The heart requires a continuous supply of oxygen and substrates to maintain contractile function. The interruption of blood flow is termed ischemia, while its resumption is called reperfusion, which itself induces a myocardial injury mechanism known as reperfusion injury. It is often challenging to distinguish this from ischemic damage, so the combined term ischemia/reperfusion injury is used. During myocardial ischemia, there is a period during which cardiac function can fully or partially recover, known as the ischemia tolerance period. Once this period is surpassed, irreversible myocardial damage will occur. In humans, this timeframe is approximately 20 minutes under normothermic conditions. 

With the advent of cardiopulmonary bypass (CPB), the need to extend heart function exclusion times increased. The primary metabolic approach applied to extend myocardial ischemia tolerance was cooling to reduce oxygen consumption. Surgeons operated under the motto “operate as fast and as cold as possible.” To improve myocardial protection (MP), inducing cardiac arrest by modifying cellular membrane potentials was also evaluated. This approach was termed “cardioplegia.” 

Cold cardioplegia (CP) is currently the most used technique in cardiac surgery (CS) worldwide. MP strategies have remained unchanged for decades, with the most recent being the Del Nido CP, dating back to the 1990s. Comparing the number of CS articles published in the 1990s and 2010s, scientific production tripled, while publications related to MP or CP halved. 

Patient profiles have changed; they are older with more comorbidities, while CP solutions remain the same. 

– Comparison of cardioplegic solutions and administration techniques: 

CP types can be differentiated based on solvent (crystalloid or blood), mechanism to achieve asystole (extra- or intracellular ionic profile, hyperdepolarization), temperature (cold-warm-hot), administration route (antegrade, retrograde), or dose frequency (single, intermittent, continuous). This results in the elimination of the spontaneous generation and propagation of electrical impulses that trigger myocardial contraction. 

The most commonly used crystalloid CP is Bretschneider (HTK or Custodiol®). Low sodium concentrations prevent rapid ion influx through the cell membrane, arresting the action potential in a hyperpolarized state. Solutions with high potassium concentrations are blood-based CPs that inhibit intracellular ion efflux during membrane repolarization, resulting in asystole in a depolarized state. Combining both is possible, as in Del Nido CP, which inhibits both mechanisms. In all cases, electrical excitation of the contractile apparatus is blocked, keeping the heart still and relaxed for easy manipulation. 

See previous articles in the blog about the use of Del Nido cardioplegia. 

The main challenge in CP solution studies lies in the significant variability in conditions and protocol applications. Nonetheless, outcomes are surprisingly similar. 

Studies comparing blood versus crystalloid CP found higher postoperative bleeding with crystalloid CP and greater inotropic use with blood CP, with no differences in other variables, primarily mortality. A meta-analysis reported lower low cardiac output syndrome (LCOS) and myocardial damage markers with blood CP, with similar mortality and myocardial infarction (MI) rates, while another study found no significant differences in study variables, including MI, LCOS, and mortality. 

Another study comparing cold versus warm blood CP found no temperature impact on survival or perioperative mortality, though CK-MB levels were higher with cold CP. A meta-analysis reported increased biomarker release and lower cardiac index with cold CP, with no effect on morbidity and mortality. 

In addition to myocardial damage markers and cardiac output indices, myocardial damage can also be assessed by cardiac edema, though it is challenging to measure. Mehlhorn et al. evaluated this in an animal model comparing blood versus crystalloid CP, finding no differences. 

Regarding the administration route, a study comparing antegrade versus retrograde cold blood CP found no differences, while another with crystalloid CP reported higher troponin levels in the antegrade route. 

A meta-analysis comparing single versus multidose administration found no significant differences in mortality or MI. 

– Cardio-specific effects of cardioplegic solutions: 

MP strategies extend myocardial ischemia tolerance, though this period may not be harmless. A study analyzing mortality with aortic cross-clamp time (TCA) reported a 2.2% mortality, identifying TCA as an independent predictor. 

Another cardiac transplant study associated prolonged ischemia with higher 30-day mortality. A strong association between TCA and mortality was found in this systematic review. There is a notable difference in CP’s ability to extend ischemia tolerance between young and older patients. Age is a key cofactor traditionally linked to increased postoperative morbidity, identified as an independent risk factor in most analyses. However, age’s specific impact on TCA and outcomes has never been evaluated in the context of CP solutions. 

