**3. Pharmacologic therapies for the prevention of POAF in cardiac surgery**

### **3.1 Established pharmacologic therapies**

### **3.1.1 Beta-blockers**

Beta-blockers work at the myocardium antagonizing the effects of catecholamines and have been studied extensively for the prevention of POAF. Meta-analyses have shown significant reduction in POAF incidence with the use of beta-blocker therapy, resulting in recommendation for their use as first-line therapy (Bradley et al., 2005; Dunning et al.; 2006, Fuster et al., 2006; Eagle et al., 2004, Kerr & Roy, 2004; [ESC], 2010). The largest meta-

shown to increase the production of proinflammatory cytokines, adhesion molecules, and selectins (Erlich et al., 2006; Boos et al., 2006). White blood cell count may also be a predictor of POAF (Lamm et al., 2006). The degree of inflammation postoperatively can negatively affect atrial conduction and duration of atrial fibrillation (Ishii et al., 2005; Tselentakis et al., 2006). Oxidative stress has also been implicated in the pathogenesis of atrial fibrillation as the atrial tissue undergoes oxidative challenge during CPB (Rodrigo et al., 2008). Patients with POAF have been shown to have increased acute myocardial oxidation when compared to patients that did not experience POAF (Ramlawi et al., 2007). Specifically, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, an enzyme associated with the formation of the reactive oxygen species, superoxide, was found to be independently associated with increased risk of POAF (Kim et al., 2008). This may be due to damage of cardiac myocytes through lipid peroxidation, breakdown of cell membrane, decreased mitochondrial function, calcium overload, and apoptosis (Elahi et al., 2008). Because NADPH is activated by numerous mediators including tumor necrosis factor- α (TNF-α) (Griendling et al., 2000), it has been

Based on these newly identified pathways, emerging pharmacologic therapies for the prevention of POAF have been under investigation including HMG Co-A reductase inhibitors (statins), renin-angiotensin-aldosterone-system modulators (including angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)), corticosteroids, omega-

The guidelines suggest additive therapies can be considered for patients at high risk of developing POAF. Risk factors that have been identified to increase the risk of POAF include advanced age, history of atrial fibrillation, COPD, valvular surgery, hypertension, poor left ventricular function, chronic renal insufficiency, diabetes mellitus, rheumatic heart disease, withdrawal of preoperative beta-blockers or ACEIs, and increased aortic crossclamp and CPB time (Mathew et al., 2004; Baker et al., 2007b; Nisanoglu et al., 2007). No simple criteria exist that allow patients to be classified as high risk for the development of POAF. A risk index model (Multicenter Study of Perioperative Ischemia Atrial Fibrillation Risk Index) (Table 2) was developed to identify subjects at high risk for POAF (Mathew et al., 2004). Patients receiving a risk score less than 14 were considered low risk, 14-31 were considered medium risk, and greater than 31 were considered high risk for developing POAF. Comparison of the predictive ability of the model revealed that the incidence of atrial fibrillation was similar in the derivation and validation cohorts across the three risk groups, and the area under the receiver operating characteristic curve applied to the final model was 0.77 (where >0.75 represents a model with good discriminate power). This risk scoring tool has been used to stratify patients into risk groups that may benefit from add-on prophylactic

**3. Pharmacologic therapies for the prevention of POAF in cardiac surgery** 

Beta-blockers work at the myocardium antagonizing the effects of catecholamines and have been studied extensively for the prevention of POAF. Meta-analyses have shown significant reduction in POAF incidence with the use of beta-blocker therapy, resulting in recommendation for their use as first-line therapy (Bradley et al., 2005; Dunning et al.; 2006, Fuster et al., 2006; Eagle et al., 2004, Kerr & Roy, 2004; [ESC], 2010). The largest meta-

proposed as a link between inflammation and oxidative stress in POAF.

3 fatty acids, ascorbic acid, N-acetylcysteine, and sodium nitroprusside.

therapy (Barnes et al., 2006).

