**6. Management**

When considering use of antiarrhythmic drugs or applying cardioversion in septic patients with atrial fibrillation and hemodynamic instability, causative factors must in parallel be addressed and corrected when feasible [34]. Since diastolic dysfunction is highly prevalent in ICU patients and is also an independent predictor of mortality [35], both excessive or insufficient fluid resuscitation should be avoided. For example, the so-called Early Goal Directed Therapy has shown marginal benefit [36] while heightening the risk of fluid overload and the overuse of betaadrenergic stimulant drugs to achieve central venous saturation above 65%. The resulting high cardiac output constitutes an arrhythmogenic setting. Interestingly, ceasing beta-stimulation and administering low-dose betablockers with concomitant preload correction has led to a dramatic decrease in mortality [37]. While the use of vasopressors in septic shock is recommended in early septic shock, preload assessment and timely administration of vasopressin can assist in diminishing the requirement of catecholaminergic drugs and consequently lower the risk of arrhythmia. Suboptimal volume replacement, on the other hand, carries the risk of higher sympathetic tone and consequent down-to regulation of adrenergic receptors which in turns leads to requirement of greater doses of vasopressor drugs. Hence, both conditions, namely fluid overload and hypovolaemia, are triggering factors for developing arrhythmias.

Electrolyte disturbances, which are commonplace in ICU patients, should be likewise identified and promptly corrected. Hypokalemia and hyperkalemia triggers supraventricular and ventricular arrhythmias. If the potassium level does not respond to adequate supplementation, magnesium levels must be assessed and corrected, since severe hypomagnesemia prevents the potassium level being corrected. It has been shown that septic patients tend to have lower serum magnesium levels when compared to nonseptic patients [38, 39]. Hypophosphatemia is associated with decreased myocardial contractility and a higher incidence of arrhythmia [40], and the correction of phosphorus level has been shown to prevent it [41]. Hypocalcemia may also be associated with arrhythmias [42, 43], although the data in septic patients is scarce.

Right ventricular dysfunction may cause acute cor pulmonale and supraventricular arrhythmias [44]. Instituting aggressive modalities of mechanical ventilation in septic patients with acute distress respiratory syndrome as an attempt to recruit consolidated lungs may trigger an increase in right ventricular afterload, with the consequent development of NOAF. Gradual opening of the consolidated lungs in a prone position [45] guided by periodic chest ultrasound and echocardiographic assessment may prevent the onset of supraventricular arrhythmias.

Guidelines for management of AF [46] do not usually apply readily to critically ill patients, since NOAF in patients treated on an ICU differs from AF in patients in the community in terms of causes of rhythm disturbance [47], and appropriate management [48].

#### **6.1 Electrical therapy**

Synchronized direct current cardioversion (SDCC) should be employed for patients with hemodynamic instability related to the arrhythmia, even though the probability of remaining in sinus rhythm may be low. In critically ill patients, SDCC has been investigated in few studies. The reported efficacy is generally low, ranging from 26.9% and 35.1% [49, 50]. Mayr et al. reported successful electrical cardioversion at one hour after the attempt in 13/37 (35.1%) ICU patients with NOAF. After 24 hours, six of these 37 patients (13.5%) remained in sinus rhythm. An additional study evaluating the efficacy of SDCC reported sinus rhythm restoration for at least 24 hours in 7/26 (26.9%) patients. Of note, 18 of these patients had received amiodarone prior to or during electrical cardioversion [49].

In septic shock patients with NOAF, there is lack of data on effectiveness. In a small series [28], SDCC was attempted in five patients due to hemodynamic instability. In three patients, the procedure was not effective, whereas, in one patient, sinus rhythm was restored. However, AF recurred shortly afterwards; and in one case, a stable sinus rhythm was obtained. The effectiveness of electrical therapy may be improved by concomitant antiarrhythmic medication. When electrically cardioverting 24% of septic shock patients on amiodarone and 36% on propafenone, the overall rate of sinus rhythm maintenance was significant (74% and 89%, respectively) [51]. After an initially successful cardioversion, failure to remain in sinus rhythm may signal a poor prognosis.

