**4.9 Levosimendan**

220 Special Topics in Cardiac Surgery

N-acetylcysteine (NAC) has been theorized to prevent POAF based on its antioxidant activity as a free radical scavenger and ability to reduce cellular damage in the atrium (Carnes et al., 2007). Two recent studies, which were randomized and placebo-controlled, found conflicting results with NAC in the prophylaxis of POAF (El-Hamamsy et al, 2007; Ozaydin et al., 2008b). The first study failed to demonstrate a significant reduction in the incidence of POAF (7% with NAC versus 12% with placebo, p=0.7). A more recent study, which included valve surgeries, did show a significant benefit with NAC compared to placebo (5% versus 21%, p=0.01). After controlling for perioperative beta-blocker use, NAC was still associated with a significant reduction in POAF (OR 0.17, 95% CI 0.04-0.69, p=0.01). Neither study found a significant reduction in LOS. Both studies reported substantial preoperative beta-blocker use while Ozaydin et al also reported substantial postoperative beta-blocker utilization. Two conflicting meta-analyses have been recently published, one that found a statistically significant reduction in POAF with NAC use (36%, 95% CI 2-58%, total n=1,338) and one larger one that did not (OR 0.67, 95% CI 0.37-1.22, p=0.19, total n=1,407) (Baker et al., 2009; Wang et al., 2011). Large, prospective, randomized clinical trials are necessary to determine if NAC is effective in

One pilot study evaluated sodium nitroprusside as an agent for POAF prophylaxis compared to placebo (Cavolli et al., 2008). This study demonstrated a significant reduction in the incidence of POAF when compared to placebo (12% versus 36%, p=0.005) and a significant reduction in mean LOS (7.3 + 0.7 days versus 9.1 + 1.2 days, p<0.001). The authors suggest that nitric oxide (NO) function may be disrupted due to ischemiareperfusion injury and that administration of NO donors such as nSNP could recover this function. SNP may also reduce POAF by reducing left atrial stretching due to preload and afterload reduction. This study also showed a significant reduction in serum CRP levels in patients given SNP when compared to placebo (p<0.05), suggesting some possible effects on inflammation. Though not significant, more patients randomized to SNP received preoperative beta-blockers when compared to the placebo group (68% versus 58% p=0.303). Postoperative beta-blocker use was not addressed. Likewise, patients in this study had relative preserved ejection fractions (60-61%). Currently, SNP is routinely used in institutions for the management of postoperative hypertension. Patients receiving this

medication may also experience an additional benefit of arrhythmia prevention.

Dofetilide has been compared to placebo for postoperative atrial tachycardia (POAT) prophylaxis in one study (Serafimovski et al., 2008). The investigators found that patients receiving dofetilide prophylaxis experienced a significant reduction in the incidence of POAT, including atrial fibrillation and atrial flutter, when compared to placebo (18% versus 36%, p<0.017). There was no significant decrease in mean LOS. Although the use of postoperative beta-blockers was not reported, the authors conclude that the dofetilide group experienced a significant decrease in POAT independent of concomitant beta-blocker use based on multivariate logistic regression accounting for preoperative beta-blocker use. Due to cost, stringent prescribing and monitoring guidelines, and lack of robust head to head trials, dofetilide is not currently recommended as first line POAF prophylaxis. Like sotalol,

reducing the occurrence of POAF in addition to beta-blockers.

**4.6 N-Acetylcysteine** 

**4.7 Sodium nitroprusside** 

**4.8 Dofetilide** 

Levosimendan is an intravenous calcium sensitizer agent that is used for the treatment of acute decompensated heart failure. It increases myocardial contraction without increasing myocardial oxygen consumption and produces coronary and peripheral vasodilation (Lilleberg et al., 1998). While the drug is not approved and will not be pursued for FDA approval in the US, it has been shown in one study to significantly reduce the incidence of POAF and increase stroke volume in patients with ejection fraction <30% when compared to milrinone (50% for milrinone, 5% for levosimendan started post anesthesia, and 35% for levosimendan started after cross clamp release, p<0.01) (De Hert et al., 2008). Very few patients in this study, however, were taking preoperative beta-blockers (~13-14%) and all patients received dobutamine after the release of the cross clamp.