**3.1.1 Beta-blockers** 

**3.1 Established pharmacologic therapies** 


aRisk Groups based on summative total point assignment using predictors from table:

Low risk = Score < 14, Medium risk = Score 14-31, High risk = Score >31

ACEI = angiotensin converting enzyme inhibitor, AF = atrial fibrillation, BB = beta-blocker, CABG = coronary artery bypass graft, COPD = chronic obstructive pulmonary disease, NSAIDs = non-steroidal anti-inflammatory drugs, POAF = postoperative atrial fibrillation

Table 2. Multicenter Study of Perioperative Ischemia Atrial Fibrillation Risk Index (Mathew et al., 2004)

analysis was published in 2002 by Crystal et al. that included 27 randomized controlled trials with 3,840 patients (Crystal et al., 2002). Use of beta-blocker therapy decreased the incidence of POAF from 33% in the control group compared to 19% in the group receiving beta-blockade. This corresponded to a number needed to treat (NNT) of seven patients. A large retrospective analysis of the Society of Thoracic Surgeons (STS) database containing 629,877 patients, demonstrated a reduction in mortality rate with use of peri-operative betablockers (Ferguson et al., 2002). It has been shown that patients receiving perioperative betablockers have reduced mortality compared to control (3.4% versus 2.8%, OR 0.8, 95% CI 0.78 – 0.82; p<0.001). Efficacy of beta-blockade in the prevention of POAF has been theorized to decrease hospital LOS. However, two beta-blocker trials reporting effect on LOS demonstrated a non-significant reduction in LOS (-0.66 days; 95% CI, -2.04-0.72) (Cybulsky et al., 2000; Wenke et al., 1999).

The importance of beta-blockers is also affirmed by the two to five-fold increase in the incidence of POAF when beta-blockers are discontinued postoperatively (Kalman et al., 1995; Jideus et al., 2000; Ali et al., 1997). The increase in POAF is thought to be caused by

Strategies for the Prevention of Postoperative Atrial Fibrillation in Cardiac Surgery 213

versus other pharmacological agents has been established. Two meta-analysis have been conducted evaluating the efficacy of amiodarone in POAF in which a statistically significant decrease in incidence was established (Bagshaw et al., 2006; Haan et al., 2002). Comparisons of amiodarone effectiveness have been made with agents such as beta-blockers (propranolol, metoprolol, and bisoprolol), sotalol, digoxin, and diltiazem. No clear superiority has been established amongst comparative trials. Amiodarone has been given in direct combination with metoprolol, magnesium, and atrial septal pacing in Bachmanns's Bundle (Auer et al., 2004a; Cagli et al.; 2006, White et al., 2003). All of these studies showed amiodarone in direct combination with the previous pharmacologic and non-pharmacologic options to be superior than that of placebo, with absolute reductions in the incidence of POAF by 20% to 24% (Auer et al., 2004a; Cagli et al., 2006; White et al., 2003). Combination therapy with amiodarone and beta-blockers has been well validated. A meta-analysis also found that amiodarone also significantly reduces the LOS by 0.91 days (95% CI, -1.59- -0.24) (Crystal et

Various dosing regimens using IV and/or oral amiodarone with varying administration times have been used in the POAF prevention trials. A meta-analysis evaluating 14 randomized, controlled trials in 2,864 patients, stratified into low (<3 g), medium (3-5 g), or high (>5 g) and timing was divided into preoperative or postoperative administration, found that cumulative doses of >3 g may be more effective than lower doses and

Amiodarone is effective for the prevention of POAF, however it has a complex side effect profile that includes QTc interval prolongation, pulmonary and liver toxicity, thyroid abnormalities, and visual disturbances. Patients with any of these pre-existing conditions may be placed at more risk with the addition of amiodarone for the prevention of POAF and the risk versus benefit must be evaluated for each patient. Side effects of amiodarone are typically associated with large cumulative doses and prolonged use. However, dosing regimens for prophylaxis tend to be short in duration, use lower cumulative dosing, and may use more convenient oral doses with or without a short course of IV amiodarone to avoid side effects associated with IV administration. The safety of amiodarone in patients undergoing cardiac surgery has been evaluated in a meta-analysis reviewing 18 randomized controlled trials (Patel et al., 2006). Results showed that amiodarone use was significantly associated with increased risk of hypotension (OR 1.79; 95% CI 1.04-3.09) and bradycardia (OR 2.33; 95% CI 1.41-3.61), especially when the intravenous formulation was utilized in high doses (greater than 1 gram). Therefore, clinicians should be cautious using amiodarone, especially in combination therapy with beta-blockers or other therapies that may cause bradycardia or hypotension. Finally, if amiodarone therapy is added to a patient's medication profile, physical and laboratory exams should be conducted and

