Evidence-based medicine and myocardial protection — where is the evidence?

Introduction

Dr. Sealy and colleagues, out of Durham, first coined the term “cardioplegia” in the mid-1950s. ¹ Since its initial discovery, cardioplegia has gone in and out of favor, its components have been manipulated and a variety of techniques have been used. Crystalloid cardioplegia, such as Custodiol HTK (Bretschneider’s) and blood cardioplegia of varying ratios, including del Nido Solution and microplegia, are all commonly used and, therefore, are the subject of this research.

Without cardioplegia, cardiac surgery must be performed with the use of aortic clamping. This presents limited anastomotic times during grafting procedures and technical challenges. Myocardial injury can be directly caused by ischemia or reperfusion injury. Cardioplegic solutions help to prevent this by reducing oxygen demand to below 10%. It only takes small decreases in myocardial function to lead to increased morbidity and mortality. Therefore, a reliable cardioplegic solution is mandatory for achieving successful myocardial protection. ²

There is abundant literature on many different types of cardioplegia, but the degree to which each solution has been researched varies greatly. Conclusive evidence representing clear advantages and disadvantages for one solution over another is often unclear. This may be due to the lack of comparative effectiveness studies, leading to a lack of standardization that should be a cause for concern in this era of evidence-based medicine.

Evidence-based medicine is an effective way of determining best practices. Comparison studies that reduce bias help to determine the best treatment possible for the patient. ³ Surgeons and perfusionists can make educated decisions backed by research supporting each potential type of treatment, in this case, regarding cardioplegic solutions. It is important that health professionals are not biased in the decision-making process when it comes to cardiac surgery. While it is important to have a number of innovators and early adopters, it is also important to analyze the facts before adopting new technologies or treatments. The Diffusion of Innovation Theory has been used to describe change by defining the stages of adaptors. Everett Rogers, a communication scholar, popularized the current theory and referred to it as the development of a new idea via communication between people. ⁴ Adoption starts out with just a few people and spreads to the point where it becomes saturated throughout the population.

It is imperative to have an equal balance of innovators/early adopters who are leaders and risk-takers to provide proof and research leading to the eventual adoption of a new idea by followers. Poor innovation outcomes can arise from an imbalance in any one category, which, in turn, can lead to the recalling of a drug or medical device in the medical community. Even the most respected names in medicine are vulnerable to this phenomenon. For example, in 2010, Johnson & Johnson endured a massive recall of an unapproved hip implant that led to 93,000 implant returns. ⁵

How long will it be before an accepted cardioplegic solution yields a similar outcome? Will standard protocols for cardioplegia ever be instituted based on evidence-based research? The purpose of this paper is to review the current literature with the goal of presenting a clearer understanding of where evidence-based research is present and where it is lacking related to cardioplegia.

Methods

A systematic review of literature regarding cardioplegia was conducted. The review was limited to evidence-based comparative studies involving at least one of the following: 4:1, microplegia, Custodial HTK and del Nido cardioplegia. Scopus, PubMed, CINAHL, Ovid/MEDLINE and Google Scholar were databases utilized to compile evidence.

The CINAHL database was searched with the keyword: “del Nido Cardioplegia,” which returned five results, all of which were included. Ovid/MEDLINE found zero articles when the keywords “del Nido randomized control” were searched. PubMed database found 27 results for “del Nido cardioplegia”, 12 of which were related to cardioplegia. All 12 articles were reviewed, but only four were related to del Nido cardioplegia specifically. Six results for “del Nido randomized control” were found on PubMed; however, these articles were not included as they were not related to cardioplegia. Finally, “del Nido cardioplegia randomized control” was searched directly and, again, zero results were found on the PubMed database.

A search of PubMed with the keywords “blood cardioplegia” returned 215 articles when limited to the 10 most recent years. The same keywords were used to search Scopus, with a time constraint of 13 years (2000-present), producing 469 results. Scopus and PubMed were then searched using the keyword “microplegia”, applying the same time restraints — 19 and 14 results were returned, respectively. Articles from this pool, which compared blood cardioplegia or microplegia to cardioplegia of any type, were evaluated further. This systematic technique narrowed the results to 20 articles.

A search of Google Scholar returned 1100 results when using the keywords “HTK versus blood cardioplegia”, 750 results with the keywords “Custodiol cardioplegia” and 1830 with the keywords “Bretschneider’s versus blood cardioplegia”. PubMed was searched with the keywords “HTK versus blood cardioplegia”, “Custodiol cardioplegia” and “Bretschneider’s cardioplegia”. This search of PubMed produced 9, 23 and 174 results covering the last 25 years, respectively.

This overall search revealed an abundance of randomized clinical trials in which 4:1 and/or Custodial HTK were used. Few human clinical trials exist on microplegia and no human clinical trials were found on del Nido. Therefore, animal trials and retrospective comparative studies were utilized to supplement our research. All articles were assessed based on the classification of recommendations and level of evidence following the guidelines developed by the Joint Task Force for Guidelines of the American College of Cardiology (ACC) and the American Heart Association (AHA). ⁶

Tables containing overviews of each article were created to compare findings. Each table contained the following data:

Results

A total of 40 journal articles were reviewed, with only the most current comparative studies being used.^7–46 Del Nido was an exception to this rule as comparative literature surrounding this solution was scarce. Review of the literature showed that 4:1 blood cardioplegia and Custodiol HTK cardioplegia were the most favored in randomized clinical trials, accounting for approximately 80% of trials. Figure 1 below in the Tables and Data section shows the demographic distribution of papers used in this study, with the overwhelming majority of papers using adult procedures and with pediatric and animal procedures accounting for a small amount of the remaining literature. Figure 2 analyzes the distribution of rankings based on the Classification of Recommendation and is described in further detail in the Tables and Data section.