#### **6.2 Antiarrhythmic pharmacological therapy**

#### *6.2.1 Amiodarone*

Amiodarone is a Vaughan-Williams class III antiarrhythmic drug that is frequently used to treat atrial fibrillation, both in community and ICU settings. It is currently approved for cardioversion of atrial fibrillation (Class I, level of evidence A) [52]. It is a highly lipophilic compound with a long half life, and it is eliminated by hepatic metabolism and not by dialysis [53]. Being one of the few antiarrhythmic drugs that does not affect significantly the left ventricular ejection fraction (LVEF), its use is however limited by the occasional occurrence of systemic hypotension and because of its relatively highly toxic profile, including thyroid, lung and liver dysfunction among other detrimental effects (eg, corneal microdeposits, skin discoloration and neuropathies).

Amiodarone success in terms of rhythm control in sepsis patients varies widely, from 30% [54] to 95% [55], although rates of sustained sinus rhythm after cardioversion are substantially lower. Comparative observational studies in ICU septic patients have shown that amiodarone achieved lower rates of rhythm control than beta-blockers, magnesium and calcium channel blockers [51, 54, 56].

Specific data on amiodarone effectiveness in septic shock patients is scant. Balik et al. [51] showed in a recent study on septic shock and supraventricular arrhythmias (AF being the most frequent encountered) that amiodarone was the drug of choice in 76% of patients, likely due to the hemodynamic instability of patients in septic shock on vasoactive agents. Restoration to sinus rhythm was achieved in 74% patients while 23.7% of them required additional electrical cardioversion. The median total dose of amiodarone was 3.0 (1.8–4.6) g, given by infusion over 4 (2–6) days with a median of 1.4 (0.9–1.8) g during the first day. Due to its limited efficacy to cardiovert and to maintain sinus rhythm (74%), the patients with a persisting arrhythmia were often switched to propafenone. Interestingly, in this study, successfully cardioverted patients (with either amiodarone, propafenone or

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

metoprolol) or those having chronic AF demonstrated not significantly lower ICU and 28-day, and 12-month mortalities compared to patients remaining in an acute onset arrhythmia.

In a retrospective review of adult medical or surgical ICU patients with septic shock and NOAF that received amiodarone (n = 239), Betthauser et al. [57] found that exposure to more than or equal to 2700 mg of amiodarone was positively correlated with longer ICU length of stay. The same investigators found that compared to non-septic shock patients, septic shock patients did not show significant difference in hemodynamic deterioration within 72 hours of intravenous amiodarone administration. Of 105 patients surviving hospital discharge, 29% continued receiving oral amiodarone at discharge.

### *6.2.2 Propafenone*

Propafenone is a Vaughan-Williams class IC antiarrhythmic drug with some (but clinically limited) beta-blocking activity as a result of a structural similarity to beta-adrenoceptor antagonists [58]. Propafenone is currently approved and used frequently for cardioversion of atrial fibrillation (Class I, level of evidence A) [52]. However, since CAST (the Cardiac Arrhythmia Suppression Trial) [59] revealed that class IC antiarrhythmic drugs flecainide and encainide could increase the mortality risk when administered to patients with ventricular arrhythmias and coronary artery disease with significant left ventricular systolic dysfunction, current guidelines have restricted the recommendation of this class of drugs (including propafenone) to patients with NOAF who do not have structural heart disease [52].

The aforementioned study by Balik et al. [51], suggests that propafenone could be a drug of choice in septic shock patients with normal to moderately reduced LVEF. Propafenone was used in septic shock patients with NOAF as a primary antiarrhythmic in 17.5% of patients, but this figure rises to 33% if one takes into account the patients who were not able to cardiovert and maintain a sinus rhythm on amiodarone and then received propafenone. The observed cardioversion success rate was 86.1% at 24 h, although 35.5% needed additional SDCC to restore sinus rhythm. The success of cardioversion was significantly higher with propafenone than with amiodarone and almost the same as metoprolol (93%). The average propafenone dose was 670 (460–700) mg/day. Compared with amiodarone, propafenone use did not result in significantly lower ICU and 28-day mortalities, but was associated with a 12-month mortality benefit, although patients in propafenone group tended to have better LVFE at baseline and lower dose of vasopressor drugs (e.g., norepinephrine), likely reflecting more severe compromise of septic shock in the amiodarone group [34].

#### *6.2.3 Beta-adrenergic blockers*

Current guidelines recommend beta-blockers as first-choice drugs to control heart rate in AF patients with LVEF >40% (class I, level of evidence B) [52].