preoperative initiation of amiodarone may be unnecessary (Buckley et al., 2007).

evaluated for the presence of drug-drug interactions or medication side effects.

Sotalol, a class III antiarrhythmic that possess beta-blocking activity, has been shown to be an effective pharmacological agent for the prevention of POAF. Within the primary literature, sotalol has demonstrated absolute reductions in the incidence of POAF between 13% - 16% (Auer et al., 2004a; Janssen et al., 1986; Suttorp et al., 1991; Weber et al., 1998; Evrard et al., 2000). Despite its demonstrated effectiveness, sotalol is contraindicated in patients with severe renal insufficiency and should be avoided in patients with heart failure. Furthermore, because of its propensity to cause torsades de pointes, it should be avoided in

al., 2002).

**3.1.3 Sotalol** 

beta-blocker withdrawal and mediated by an upregulation of beta adrenergic receptors and sympathetic stimulation (Kalman et al., 1995). Beta-blocker withdrawal is significantly associated with a greater than two-fold risk of developing POAF in cardiac surgery patients (Adjusted OR 2.17, 95% CI 1.11-4.25, p=0.04) (Lertsburapa et al., 2008). Thus, timing of betablocker administration appears play an important role and evidence supports the continuation of beta-blocker therapy from the preoperative stage through postoperative management. The guidelines emphasize the importance of reinitiating beta-blockers postoperatively without delay (Bradley et al., 2005).

In addition, the mode of administration of beta-blocker therapy has been evaluated in the prevention of POAF. Intravenous administration of metoprolol has demonstrated superiority to oral administration when accessing for the prevention of POAF. This is theorized to be a result of diminished gastrointestinal absorption with oral administration early after surgery. This phenomenon has been demonstrated by Halonen et al., when a significant reduction (p=0.036) of POAF occurrence by 11.3% was noted to occur in patients assigned to receive intravenous metoprolol therapy compared to patients assigned oral therapy (Halonen et al., 2006).

Controversy exists around selection of the most effective beta-blocker in reducing POAF. Two studies have demonstrated improved efficacy of carvedilol when compared to metoprolol (Acikel et al., 2008; Haghjoo et al., 2007). This was confirmed by approximately 18%-20.4% less episodes of POAF in those patients assigned to receive carvedilol.

Despite the overwhelming evidence to support beta-blocker therapy in the prevention of POAF, contraindications to this therapy exist. Alternative pharmacologic and nonpharmacologic modalities are warranted for patients who cannot tolerate or have the following contraindications to beta-blockers: bradycardia (<45 bpm), heart block, cardiac failure, severe peripheral edema, sick-sinus syndrome, bronchospastic disease (non-selective beta-blockers), and hypotension (SBP < 100 mmHg) with myocardial infarction.

### **3.1.2 Amiodarone**

Amiodarone, a class III antiarrhythmic agent, has shown efficacy in the prevention of POAF. Its activity is demonstrated through blockade of alpha and beta-adrenergic receptors as well as sodium, calcium and potassium channels. Only beta-blockers have more safety and efficacy data to support their effectiveness in the prevention of POAF. Most randomized, controlled trials have supported the efficacy of amiodarone over placebo in the prevention of POAF by showing reduction of occurrence between 12% to 51% (Auer et al., 2004a; Barnes et al., 2006; Daoud et al., 1997; Guarnieri et al., 1999; Giri et al., 2001; White et al., 2002; Yazigi et al., 2002; Tokmakoglu et al., 2002; White et al., 2003; Mitchell et al., 2005a; Budeus et al., 2006; Zebis et al., 2007). Therefore, amiodarone has been granted a class IIa recommendation for POAF prophylaxis, behind beta-blockers, according to the ACC/AHA/ESC 2006 AF Guidelines, ACC/AHA 2004 CABG Guidelines, 2004 CCS AF/POAF Consensus statement, and ESC 2010 (Fuster et al., 2006; Eagle et al., 2004; Kerr & Roy, 2004; ESC, 2010). Additionally, the guidelines support amiodarone as prophylactic therapy in patients unable to tolerate beta-blockers or in high-risk patients with or without beta-blocker therapy (Bradley et al., 2005).

