Brugada syndrome (BrS) is an inherited cardiac channelopathy affecting ionic sodium channels.1 Most patients remain asymptomatic for life, but a minority can develop palpitations, syncope or nocturnal agonal respiration due to ventricular arrhythmias (VA) potentially leading to sudden cardiac death (SCD).
A cornerstone in the management of these patients is the eviction of drugs known to interact with ionic sodium cardiac channels (brugadadrugs.org). Based on scientific evidence, drugs are listed as ‘drugs to be avoided’ along with a recommendation from I to IIb or ‘drugs preferably to be avoided’ with IIb recommendation.
Propofol, a widely used sedative-hypnotic, has been listed as a drug to be avoided.2 Propofol could affect transmembrane sodium ionic channels, alter the balance between the sympathetic and parasympathetic systems in favour of the latter, and have a negative cardiac inotropic activity. Collectively, these factors could theoretically increase the risk of serious VA during the use of this drug. Precautions for using propofol in BrS patients during emergencies, particularly in lower-risk individuals, have been described. However, data on its safety profile in higher-risk patients are limited.
We retrospectively included, from January 2008 to June 2023, within the Reference Center for Hereditary Rhythm Disorders of Bordeaux University Hospital, all patients managed for BrS who underwent cardiac or extra-cardiac general anaesthesia (GA) procedures involving propofol. Patients were included based on a confirmed BrS pattern on electrocardiogram (ECG)—either spontaneous, fever-induced, or drug-induced—defined by a > 2 mm coved-type elevation of the ST-segment followed by a negative T wave in at least one of the right precordial leads.3 Data included baseline BrS characteristics, procedure type, propofol dosing, ECG changes, and occurrence of perioperative arrhythmic events.
In total, 146 GA procedures using propofol were performed in 92 BrS patients with high-risk characteristics: 53.3% spontaneous BrS pattern, 48.5% symptomatic patients, 81.3% of positive programmed ventricular stimulation, and 95.7% of implantable cardiac defibrillator (ICD) implantations (detailed characteristics in Table 1). During a 74.9 (69.2–87.3) months follow-up, VA rate was 2.26 per 100 patients-year. Of the procedures, 119 involved cardiac device interventions, 13 ventricular fibrillation (VF) ablations, and 11 extra-cardiac surgeries. Propofol was used for induction only (n = 104) or for both induction and maintenance (n = 42) using target-controlled infusion. All procedures were performed under continuous but standard cardiac monitoring. Apart from VF ablation, no arrhythmic events or ECG changes were reported during or after GA. The 95% confidence interval for VA occurrence was 0–0.022 (Clopper–Pearson formula).
Table 1.
Patients and procedures characteristics
| Patients | |
|---|---|
| Age at diagnosis (years) | 44.5 ± 12.4 |
| Male gender | 73 (79.3%) |
| Spontaneous Brugada pattern | 49 (53.3%) |
| Proband | 74 (80.4%) |
| 1st degree SCD history | 19 (20.7%) |
| Symptoms at baseline | |
| Asymptomatic | 47 (51.1%) |
| Routine ECG | 30 (32.6%) |
| Family screening | 17 (18.5%) |
| Syncope | 35 (38.0%) |
| Aborted SCD | 10 (10.9%) |
| Programmed Ventricular Stimulation | |
| Performed | 48 (52.2%) |
| Positive | 39/48 (81.3%) |
| SCN5A mutation | 24 (26.1%) |
| ICD implantation | 88 (95.7%) |
| Primary prevention | 45/88 (51.1%) |
| Secondary prevention | 43/88 (48.9%) |
| Follow-up (months) | 74.9 [69.2–87.3] |
| Events during follow-up | 13 (14.1%) |
| Syncope | 2 (2.2%) |
| Malignant VA | 11 (11.9%) |
| Event-rate per 100 patients-year | 2.26 [1.97 –2.56] |
| Procedures | |
| GA procedures (n) | 146 (100%) |
| Cardiac | 135 (92.5%) |
| Pacing procedures | 119 (81.5%) |
| ICD implantation | 50 (34.2%) |
| ICD changes | 59 (40.4%) |
| ICD extraction | 7 (4.8%) |
| Lead replacement | 1 (0.7%) |
| VF induction | 2 (1.4%) |
| VA ablations | 13 (8.9%) |
| Cardiac surgery | 3 (2.1%) |
| Coronary bypass | 2 (1.4%) |
| Tyron David | 1 (0.7%) |
| Extra-cardiac | 11 (7.5%) |
| Digestive | 7 (4.8%) |
| Thoracic | 2 (1.4%) |
| Orthopedic | 1 (0.7%) |
| Other | 1 (0.7%) |
| Propofol use for GA | |
| Induction | 104 (71.2%) |
| Induction and maintenance | 42 (28.8%) |
| Total dose available | 27/42 (64.3%) |
| Total dose unavailable | 15/42 (35.7%) |
| Propofol dose (mg) | |
| All (N = 131) | 380.3 ± 371.1 |
| Induction (N = 104) | 305.8 ± 305.4 |
| Induction and maintenance (N = 27) | 667.0 ± 459.9 |
| VA episode during GA | 0 [0–0.022] |
SCD, sudden cardiac death; VA, ventricular arrhythmias; GA, general anesthesia. ICD, implantable cardioverter-defibrillator.
We thus report no occurrence of VA or significant ECG changes related to propofol use in this cohort which representing a BrS subgroup with a significant arrhythmic risk, supported by cohort characteristics and by the VA rate.
