**2. Pathogenesis**

The negative effects of sepsis on the heart are not limited to the contractile function and ventricular relaxation, but also affect the electric function. Although the precise mechanisms remain to be elucidated, inflammation seems to play an important role. The electrical instability of cardiomyocytes in patients with sepsis has been considered to be due to the use of vasopressor drugs and the presence of electrolyte disturbances. However, according to recent findings, atrial fibrillation (AF) could be the result of the necrosis and fibrosis induced by inflammation [7, 8]. These alterations are supposed to be able to trigger an arrhythmia due to a fluctuation in the myocardial cells' membrane potential [9].

The development of NOAF in septic shock patients depends upon the presence of an arrhythmogenic substrate, the trigger factors and the modulation factors such as autonomic nervous system or inflammation. Triggered activity has been shown in the musculature of the atrium. An imbalance between sympathetic and vagal tone leading to a reduction of heart rate variability has been proposed as an explanation for the development of NOAF in septic patients [10]. Vagal stimulation normally attenuates the inflammatory response [11]. In human atrial cardiomyocytes, partial blockage of the I(f) 'funny' pacemaker current has been observed after exposition to gram-negative bacteria endotoxin [12], which may contribute to a reduced responsiveness to both sympathetic and vagal autonomic stimuli (the name "funny current" arose because of its numerous unusual characteristics, including the mixed Na + and K+ current permeability, activation on hyperpolarization, and

#### **Figure 1.**

*Schematized transmembrane action potential of sinus node (pacemaker) cells. The black line shows normal slope in sinus rhythm. During gram-negative bacteria induced-sepsis, it has been shown I(f) current blockage, which results in an increased phase 4 slope, triggering sinus tachycardia and facilitating AF onset (red line) [12].*

#### **Figure 2.**

*Schematized transmembrane action potential of atrial myocytes in normal and septic animals. The orange line indicates how sepsis decrease phase 2 (plateau phase) duration and leads to decrease in APD (action potential duration). This is due to a decrease in influx of calcium through the voltage-dependent L-channels, which is at least in part caused by sepsis-induced tachycardia. The decrease in APD (and hence in the atrial refractory period) has been proposed to effectively trigger AF [15].*

slow activation and deactivation kinetics [13]) (see **Figure 1**). This would result in a high heart rate output, which is commonly observed in septic patients. Unopposed sustained tachycardia during the will further increase calcium influx through L-type Ca2+ channels, which leads to marked shortening of the atrial refractory period and action potential duration (**Figure 1**) and elicit triggered activity, hence facilitating the onset of AF [14, 15] (see **Figure 2**). This process has been shown to be further enhanced due to beta-adrenergic stimulation after endotoxin application [16], which increases channel activity by prolonging the open time and shortening the close time of Ca2+ channel. These findings might explain the high sensitivity of cardiac pacemaker cells to positive inotropic effect of adrenergic stimulation and most likely development of new AF episode especially in the early stages of sepsis [17].

#### **3. Risk factors**

Sepsis itself is a strong risk factor for NOAF in the critical care setting. An extensive retrospective population-based cohort analysis by Walkey et al. revealed that compared to those without severe sepsis, patients with severe sepsis (n = 49,082) exhibited a significantly increased risk of NOAF (odds ratio (OR), 6.82; 95% confidence interval (CI), 6.54–7.11; P < 0.001) [18]. Multiple studies have been shown that the classic risk factors for the development of chronic atrial fibrillation in the general population may differ from those present in septic patients with NOAF. Risk factors for the occurrence of NOAF in septic patients include conditions that are not related to chronic cardiovascular disease, such as increased number of acute organ failures/ dysfunction, mechanical ventilation, increased comorbidities, and use of pulmonary artery catheterization [18–22]. NOAF has been also associated with lower EF, older age, higher level of troponin-HS and NT-pro-BNP and longer QRS duration.

#### *Atrial Fibrillation during Septic Shock DOI: http://dx.doi.org/10.5772/intechopen.100317*

Sepsis due to bacterial pneumonia has been associated with a high risk of developing NOAF, while sepsis due to gastrointestinal infections has been related to AF recurrence with worse long-term prognosis [23]. It has been hypothesized that the type and severity of infection could have an impact on the atrial remodeling and the variety of cytokine expression during sepsis. Current evidence suggests that the severity of the inflammatory response in critically ill patients is associated with a higher risk of NOAF, and septic shock patients have in general a heightened probability of developing NOAF than patients with other acute critical illnesses after adjustment for underlying risk factors [21].

In a systematic review that included 11 studies, Kuipers et al. [19] identified independent risk factors with a high level of evidence for NOAF in septic patients. White race, organ failure and pulmonary catheter use were moderately associated with NOAF development, while there was a weak association with age and respiratory tract infection. On the other hand, history of diabetes and urinary tract infections were found to be weak protective factors. In other studies, markers of illness severity (such as the presence of organ failure and shock) as well as several critical care interventions were associated with an increased risk of NOAF in septic patients. Known risk factors for chronic or paroxysmal AF in the general population, such as advanced age, white race, male gender, obesity and (ischemic) heart failure, were in some studies also associated with the development of AF during sepsis [24, 25]. Specific electrocardiographic or echocardiographic features of AF such as P-wave duration or left atrial area, remain to be studied in septic shock patients, although both factors are known to predict the occurrence of AF in the general population [26, 27].

Data regarding risk factors for the occurrence of NOAF in septic shock patients is more limited. Guenancia et al. [26] found that NOAF patients were older and had higher levels of cardiac biomarkers (troponin (p < 0.01) and NT-pro-BNP (p = 0.03)), lower left ventricular ejection fraction (LVEF), longer duration of the QRS complex and more nonsustained supraventricular arrhythmias (< 30 seconds) on day 1 than patients who maintained sinus rhythm. Age (OR: 1.06; p = 0.01) and LVEF <45% (OR: 13.01, p = 0.03) were associated with NOAF in their multivariate analysis.