Two trials evaluating amiodarone versus placebo have demonstrated clear reduction of POAF occurrence (Mitchell et al., 2005b; Daoud et al., 1997). Compared to placebo, amiodarone reduced POAF incidence by 13.4%-19%. Effectiveness between amiodarone versus other pharmacological agents has been established. Two meta-analysis have been conducted evaluating the efficacy of amiodarone in POAF in which a statistically significant decrease in incidence was established (Bagshaw et al., 2006; Haan et al., 2002). Comparisons of amiodarone effectiveness have been made with agents such as beta-blockers (propranolol, metoprolol, and bisoprolol), sotalol, digoxin, and diltiazem. No clear superiority has been established amongst comparative trials. Amiodarone has been given in direct combination with metoprolol, magnesium, and atrial septal pacing in Bachmanns's Bundle (Auer et al., 2004a; Cagli et al.; 2006, White et al., 2003). All of these studies showed amiodarone in direct combination with the previous pharmacologic and non-pharmacologic options to be superior than that of placebo, with absolute reductions in the incidence of POAF by 20% to 24% (Auer et al., 2004a; Cagli et al., 2006; White et al., 2003). Combination therapy with amiodarone and beta-blockers has been well validated. A meta-analysis also found that amiodarone also significantly reduces the LOS by 0.91 days (95% CI, -1.59- -0.24) (Crystal et al., 2002).

Various dosing regimens using IV and/or oral amiodarone with varying administration times have been used in the POAF prevention trials. A meta-analysis evaluating 14 randomized, controlled trials in 2,864 patients, stratified into low (<3 g), medium (3-5 g), or high (>5 g) and timing was divided into preoperative or postoperative administration, found that cumulative doses of >3 g may be more effective than lower doses and preoperative initiation of amiodarone may be unnecessary (Buckley et al., 2007).

Amiodarone is effective for the prevention of POAF, however it has a complex side effect profile that includes QTc interval prolongation, pulmonary and liver toxicity, thyroid abnormalities, and visual disturbances. Patients with any of these pre-existing conditions may be placed at more risk with the addition of amiodarone for the prevention of POAF and the risk versus benefit must be evaluated for each patient. Side effects of amiodarone are typically associated with large cumulative doses and prolonged use. However, dosing regimens for prophylaxis tend to be short in duration, use lower cumulative dosing, and may use more convenient oral doses with or without a short course of IV amiodarone to avoid side effects associated with IV administration. The safety of amiodarone in patients undergoing cardiac surgery has been evaluated in a meta-analysis reviewing 18 randomized controlled trials (Patel et al., 2006). Results showed that amiodarone use was significantly associated with increased risk of hypotension (OR 1.79; 95% CI 1.04-3.09) and bradycardia (OR 2.33; 95% CI 1.41-3.61), especially when the intravenous formulation was utilized in high doses (greater than 1 gram). Therefore, clinicians should be cautious using amiodarone, especially in combination therapy with beta-blockers or other therapies that may cause bradycardia or hypotension. Finally, if amiodarone therapy is added to a patient's medication profile, physical and laboratory exams should be conducted and evaluated for the presence of drug-drug interactions or medication side effects.