Propofol is currently listed as a drug ‘to be avoided’ in BrS (Class IIB) reflecting ‘conflicting evidence and/or divergence of opinion about the drug, and the potential proarrhythmic effect in BrS patients is less well established’. Precautions for using propofol in BrS patients during emergencies, particularly in lower-risk individuals, have been described (www.brugadadrugs.org/emergencies). However, these recommendations were initially based on a limited number of often outdated studies with small patient cohorts.
One of these articles is a physiology study describing the in vitro effects of propofol on the sodium channel function from rat myocytes.4 It reports a dose-dependent effect on sodium currents, a hyperpolarization shift, a decreased conductance, a reduced rate of recovery from inactivation, a decreased sodium channel activation rate, as well as a reduction in sodium channel opening time. However, the propofol doses used were high (30 µg/mL or 168 µM), far exceeding the therapeutic in vivo concentrations targeted during GA (1.5–3.5 µg/mL in the brain).5 Additionally, these results were obtained in vitro on isolated myocytes and only modifications in the functional properties of sodium channels were studied. Another study on perfused canine cardiac tissue preparations with equivalent concentrations (168 µM) did not show any ECG modifications upon propofol administration.6
More recently, three studies supporting propofol safety profile in BrS have been published. In 2018, a retrospective study reported no ECG changes or adverse outcome in 53 ICD implantation procedures with propofol induction.7 In 2020, a randomized study compared anaesthesia induction with propofol or etomidate in 98 BrS patients: no significant differences in ST-segment changes nor VA were reported.8 Finally, in 2021, a retrospective analysis of 304 propofol procedures in 135 patients reported no VA.9
We know that prolonged high-dose propofol administration (generally >4 mg/kg/h for >48 h) can lead to the development of a ‘propofol infusion syndrome’ in anaesthesia and intensive-care units (ICU).10 These patients are primarily those sedated for extended durations in ICU. They exhibit metabolic disturbances with acidosis, hyperlipidaemia, rhabdomyolysis, multi-organ damages, haemodynamic collapse, and pseudo-BrS ECG patterns accompanied by a significant rhythmic instability.6 However, this syndrome is pathophysiologically and clinically distinct from brief perioperative exposures in anaesthetic practice.
Some limitations must be noted: this is a single-centre retrospective analysis; with a small sample size because BrS a is rare disease; and post-procedure ECG changes as recorded in medical reports may have been underreported since raw ECG were not available for all patients. An additional limitation worth mentioning is the uneven distribution of data between induction only and maintenance use of propofol: only 42 procedures involved both induction and maintenance, for which detailed dosing information is more limited. Moreover, in contrast to other anaesthesia departments in our center, the cardiac department routinely performed all GA in BrS patients using propofol. Therefore, most GA procedures included were electrophysiology procedures. Although this can be seen as a limitation, it resulted in a cohort of higher-risk patients.
In conclusion, we report a BrS population that underwent numerous procedures under GA using propofol—primarily for induction and, in a subset, also for maintenance—without any observed perioperative arrhythmic events. These procedures were all performed in an anaesthesia setting with close and continuous cardiac monitoring. Consequently, despite the inclusion of propofol on the list of contraindicated drugs for BrS, its use for anaesthesia, when combined with continuous cardiac monitoring, appears to be safe, for short-term GA, even in higher-risk patients.
Contributor Information
Romain Tixier, Univ. Bordeaux, INSERM, CRCTB, U 1045, IHU Liryc Bordeaux F-33000, France; Service d’électrophysiologie Cardiaque, Hôpital Cardiologique du Haut Leveque CHU de BORDEAUX, 1 Avenue de Magellan Pessac 33600, France.
Elise Langouet, Univ. Bordeaux, INSERM, CRCTB, U 1045, IHU Liryc Bordeaux F-33000, France; Cardiovascular Anesthesia and Critical Care Department, Bordeaux University Hospital Bordeaux F-33000, France.
Josselin Duchateau, Univ. Bordeaux, INSERM, CRCTB, U 1045, IHU Liryc Bordeaux F-33000, France.
Nicolas Derval, Univ. Bordeaux, INSERM, CRCTB, U 1045, IHU Liryc Bordeaux F-33000, France.
Thomas Pambrun, Univ. Bordeaux, INSERM, CRCTB, U 1045, IHU Liryc Bordeaux F-33000, France.
Rémi Chauvel, Univ. Bordeaux, INSERM, CRCTB, U 1045, IHU Liryc Bordeaux F-33000, France.
Benjamin Bouyer, Univ. Bordeaux, INSERM, CRCTB, U 1045, IHU Liryc Bordeaux F-33000, France.
Marine Arnaud, Univ. Bordeaux, INSERM, CRCTB, U 1045, IHU Liryc Bordeaux F-33000, France.
Nadir Tafer, Univ. Bordeaux, INSERM, CRCTB, U 1045, IHU Liryc Bordeaux F-33000, France; Cardiovascular Anesthesia and Critical Care Department, Bordeaux University Hospital Bordeaux F-33000, France.
Pierre Bordachar, Univ. Bordeaux, INSERM, CRCTB, U 1045, IHU Liryc Bordeaux F-33000, France.
Mélèze Hocini, Univ. Bordeaux, INSERM, CRCTB, U 1045, IHU Liryc Bordeaux F-33000, France.
Pierre Jais, Univ. Bordeaux, INSERM, CRCTB, U 1045, IHU Liryc Bordeaux F-33000, France.
Michel Haïssaguerre, Univ. Bordeaux, INSERM, CRCTB, U 1045, IHU Liryc Bordeaux F-33000, France.
Frédéric Sacher, Univ. Bordeaux, INSERM, CRCTB, U 1045, IHU Liryc Bordeaux F-33000, France.
Funding
This work was funded by a grant IHU LIRYC ANR-10-IAHU-04.
References
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