Across the globe, sepsis cause more than 11 million deaths per year. Septic shock, has associated with an in-hospital mortality rate approaching 40%.1 Atrial fibrillation (AF) is the most common arrythmia in septic patients.2 It may result in hemodynamic instability, high mortality rate, prolonged intensive care unit (ICU) stay and increased healthcare costs. The incidence of new-onset AF (NOAF) ranges from 4% to 9% in patients with sepsis and up to 46% in patients with septic shock.3,4 Regarding treatment, intravenous amiodarone and beta-blockers (BBs) are the most common agents used in practice.5

However, for septic patients with NOAF, it remains unclear which medication should be used. Amiodarone and BBs have been compared on several retrospective studies with inconsistent results regarding important outcomes such as in-hospital mortality, ICU length of stay, complications, pharmacological cardioversion rate, heart rate control, ventilator-free days and others.6 A large study reviewed 39,693 patients with sepsis treated with amiodarone or BB.7 After adjustment for confounding factors, BBs were associated with lower in-hospital mortality than amiodarone (RR 0.67, 95% CI: 0.59–0.77). Nonetheless, time of onset of AF was not documented and up to 40% of patients were not critically ill. There has been no systematic evaluation of the prognosis and safety of these two classes of medications in septic patients admitted to ICUs with NOAF.

In the present study, we aimed to compare in-hospital mortality, ventilator-free days and safety of intravenous BBs and amiodarone in septic patients with NOAF, utilizing the Medical Information Mart for Intensive Care (MIMIC)-IV database, MIMIC-IV is a publicly available database sourced from the electronic health record of the Beth Israel Deaconess Medical Center.

There is a lack of high-quality studies comparing the efficacy of amiodarone and BB in septic patients with NOAF in the ICU. Our study showed that BB use was associated with lower in-hospital mortality compared with amiodarone in septic patients with NOAF. But patients who received amiodarone had shorter during of AF. These results may be related to the different pharmacological mechanisms.

Our study revealed that prescription of a BB was significantly associated with lower in-hospital mortality compared with amiodarone. Consistent with our study, a previous retrospective study found that BBs appeared to lower in-hospital mortality compared with amiodarone.7 In critically ill patients with sepsis and NOAF, the lower mortality risk with BB could be explained by several mechanisms. In the management of AF in hospitalized patients, it is crucial to prioritize the identification and treatment of potential triggers. This is because attempts at rate and rhythm control may be less effective until the acute illness improves.12 During sepsis, elevated levels of circulating catecholamines predispose to AF by triggering electrical remodeling and also increase atrioventricular node conduction which leads to a rapid ventricular response.13 This leads to reduced diastolic filling time and an elevated risk of hemodynamic compromise. BBs exert their sympathetic blocking effects primarily by antagonizing beta1 receptors, resulting in reduced AV node conduction and reduced catecholamine effects on the myocardium.13 Administration of BBs can stabilize hemodynamics by enhancing ventricular filling, thereby improving cardiac output and the patient's prognosis. Notably, the use of BBs during sepsis also enhances arterial elasticity and ventricular-arterial coupling, potentially addressing another possible cause of mortality.14,15

Amiodarone is a class III antiarrhythmic drug that is widely available in the ICU. It is a complex iodinated compound that, along with its active metabolite N-desethylamiodarone, blocks IKr, INa, IKur, Ito, ICaL, IKAch, and If channels with noncompetitive antagonism of alpha and beta-receptors.16 Our study similarly showed that the amiodarone group had shorter AF recording times. Nonetheless amiodarone is distinguished by a long half-life of weeks that can lead to numerous side effects.

Several studies have shown the efficacy of amiodarone in the management of atrial fibrillation in critically ill patients, but have not explained this potentially serious complication.6 Although amiodarone rapidly terminates atrial fibrillation, the long metabolism time of amiodarone may contribute to the poor prognosis. Serum amiodarone accumulation frequently impacts the thyroid, lungs, and liver. There are also reports of amiodarone-associated acute bleeding,17 which may be related to the two factors: first, amiodarone hinders the activity of numerous Cytochrome P450(CYP) isozymes involved in the metabolism of aspirin and other anticoagulant drugs; second, serum amiodarone can accumulate in the liver affecting the function of the liver, an important coagulation factor synthesizing organ.18,19 However, the full impact of these findings on ICU patient care requires more extensive research.