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Figure 1.

The majority of papers in this search consisted of mostly adult procedures, with no particular type of procedure being favored over any others. These data show that the majority of comparison studies contained standard 4:1 blood cardioplegia, which correlates to its widespread usage.

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Figure 2.

Papers considered to be Class IIa, Level B were the most readily available with Class IIa papers, in general, making up the bulk of the literature found. Class III papers, indicating an unfavorable comparison according to the author, were the rarest category, consisting of only one article. Level A papers, which consist of multiple randomized clinical trials, were non-existent in the literature search.

Each paper was analyzed for the patient outcomes they measured as a means for standardizing cardioplegia usage. Outcomes were tallied and the nine largest overarching categories were selected to be included in our data collection:

At this point, the papers were further divided to match one particular type of cardioplegia with another particular type, attempting to keep the comparisons between the four main types of cardioplegia being focused on (4:1, del Nido, microplegia and HTK). This excluded some of the data of other comparisons using different types of crystalloid solutions, buffered and unbuffered solutions and so on. Four types of comparisons were created using the cardioplegic solutions of interest:

The two remaining combinations of comparisons — HTK versus del Nido and microplegia versus del Nido — could not be completed as no data from the literature search could be found specifically related to them.

These four comparisons are graphically displayed to characterize the benefits of the comparison solutions. Significant outcomes (p<0.05) can be seen in Figures 3, 4 and 5. The microplegia versus HTK group consisted of only one paper and there were no significant differences.

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Figure 3.

Microplegia outperformed standard blood cardioplegia in most respects, especially in regards to hemodynamics. Microplegia was found to cause fewer cases of edema, have a lower incidence of low cardiac output syndrome and have an overall improved cardiac index. Of important note is that no pediatric studies were found in this comparison.

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Figure 4.

Papers comparing these two types of cardioplegic solutions showed great variation in positive patient outcomes, but only a few categories were statistically significant. Blood cardioplegia tended toward less spontaneous postoperative fibrillation, less need for intervention and higher residual phosphate levels, with HTK benefiting from offering similar results with a lower number of cardioplegia administrations.

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Figure 5.

Not many statistically significant findings were found separating del Nido cardioplegia from standard blood cardioplegia and there are very few sources to reference. While del Nido seemed to outperform blood cardioplegia in most instances, only a small amount of data was found to be significant.

Discussion

One would expect a strong correlation between the most researched cardioplegia and the most used cardioplegic solutions. The findings of our research seem to contradict this expectation. For example, according to a recent survey, a reasonable percentage of medical centers use del Nido cardioplegia without strong support in comparison studies for its effectiveness. ²² One goal of this article was to provide an understanding of how cardioplegia studies can be standardized using common categories of patient outcomes, but no discernable pattern could be interpreted from the data that was collected. It is unclear at this point what the most indicative marker for poor patient outcomes is, though there is some literature pointing to troponin as being the clearest indicator of myocardial infarction and, therefore, increased morbidity. ⁴⁷ However, this was not made evident by the data we collected.

Other studies, such as this, have sought for similar answers in the realm of finding the ideal cardioplegic solution. One such study by Guru et al. compared outcomes between 2,582 patients who received blood cardioplegia and 2,462 patients who received crystalloid cardioplegia across 34 separate, randomized trials. ⁴⁸ The outcomes measured were low output syndrome (LOS), myocardial infarction (MI) and death and all but two of the trials were related to CABG procedures (the other two were valve procedures). After a meta-analysis was performed, the authors concluded that blood cardioplegia was associated with lower rates of LOS, but similar rates of MI and death, offering blood cardioplegia as the superior choice. Not all the studies have offered similar sentiments, however, with another study by Sa et al. performing an analogous meta-analysis across 36 randomized clinical trials and reviewing the same three outcomes (LOS, MI and death). ⁴⁹ This meta-analysis included 2,834 patients who received blood cardioplegia and 2,742 patients who received crystalloid cardioplegia, again focusing mainly on CABG procedures (28 CABG, 4 pediatric/congenital, 1 transplant and 3 valve procedures), with the authors concluding that no discernible difference could be ascertained among outcomes between the two types of cardioplegia.

In order for additional evidence-based approaches to occur, a more standardized approach to outcome data collection must take place as well as more comparisons between solutions outside the standard 4:1 cardioplegia. This is particularly important in regards to del Nido Solution, given its popularity in the operating room and the lack of comparison studies that we found in our search related to it. Surgeons and perfusionists should be hesitant to use any drug that has not been verified. This is not to propose that del Nido Solution is overly dangerous or ineffective at myocardial protection, as its widespread use and overall outcomes would indicate otherwise, but it cannot be argued that sufficient data has been acquired over the duration of this solution’s use, at least with regard to published comparison effectiveness studies.

To conclude, it is well known that there are a myriad of factors that go into ideal myocardial protection and this study only examined those that were found most relevant in our comparisons of each type of cardioplegia. In future studies, it would be assuring to see some comparisons including other types of cardioplegic solutions, such as St. Thomas and UW solutions among others that were found in our search, but that did not meet the criteria to be included in this particular study, whether by insufficient numbers of comparison studies or by not analyzing the outcomes that we set forth. Meanwhile, it is the hope of this review that further scrutiny can be made on the types of solutions that were able to be included so that further evidence-based selections can be made. That being said, substantial clinical trials exist for blood-based cardioplegia and HTK while additional research should be conducted on microplegia and del Nido solutions. This systemic review of research published on these solutions allows for clinicians to assess the quantity and quality of the literature and make evidence-based decisions regarding their use.