital status parameters (blood pressure, heart rate, saturation) as well as delay, length of procedure, length of monitoring and hospitalization were registered.
The primary safety endpoint was a composite of death and the following peri-procedural adverse events requiring medical intervention: bradycardia (defined as heart rate < 50 bpm for at least 30 seconds), severe hypotension (defined as systolic blood pressure < 80 mmHg), severe hypoxia (defined as oxygen saturation < 85%), stroke, transient ischaemic attack and need for orotracheal intubation.
Other safety endpoints included the variation of blood pressure, heart rate and oxygen saturation registered before induction, before delivery of the shock, after the shock and after recovery. Tolerability of the procedure was assessed using the VAS.
Efficacy was assessed based on the number of very early recurrences (within 2 hours) and early recurrences (within 24 hours). All patients discharged before 24 hours from the Emergency Department were called by phone the day after the procedure in order to confirm stable sinus rhythm. Time-related issues (delay and length of the procedure, monitoring time and length of hospitalization) were also considered.
Finally, we analysed the cost-effectiveness of the procedure carried out by the cardiologist alone with midazolam, compared to procedural sedation with propofol and anaesthesiologist assistance. Direct total costs were defined as the total of personnel costs, material costs and hospitalization costs. For a more detailed definition of costs calculation please refer to our previous study . Indirect costs were not taken into account.
Quantitative variables were checked for normality by the Kolmogorov–Smirnov test, and described as mean and standard deviation (if normally distributed) or median and first to third quartile (if not normally distributed). ANOVA adjusted by age and sex was used to compare normally distributed quantitative variables. Kruskal– Wallis ANOVA adjusted by age and sex was used to compare non-normally distributed quantitative variables. Categorical variables were described by absolute number and assessed by using χ2 analysis. General linear model for repeated measures was used to assess time-dependent changes of blood pressure, heart rate and oxygen saturation. As one patient per group ended up having both interventional drugs administered (Fig. 1), an intention-to-treat analysis was adopted.
Being a feasibility study, a formal, a-priori, sample size calculation was not performed. However, considering an expected composite endpoint rate of 18% from our pilot study, a population of ≥ 34 subjects in each group would have a > 80% power to show that the primary safety endpoint (composite of death and the following peri-procedural adverse events) for the midazolam group was non-inferior to the control group, considering a two-fold increase in hazard ratio between the two groups as clinically significant (α = 0.05, one-tail test).
SPSS 25.0 for Windows (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. Values of p < 0.05 were taken as statistically significant.