To examine the risk in specific types of patients, we explored effect modification by age, heart failure, anticoagulation, antiplatelet, SOFA score, heart rate, septic shock, digoxin, diltiazem, and heart rate. In the subgroup of patients with septic shock, BBs had lower in-hospital mortality compared with patients of the amiodarone group. Similarly, a recent study proved the hemodynamic safety of the betablocker-derivative propafenone in patients with septic shock with AF, and the lower hospital mortality compared with patients prescribed amiodarone (36.5% vs 41%). It suggested that within a certain range of shock, BBs do not worsen a patient’s hemodynamics, this finding may indicate that is safe using BB in these group of patients.20 Due to the inability to accurately obtain information related to the dosage of vasoactive drugs, we did not conduct further analysis, considering the side effects of BBs, its use in patients with severe septic shock still needs to be carefully considered, which requires more clinical studies to prove its safety.21 In the heart failure subgroup, regardless of the presence of heart failure, the BB group had no significantly for in-hospital mortality. However, the pharmacokinetic advantages of BBs, particularly the ultrashort-acting agent esmolol, that allows for rapid titration and discontinuation, with a metabolism time of about 5&#¿;min and the potential for rapid recovery from drug-associated hypotension.22 This positions esmolol as a potentially valuable medication for treating acute atrial fibrillation in the future. Nonetheless although BBs showed an advantage in different heart rate subgroups, a statistically significant difference was noted only when heart rate exceeded 120&#¿;bpm, possibly because the fast ventricular rates associated with AF are an important contributor to poor prognosis but can be moderated by BBs in critically ill patients.23 In addition, the BB and amiodarone groups did not show statistically significant differences in the subgroups using diltiazem. This is likely because BBs and calcium channel blockers (CCBs), such as verapamil and diltiazem, have similar pharmacological effects, including on voltage calcium channels, reducing depolarization of the AV node and slowing heart rate.13

First, it is difficult to balance the multiple confounding factors that are likely to affect the treatment of AF, including electrolytes, source of infection, body temperature, and positive end expiratory pressure. Despite propensity score matching to balance observed baseline characteristics between some groups, there may be unmeasured confounders that influenced the results. Second, we used nurse-recorded instances of NOAF and duration of atrial fibrillation: these nurse-recorded data, although validated, still have a percentage of bias. Third, medication times were derived from the time of prescription and do not reflect the true length of medication use. In addition, our study did not consider the effects produced by drug dose.

BB was associated with lower in-hospital mortality compared with amiodarone in septic patients with NOAF. On the other hand, amiodarone group had a shorter duration of atrial fibrillation. There was no significant difference in ventilator-free days between the BB group and the amiodarone group. The risk-benefit balance should be taken into consideration based on different populations when clinicians choose between these two medications.

G.H., H.L. and F.S. contributed equally to this work. W.J. and B.H. designed the study. G.H. extracted the data from the MIMIC-&#¿; Database. H.L., C.Z., M.J., C.H. and Y.Z. participated in processing the data and doing the statistical analysis. W.J., G.H., and F.S. wrote the manuscript. B.H. planned the analyses and guided the literature review. All authors read and approved the final version of the manuscript.

Not applicable.

The establishment of this database was approved by the Massachusetts Institute of Technology (Cambridge, MA) and Beth Israel Deaconess Medical Center (Boston, MA), and consent was obtained for the original data collection. Therefore, the need for informed consent were waived for this manuscript. This study was reviewed and approved by the Guangdong Provincial People’s Hospital Ethics Committee (No.KY2023-881-01).

The authors received financial support for the research, authorship, and/or publication of this article from the National Key Research and Development Program intergovernmental key projects (2023YFE0114300), Zhongnanshan Medical Foundation of Guangdong Province (ZNSXS-20240052), Natural Science Foundation of Guangdong (2022A1515012428, 2024A1515011329), the Peking Union Medical Foundation-Ruiyi Emergency Medical Research Fund (R2021002) and the China International Medical Foundation-Clinical Development Research Fund (Z-2018–31-2102–2). The funding agents had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.