### **3.1.3 Sotalol**

212 Special Topics in Cardiac Surgery

beta-blocker withdrawal and mediated by an upregulation of beta adrenergic receptors and sympathetic stimulation (Kalman et al., 1995). Beta-blocker withdrawal is significantly associated with a greater than two-fold risk of developing POAF in cardiac surgery patients (Adjusted OR 2.17, 95% CI 1.11-4.25, p=0.04) (Lertsburapa et al., 2008). Thus, timing of betablocker administration appears play an important role and evidence supports the continuation of beta-blocker therapy from the preoperative stage through postoperative management. The guidelines emphasize the importance of reinitiating beta-blockers

In addition, the mode of administration of beta-blocker therapy has been evaluated in the prevention of POAF. Intravenous administration of metoprolol has demonstrated superiority to oral administration when accessing for the prevention of POAF. This is theorized to be a result of diminished gastrointestinal absorption with oral administration early after surgery. This phenomenon has been demonstrated by Halonen et al., when a significant reduction (p=0.036) of POAF occurrence by 11.3% was noted to occur in patients assigned to receive intravenous metoprolol therapy compared to patients assigned oral

Controversy exists around selection of the most effective beta-blocker in reducing POAF. Two studies have demonstrated improved efficacy of carvedilol when compared to metoprolol (Acikel et al., 2008; Haghjoo et al., 2007). This was confirmed by approximately

Despite the overwhelming evidence to support beta-blocker therapy in the prevention of POAF, contraindications to this therapy exist. Alternative pharmacologic and nonpharmacologic modalities are warranted for patients who cannot tolerate or have the following contraindications to beta-blockers: bradycardia (<45 bpm), heart block, cardiac failure, severe peripheral edema, sick-sinus syndrome, bronchospastic disease (non-selective

Amiodarone, a class III antiarrhythmic agent, has shown efficacy in the prevention of POAF. Its activity is demonstrated through blockade of alpha and beta-adrenergic receptors as well as sodium, calcium and potassium channels. Only beta-blockers have more safety and efficacy data to support their effectiveness in the prevention of POAF. Most randomized, controlled trials have supported the efficacy of amiodarone over placebo in the prevention of POAF by showing reduction of occurrence between 12% to 51% (Auer et al., 2004a; Barnes et al., 2006; Daoud et al., 1997; Guarnieri et al., 1999; Giri et al., 2001; White et al., 2002; Yazigi et al., 2002; Tokmakoglu et al., 2002; White et al., 2003; Mitchell et al., 2005a; Budeus et al., 2006; Zebis et al., 2007). Therefore, amiodarone has been granted a class IIa recommendation for POAF prophylaxis, behind beta-blockers, according to the ACC/AHA/ESC 2006 AF Guidelines, ACC/AHA 2004 CABG Guidelines, 2004 CCS AF/POAF Consensus statement, and ESC 2010 (Fuster et al., 2006; Eagle et al., 2004; Kerr & Roy, 2004; ESC, 2010). Additionally, the guidelines support amiodarone as prophylactic therapy in patients unable to tolerate beta-blockers or in high-risk patients with or without

Two trials evaluating amiodarone versus placebo have demonstrated clear reduction of POAF occurrence (Mitchell et al., 2005b; Daoud et al., 1997). Compared to placebo, amiodarone reduced POAF incidence by 13.4%-19%. Effectiveness between amiodarone

18%-20.4% less episodes of POAF in those patients assigned to receive carvedilol.

beta-blockers), and hypotension (SBP < 100 mmHg) with myocardial infarction.

postoperatively without delay (Bradley et al., 2005).

therapy (Halonen et al., 2006).

**3.1.2 Amiodarone** 

beta-blocker therapy (Bradley et al., 2005).