Another CP-related factor is the need for CPB, which introduces additional trauma during cannulation and manipulation. Data from the PARTNER 3 study comparing low-risk surgical patients in conventional surgery versus transfemoral TAVI showed right ventricular dysfunction in most surgical patients, absent in TAVI. Further investigation is required, as despite this, long-term morbidity and mortality outcomes still favor conventional surgery. 

– Extra-cardiac effects of cardioplegic solutions: 

Significant volumes of CP solution enter the systemic circulation, potentially leading to adverse extra-cardiac effects. 

Systemic vascular resistance (SVR) reduction is known in CPB CS. Characterized by hypotension, it is associated with higher morbidity and longer recovery times. Carrel et al. demonstrated that low SVR correlates with total CP volume. Certain CP types (crystalloids) result in more severe vasoplegia, necessitating higher vasopressor support. This effect can be significantly reduced by aspirating the solution from the coronary sinus during administration to prevent systemic entry. 

Perioperative renal dysfunction is a dreaded complication associated with increased morbidity and mortality. The main risk factor for acute renal damage is pre-existing renal insufficiency, which can be exacerbated by hypotension, LCOS, inotropic/vasopressor support, or low perioperative hematocrit. Renal damage is often evaluated as a secondary outcome in studies, leading to statistical Type I error. Therefore, dedicated randomized trials are needed to investigate renal function parameters as primary outcomes. 

CP administration may affect brain function due to electrolyte imbalance (hyponatremia) or hemodilution. Studies indicate higher cerebral infarction incidence with warm and retrograde CP, as well as greater postoperative delirium and seizures (in pediatric patients) and cerebral edema (animal models). 

– Current innovations: 

Research has continued, though rarely seen in the operating room. Dobson et al. tested a normokalemic hyperpolarizing solution, resulting in superior MP compared to St. Thomas solution. 

The main innovation is Custodiol-N®, an improved version of classic Custodiol® with added iron chelator to reduce oxidative damage and L-arginine to enhance endothelial function, showing reduced postoperative CK-MB levels. 

Another MP optimization method involves ischemia/reperfusion conditioning techniques, though evidence remains inconclusive. 

These results suggest that current CP solutions are equally effective. However, the role of age, impact on other organs, and effects on short- and long-term left and right ventricular function must be evaluated to select the best MP strategy. Specifically, factors such as ischemia duration, impact on baseline cardiac function, and extra-cardiac CP effects require further detailed investigation. 

COMMENTARY: 

The emergence of new CP solutions or “miracle” strategies to improve MP seems unlikely. As reflected in the article, CS outcomes continue to improve over time, despite the absence of changes in MP in recent decades. Therefore, we can consider that CP fulfills its function, and the improvements observed are attributed to advances in perioperative care, surgical techniques, materials, and perfusion methods. 

Each surgical team selects the CP they deem most suitable, and the similarity in results among different strategies highlights the lack of evidence favoring one over others. Each CP type has unique properties that should be considered in individualized selection based on comorbidities (diabetes, HTN, renal insufficiency), CS type (long, short, with circulatory arrest), and patient characteristics (hematocrit, body surface area), etc. 

Crystalloid CPs cause more hemodilution, reducing hematocrit. Hyperpolarizing crystalloid CPs cause hyponatremia, and others containing glucose can lead to hyperglycemia, especially in diabetic patients. Single-dose CP administration must be accurate, as errors lead to insufficient MP with severe consequences, and there are no established protocols for redosing. Multidose strategies may extend CPB time. Solutions exist for all these side effects, such as diuretics, hemoconcentrators, sodium administration, insulin, CP redosing in single doses, or optimal administration timing in multidose strategies to minimize surgical interference. 

Thus, even today, CP selection often remains a matter of “it works for me.” 

REFERENCE: 

Mukharyamov M, Schneider U, Kirov H, Caldonazo T, Doenst T. Myocardial protection in cardiac surgery-hindsight from the 2020s. Eur J Cardiothorac Surg. 2023 Dec 1;64(6):ezad424. doi: 10.1093/ejcts/ezad424. PMID: 38113432.