**4. Incidence**

Atrial fibrillation is a common occurrence in patients with sepsis and septic shock, and its incidence varies widely among investigators. This may be due to the different criteria used to define sepsis and septic shock, or the method used for the diagnosis of AF [28]. In the aforementioned systematic review, Kuipers et al. [19] showed that the mean incidence of new-onset AF was 8% in patients with sepsis and 23% in patients with septic shock. The authors of that study also observed a significant increase in ICU length of stay in this group of patients. In a large study conducted by Walkey et al. [21], which retrospectively analyzed data from over 60,000 patients admitted for sepsis, the investigators found an overall incidence of AF during sepsis of 25.5%. This number rose to 31.6% when considering only the ICU population.

To date, there have been relatively few published prospective investigations regarding the incidence of AF in septic shock patients, although there is more available information about the general topic of AF in septic patients. Seguin et al. [29] found AF developed in 24 patients (5.3%) of 460 patients admitted to the surgical intensive care unit and followed prospectively during a 6-month period. They reported that 29.2% (7 of 23 patients) of septic shock patients developed AF. They concluded the presence of shock (especially septic shock) appeared to be an independent risk factor of AF in their cohort. It has to be recognized, however, that the operative definition of septic shock used at that time, the one proposed by Bone et al. [30], has since been substantially modified.

Steinberg et al. [28] published recently a one-year observational prospective study of 27 septic shock patients. Their aim was to evaluate the incidence of AF, and the mortality rate of patients with AF versus patients that maintained sinus rhythm. Nine (33%) patients developed AF during the first 72 hours. At admission and at 72 hours, SOFA was statistically higher in the patients with AF (p = 0.012 and p = 0.002, respectively).

In a single-center study, Meierhenrich et al. [31] prospectively studied all patients with NOAF and all patients suffering from septic shock in ICU during a 13 month period. Patients with preexisting chronic AF were excluded from their analysis. They found 23 out of the 50 patients with septic shock (46%) developed NOAF, compared to an overall incidence (septic and non-septic patients taken into account) of NOAF of 7.8% (49/629). The same aforementioned limitation in septic shock definition applies to this data.

Guenancia et al. [26] conducted a single-center prospective, observational study on patients with septic shock, and they found an incidence of new-onset AF of 44% (29 of 66 patients). Noteworthy, a 34% of new-onset AF would not be diagnosed without Holter ECG monitoring (silent AF).

More recently—and using an updated definition of septic shock—Rabie et al. [32] prospectively studied 100 septic shock patients, one of the largest series ever published. All patients were continuously monitored by three/five-lead monitor with arrhythmia detection algorithms, alarms, and Holter recording capabilities throughout the ICU stay. The investigators found the development of NOAF in 29 (29%), of which 22 (75,8%) patients had a single occurrence and 7 (24,2%) had recurrent AF during their ICU stay.

#### **5. Prognosis**

Whether NOAF acts as a surrogate marker for increased illness severity and subsequently poor prognosis in sepsis or whether it directly contributes to mortality and poor outcomes is not entirely clear. As stated before, the sepsis state can trigger AF mainly because of the combined mechanisms of inflammation, surge in catecholamines, and direct and indirect myocardial injury, and the poor prognosis noted whenever AF develop in critically ill patients may be the consequence of the presence of these factors.

In a retrospective analysis, Walkey et al. [33] found that patients with NOAF during a hospitalization for sepsis showed a higher five-year risk of hospitalization for heart failure (11.2% vs. 8.2%; HR, 1.25; 95% CI, 1.16–1.34), ischemic stroke (5.3% vs. 4.7%; HR, 1.22; 95% CI, 1.15–1.47), and death (74.8% vs. 72.1%; HR, 1.04; 95% CI, 1.01–1.07) than patients who did not develop NOAF.

Specific prospective data regarding the prognosis of NOAF in septic shock patients is also sparse. In a small series of 27 septic shock patients followed prospectively for one year, Steinberg et al. [28] reported that mortality was higher in AF patients (66%) than in patients in sinus ryhtm (11%) (p = 0.006). Age, rhythm and noradrenaline dosage were univariate predictors of total mortality. In the aforementioned study of Meierhenrich et al. [31], mortality in septic shock patients with NOAF was 44% compared with 22% in septic shock patients with maintained sinus rhythm (p = 0.14). The average length of ICU stay was shown to be increased in patients with NOAF (30 versus 17 days, p = 0.017). Failure to achieve sinus rhythm

restoration was associated with greater ICU mortality (71.4% vs. 21.4%, p = 0.015). After two years, the investigators observed a statistically nonsignificant increase in mortality in septic shock patients with NOAF (p = 0.075).

In a larger prospective series, Rabie et al. [32] found that mortality in patients with single AF attacks were not statistically higher than non-AF patients (p = 0.143). However, recurrent attacks of AF had significantly higher mortality than non-AF or single AF attack (p < 0.05). Recurrent AF was associated with increased length of UCI stay (21.6 ± 7.2 vs. 12.9 ± 7.3 days, p = 0.004).