Sotalol, a class III antiarrhythmic that possess beta-blocking activity, has been shown to be an effective pharmacological agent for the prevention of POAF. Within the primary literature, sotalol has demonstrated absolute reductions in the incidence of POAF between 13% - 16% (Auer et al., 2004a; Janssen et al., 1986; Suttorp et al., 1991; Weber et al., 1998; Evrard et al., 2000). Despite its demonstrated effectiveness, sotalol is contraindicated in patients with severe renal insufficiency and should be avoided in patients with heart failure. Furthermore, because of its propensity to cause torsades de pointes, it should be avoided in

Strategies for the Prevention of Postoperative Atrial Fibrillation in Cardiac Surgery 215

medications. If magnesium is utilized in the prevention of POAF, doses of 2.5-5 g have been most commonly utilized (Nurozler et al., 1996; Maslow et al., 2000; Kohno et al., 2005). When utilized in combination with B-blockers, clinicians should monitor for hypotension as combination therapy has been shown to significantly increase the risk of hypotension compared to B-blocker therapy alone (24.4% versus 43.5%, p=0.01) (Solomon et al., 2000). Finally, it should be noted that magnesium levels need to be monitored carefully throughout cardiac surgery and postoperatively regardless if magnesium is being utilized as

**4. Emerging pharmacologic therapies for the prevention of POAF in cardiac** 

HMG Co-A reductase inhibitors (statins) may possess pleiotropic activity beyond lipid lowering effects and may be protective against POAF. They have been shown to reduce oxidative stress by inhibiting oxidant enzymes, up-regulate antioxidant enzymes, and enhance nitric oxide bioavailability (Paraskevas, 2008). It is also proposed that they possess direct antiarrhythmic effects mediated through cell membrane stabilization, downregulation of the renin-angiotensin-aldosterone-system (RAAS), and protection of ischemic myocardium (Howard & Barnes, 2008). They also have been shown to reduce the expression of inflammatory mediators (i.e. interleukin-6 **(**IL-6), interleukin-8 **(**IL-8), tumor necrosis factor- α (TNF-α), C-reactive protein (CRP), cyclooxygenase 2) and decrease the expression of CD11b with consequential decreased adherence to endothelial cells of vein grafts (Chello et al., 2006; Patel et al., 2007). Therefore, statins may favorably impact the acute inflammatory response and alter atrial refractoriness or sympathetic activation that could

Many trials have evaluated the effect of statins on the incidence of POAF in cardiac surgery patients. Prospective, randomized trials found an absolute reduction in the incidence of POAF of 14% to 22% with statins compared to placebo or usual care (Chello et al., 2006; Patti et al, 2006; Song et al., 2008; Ji et al., 2009). The largest and most robust of these three trials was the Atorvastatin for Reduction of MYocardial Dysrhythmia After cardiac surgery study (ARMYDA-3) in which a significant reduction in POAF of 22% and a reduction in LOS of 0.6 days was observed with a statin compared to placebo (Patti et al., 2006). This study enrolled only patients who had no previous history of statin use and these patients could have less risk of pre-existing atherosclerotic disease and subsequently been at lower risk for

Other statin trials in CABG patients are observational, cohort studies with conflicting results of no benefit (Thielmann et al., 2007; Mithani et al., 2009) or a significant reduction in the incidence of POAF (Lertsburapa et al., 2008; Subramaniam et al., Mariscalco et al., Ozaydin

One study evaluated the combination of a statin and beta-blocker on the incidence of POAF. Monotherapy with atorvastatin or a beta-blocker reduced the risk of POAF by 61% (OR 0.39; 95% CI 0.18-0.85) and 82% (OR 0.19; 95% CI 0.08-0.44), respectively. However, the combination of atorvastatin plus a beta-blocker performed better by reducing the risk of POAF by 90% (OR 0.10; 95% CI 0.02-0.25) (Patti et al., 2006). The combination of preoperative and postoperative beta-blocker and amiodarone prophylaxis in 40% of patients may have also influenced the positive results in the statin group (Lertsburapa et al., 2008).

a pharmacological agent for the prophylaxis of POAF.

**4.1 HMG Co-A reductase inhibitors** 

lead to POAF after cardiac surgical procedures.

et al., 2007; Miceli et al., 2009a; Kinoshita et al., 2010).

