Superior Myocardial Protection Using “Polarizing” Adenosine, Lidocaine, and Mg²⁺ Cardioplegia in Humans

Myocardial protection with current methods of cardioplegia is still incomplete (1–3). Several studies have shown that hyperkalemic solution may lead to cell injury (1,2). Adenosine-lidocaine-magnesium (ALM) is a new normokalemic, “polarizing” method of cardioplegia that arrests the heart at its resting membrane potential (1). Pre-clinical studies have shown ALM to provide improved protection compared with hyperkalemic solutions (1,2). A recent clinical trial also observed improved outcomes with ALM-enriched hyperkalemic cardioplegia (3). We hypothesized that normokalemic, “full-polarizing” ALM microplegia from induction to reanimation provides improved myocardial protection compared with hyperkalemic arrest (3).

After institutional review board approval was obtained, 208 patients requiring elective, isolated, low-risk coronary artery bypass graft surgery or aortic valve replacement were prospectively enrolled and provided informed consent. Patients were randomized to standard 4:1 Buckberg cardioplegia (3) (104 patients; high-K⁺ group) or full-polarizing ALM microplegia (104 patients; ALM group). ALM microplegia had physiological [K⁺] in the arrest/induction bolus (5 mEq/l; reference range: 3.5 to 5.0 mEq/l), and in the high-K⁺ group, K⁺ >15 mEq/l (3). The primary efficacy endpoint was troponin I, measured before anesthetic induction (T0), at intensive care unit (ICU) admission (T1), at the 6th hour post-operatively (T2), and at the 18th hour post-operatively (T3). Using a superiority design, with 80% power and an alpha value of 5%, 100 patients per arm were required to detect a 20% troponin I difference at T2 (high-K⁺ group, mean 5.1 ± 2.5 μg/l) (3). Coronary sinus troponin I, lactate, venous oxygen saturation (SvO₂), and base excess (BE) were measured before aortic cross clamping (T0_cs) and 10 min after aortic-declamping (T1_cs). The “myocardial anaerobic index” was calculated from coronary sinus lactate/SvO₂.

Secondary endpoints were cardiac index, indexed systemic vascular resistance, pulmonary capillary wedge pressure, indexed pulmonary vascular resistance, and central venous pressure, collected pre-operatively (T0), at the end of cardiopulmonary bypass (T1), at ICU admission (T2), at the 6th hour post-operatively (T3), and at the 18th hour post-operatively (T4).

European System for Cardiac Operative Risk Evaluation scores were low and comparable in the 2 groups (ALM group 1.6 ± 0.9% vs. high-K⁺ group 1.7 ± 0.9, p = 0.58); similarly, the percentage of patients undergoing coronary artery bypass graft surgery and aortic valve replacement was similar (ALM group 78 [75%] and 26 [25%] vs. high-K⁺ group 72 [69.2%] and 32 [30.8%], p = 0.35). ALM induction required 34 s longer to cardiac arrest (162 vs. 128 s, p = 0.03). After declamping, 79% of ALM patients spontaneously returned to sinus rhythm, compared with 48% in the high-K⁺ group (p < 0.001). Aortic cross-clamping time (ALM group 53.0 ± 18.4 min vs. high-K⁺ group 52.2 ± 19.9 min, p = 0.78) and cardiopulmonary bypass time (ALM group 75.4 ± 25.2 min vs. high-K⁺ group 79.9 ± 24.3 min, p = 0.18) were comparable. In the ALM group, coronary sinus troponin I and lactate were lower and SvO₂ and BE higher: troponin I (ALM group T0_cs 0.9 ± 0.7 μg/l and T1_cs 1.3 ± 0.7 μg/l vs. high-K⁺ group T0_cs 0.9 ± 1.0 μg/l and T1_cs 2.3 ± 2.6 μg/l, p = 0.002), lactate (ALM group T0_cs 1.0 ± 0.4 mmol/l and T1_cs 1.5 ± 0.5 mmol/l vs. high-K⁺ group T0_cs 0.9 ± 0.3 mmol/l and T1_cs 1.8 ± 0.5 mmol/l, p < 0.001), SvO₂ (ALM group T0_cs 51.4 ± 10.8% and T1_cs 62.9 ± 12.3% vs. high-K⁺ group T0_cs 53.2 ± 12.2% and T1_cs 51.1 ± 11.5%, p < 0.001), and BE (ALM group T0_cs 0.5 ± 2.8 and T1_cs −0.1 ± 1.4 vs. high-K⁺ group T0_cs 0.7 ± 3.0 and T1_cs −0.9 ± 2.2, p = 0.001). In the ALM group, the myocardial anaerobic index at reperfusion was lower than in the high-K⁺ group (0.02 ± 0.02 vs. 0.04 ± 0.01, p = 0.001, between-group p = 0.003). Coronary sinus [K⁺] in the ALM group was significantly lower at reperfusion (3.9 ± 0.4 mEq/l vs. high-K⁺ group 5.8 ± 0.4 mEq/l, p = 0.012) and remained within normal reference values. When “peak” troponin I was considered, the following distribution was observed in patients: 1) ≤50 × 99th percentile upper reference limit (URL) = ALM group 24% versus high-K⁺ group 34.6%; 2) 50 to 100 × 99th percentile URL = ALM group 6.7% vs. high-K⁺ group 5.8%; 3) 100 to 150 × 99th percentile URL = ALM group 59.6% vs. high-K⁺ group 21.2%; and 4) >150 × 99th percentile URL = ALM group 9.6% vs. high-K⁺ group 38.5% (p < 0.001). Peripheral blood troponin I and lactate were significantly lower after ALM, with an improved “cardiodynamic” pattern (Table 1). There were no acute myocardial infarctions or hospital deaths. Perioperative low–cardiac output syndrome (3.8% in the ALM group vs. 4.8% in the high-K⁺ group, p = 0.75), inotropic support (p = NS), and length of hospitalization (8.2 ± 4.1 days vs. high-K⁺ group 8.1 ± 2.9 days, p = 0.78) were similar. A shorter ICU stay was reported after ALM (27.2 ± 13.5 h vs. 36.6 ± 26.1 h, p < 0.01).

High-potassium arrest has been the standard of care in cardiac surgery for decades (1). The present study is the first prospective, randomized human trial examining fully polarized “normokalemic” blood ALM cold cardioplegia. Previous studies relate to “substrate enrichment” of K⁺-based depolarizing solutions with membrane-polarizing substances (1–3). We report that normokalemic ALM cardioplegia led to superior cardioprotection on the basis of: 1) significantly higher spontaneous return to sinus rhythm; 2) significantly lower coronary sinus troponin I, lactate, and K⁺ at reperfusion; and 3) significantly lower peripheral blood troponin I and lactate with improved cardiac index during the first 18 h (Table 1). These benefits were associated with 1 less day in the ICU. ALM was also associated with lower myocardial anaerobic index at reperfusion, indicating improved oxygen-based ATP support of cardiac work in a normokalemic environment, consistent with a higher BE and less myocardial acidosis (4).

In summary, this prospective randomized trial shows that normokalemic “polarized” ALM cardioplegia is safe and efficacious in elective surgery. Further multicenter trials are in the planning stages.

• American College of Cardiology Foundation