Autonomic dysfunction in septic shock may be accompanied by extreme tachycardia and high cardiac output. Tachycardia increases cardiac workload and myocardial oxygen consumption. In addition, shortening of diastolic relaxation time and impairment of diastolic function further affect coronary perfusion, contributing to a lower ischemic threshold. Although norepinephrine is the current recommended mainstay of treatment for sepsis-related hypotension, excessive adrenergic stress has multiple adverse effects including direct myocardial damage (e.g., takotsubo or stress cardiomyopathy and tachyarrhythmias), insulin resistance, thrombogenicity, immunosuppression, and enhanced bacterial growth [60]. Taken together, these mechanisms contribute to worsening of septic myocardial dysfunction and increased mortality [61].

The use of beta-adrenergic blockers has been proposed to mitigate the persistent sympathetic stimulation in septic shock patients, and this mechanism may in part be responsible of the observed improvement in prognosis. The production of cytokines may also be reduced with the consequent improvement in the metabolic dysregulation by means of reducing protein catabolism and by inhibiting gluconeogenesis [62]. On the other hand, using beta-blockers in septic shock patients is not without risks. Many patients with septic shock are already being treated with vasopressor and inotropic drugs, and treating them with beta-blockers can exacerbate hypotension and bradycardia promoting further hemodynamic instability [63].

In order to reduce the unnecessary load of catecholamines and the stimulation of their receptors, an easily titratable beta-blocker (e.g. esmolol or landiolol), may be safe in those patients who require vasopressor drugs in parallel for low systemic vascular resistance and hypotension. In an open-label, randomized single-center study (n = 154) by Morelli et al. [64], septic shock patients were assigned to receive a continuous infusion of esmolol titrated to maintain heart rate between 80/min and 94/min versus standard treatment. It was not specified how many of those patients had atrial fibrillation, so its main interest in this discussion relates to its tolerability, since traditionally it has been feared that betablockage in septic patients could result in hemodynamic deterioration. Nonetheless, the mean arterial pressure was maintained despite a marked reduction in norepinephrine requirements in the esmolol group. Also, stroke volume, systemic vascular resistance, and left ventricular stroke work indices were increased in the esmolol group. Noteworthy, it was shown that 28-day mortality was 49.4% in the esmolol group vs. 80.5% in the control group (adjusted hazard ratio, 0.39; 95% CI, 0.26 to 0.59; p < 0.001). These findings suggest that lowering of heart rate by esmolol allows better ventricular filling during diastole, hence improving stroke volume and thereby improving the efficiency of myocardial work and oxygen consumption.

Metoprolol is also well tolerated in septic shock patients with supraventricular arrhythmias. In septic shock patients with NOAF treated with intravenous metoprolol, Balik et al. [51] found that sinus rhythm was achieved in 92.3% patients with no additional electrical cardioversion. The median length of treatment was 5 (2–9) days, while the median intravenous metoprolol dose was 84 (48–120) mg/day.

A relatively new beta-blocker with high selectivity for beta1 receptors and a half-life of only 4 minutes, landiolol, has also been shown to be well tolerated in the critically ill for its limited negative inotropic effect and limited impact on blood pressure, as different Japanese teams of investigators have reported [65–67]. The use of low doses (5–10 mcg/kg/min) of landiolol is usually sufficient for the cardioversion of AF compared to controls. In sinus tachycardia, landiolol may prevent the occurrence of arrhythmias using an even lower dose (3–5 mcg/kg/min). In a multicenter, open-label, randomized controlled trial at 54 hospitals in Japan, in which 76 patients with sepsis or septic shock received intravenous landiolol and 75 patients were assigned to the control group, Kakihana et al. [68] found that Landiolol resulted in significantly more patients with sepsis-related tachyarrhythmia (55% vs. 33%, p = 0.031) achieving a heart rate of 60–94 bpm at 24 h and significantly reduced the incidence of new-onset arrhythmia. The investigators report that landiolol was also well tolerated, but should be used under appropriate monitoring of blood pressure and heart rate owing to the risk of hypotension in patients with sepsis and septic shock.

Balik et al. [34], based on studies on tachycardic patients with septic shock requiring catecholamine administration suggest the benefit of slowing heart rate by approximately 20%, but also warn that lowering heart rate below 100 per minute

by means of betablockage may result in a cardiac output inadequate to meet the systemic oxygen demands in septic shock. Appropriately powered, randomized, controlled multicenter trials are required to further clarify the role of beta-blockers in septic shock patients with NOAF.