**surgery** 

developing POAF.

patients with congenital long QT syndrome or a baseline corrected QT interval greater than 440 msec. Due to its beta-blocking properties, sotalol is contraindicated in patients intolerant of beta-blockers. Because of the aforementioned limitations of this agent, sotalol has been granted a class IIb recommendation for POAF prophylaxis behind beta-blockers according to the ACC/AHA/ESC 2006 AF Guidelines and the ACC/AHA 2004 CABG Guidelines (Fuster et al., 2006; Eagle et al., 2004). The most recent 2010 ESC guidelines have assigned a Class IIb recommendation for sotalol due to its proarrhythmic risk (ESC, 2010). However, the earlier 2006 EACTS guidelines gave sotalol a stronger grade A recommendation based upon its comparative efficacy trials versus beta-blockers (Dunning et al., 2006) similar to ACC recommendations.

Patel and Dunning evaluated seven different randomized trials comparing sotalol to conventional beta blockers (Patel et al., 2005). Out of the seven trials evaluated, five studies demonstrated a statistically significant reduction in POAF for those patients assigned to sotalol compared to conventional beta-blockade. The number of patients needed to be treated with sotalol to prevent POAF over that of conventional beta-blocker therapy was found to be 10. Conversely, because of the pro-arrythmic properties of sotalol, conventional beta-blocker therapy may be a safer option.

### **3.1.4 Magnesium**

POAF has been associated with decreased postoperative magnesium levels (Kalman et al., 1995). In fact, plasma magnesium concentration levels less that 0.9 mmol have been found to be an independent predictor of POAF (OR 6.7) when using multivariate logistic regression models (Treggiari-Venzi et al., 2000). Multiple large, randomized, controlled trials with magnesium have failed to demonstrate superiority to usual care with no magnesium in the prevention of POAF. These trials included various delivery forms of magnesium including: IV infusion (Treggiari-Venzi et al., 2000; Serafimovski et al., 2008; Caspie et al., 1995; Bert et al., 2001; Zangrillo et al., 2005), IV infusion based on serum levels (Wilkes et al., 2002), magnesium supplementation in maintenance fluids (Colquhoun et al., 1993) and in supplementation through cardioplegia solution (Shakerinia et al., 1996). Surprising lower cumulative doses of magnesium supplementation (mean cumulative dose 8.2 g) have shown to be more effective in reducing the incidence of POAF (OR 0.36, 95% CI 0.23-0.56), compared to higher doses (mean cumulative dose 15 g) (OR 0.99, 95% CI 0.70-1.41) (Henyan et al., 2005). Results from the same meta-analysis found that preoperative administration of magnesium was more effective at decreasing the incidence of POAF (OR 0.46, 95% CI 0.31- 0.67) compared to intraoperative or postoperative administration. Results from several meta-analysis (Woodend et al., 1998; Burgess et al., 2006; Shiga et al., 2004; Miller et al., 2005; Alghamdi et al., 2005; Henyan et al., 2005; Shepard et al., 2008) have shown inconsistent efficacy with magnesium use. A few studies have demonstrated a significant benefit of magnesium when compared to usual care with absolute reductions in the incidence of POAF by 16% to 34% (Nurozler et al., 1996; Maslow et al., 2000; Kohno et al., 2005). However, at this time there is a lack of statistically significant data to support magnesium supplementation as monotherapy compared to that of beta-blocker, amiodarone, or sotalol therapy in the treatment of POAF (Bert et al., 2001; Solomon et al., 2000; Cagli et al., 2006). Only the CCS consensus statement includes magnesium as a Class IIa recommendation, however no other guidelines strongly recommend its use for the prevention POAF (Kerr & Roy, 2004). Magnesium therapy may be considered in combination with amiodarone and/or B-blocker therapy for those patients deemed at high risk or intolerant to the latter medications. If magnesium is utilized in the prevention of POAF, doses of 2.5-5 g have been most commonly utilized (Nurozler et al., 1996; Maslow et al., 2000; Kohno et al., 2005). When utilized in combination with B-blockers, clinicians should monitor for hypotension as combination therapy has been shown to significantly increase the risk of hypotension compared to B-blocker therapy alone (24.4% versus 43.5%, p=0.01) (Solomon et al., 2000). Finally, it should be noted that magnesium levels need to be monitored carefully throughout cardiac surgery and postoperatively regardless if magnesium is being utilized as a pharmacological agent for the prophylaxis of POAF.
