Comparison of lactated Ringer's solution and Plasma-Lyte A as a base solution for del Nido cardioplegia: a prospective randomized trial

Abstract

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OBJECTIVES

The use of del Nido cardioplegia has been increasing in popularity for adult cardiac surgery. However, the base solution, Plasma-Lyte A, is not always available in many countries. This prospective randomized controlled trial evaluated myocardial preservation and clinical outcomes when using lactated Ringer's solution (LRS) compared to Plasma-Lyte A as a base solution for del Nido cardioplegia.

METHODS

Adult patients undergoing first-time elective cardiac surgery for acquired heart disease, including isolated coronary artery bypass grafting, isolated valve surgery, combined valve surgery or concomitant coronary artery bypass grafting and valve surgery were randomized to receive either LRS (n = 100) or Plasma-Lyte A (n = 100).

RESULTS

There were no significant differences between the 2 groups in terms of age, comorbidities, Society of Thoracic Surgeons risk score and type of procedures. The primary outcome, postoperative troponin-T at 24 h, was similar in both groups (0.482 vs 0.524 ng/ml; P = 0.464). Other cardiac markers were also similar at all time points. The LRS group had a lower pH (7.228 vs 7.246; P = 0.005) and higher calcium levels (0.908 vs 0.358 mmol/l; P < 0.001) in the delivered cardioplegia, but there were no significant differences in clinical outcomes, such as ventricular fibrillation, left ventricular ejection fraction, inotrope/vasopressor requirement, intra-aortic balloon pump support, intensive care unit stay, hospital stay, atrial fibrillation, red cell transfusion and complications.

CONCLUSIONS

The results suggest that LRS can be used as an alternative to Plasma-Lyte A as the base solution for del Nido cardioplegia, with similar myocardial preservation and clinical outcomes.

INTRODUCTION

Effective myocardial preservation is essential to ensure optimal patient outcomes in cardiac surgery. Over the years, significant advancements have been made in the development of cardioplegic solutions, each uniquely tailored to meet the specific demands of various cardiac surgical procedures. One notable innovation in this field is del Nido cardioplegia, which was first conceptualized in the 1990s by Dr Pedro del Nido and his pioneering team [1]. del Nido cardioplegia consists of key components, including lidocaine, a sodium channel blocker that induces hyperpolarization and magnesium sulphate, a calcium antagonist that effectively reduces intracellular calcium accumulation. Together with mannitol for free radical scavenging and myocardial cell swelling reduction, as well as sodium bicarbonate for buffering, these distinctive properties make del Nido cardioplegia an exceptional choice for myocardial preservation during cardiac surgery. The use of del Nido cardioplegia has an extensive background in paediatric cardiac surgery, where its efficacy has been demonstrated over decades. Recent studies have also provided evidence to support its safety, efficacy and cost-effectiveness in adult cardiac surgery [2–8]. As a result, its use has steadily increased. One of its key advantages is that it can be administered as a single-dose infusion or with extended dosing intervals, which minimizes surgical interruptions and streamlines the overall workflow in the operating room [2–6].

The standard base solution for del Nido cardioplegia is Plasma-Lyte A (Baxter Healthcare Corporation, Deerfield, IL), a solution with an electrolyte composition similar to extracellular fluid and free of calcium [1]. However, a significant challenge arises in regions where Plasma-Lyte A is not readily available. This limitation prevents many cardiac centres from taking advantage of the benefits of del Nido cardioplegia. In our recent study, we investigated the application of a modified del Nido cardioplegia, using lactated Ringer's solution (LRS) as an alternative base solution. Our preliminary findings suggested that this adaptation provides myocardial protection and clinical outcomes comparable to those achieved with our institution’s standard blood cardioplegia [9]. However, a comprehensive assessment of its clinical safety and efficacy compared to the original del Nido cardioplegia is yet to be established.

The primary objective of this randomized controlled trial study is to evaluate myocardial preservation and clinical outcomes when using LRS compared with Plasma-Lyte A as a base solution for del Nido cardioplegia in adult cardiac surgery.

PATIENTS AND METHODS

Ethical statement

This randomized controlled trial study was conducted at Ramathibodi Hospital in Bangkok, Thailand. The study protocol received approval from the institutional review board (reference ID: 03-61-43, date of approval: 05/03/2018), requiring informed consent from all participating patients. Additionally, the study was registered with ClinicalTrials.gov (NCT04051580) prior to commencement.

Patients

Inclusion criteria consisted of patients aged 18 years or older undergoing their first-time elective cardiac surgery for acquired heart disease. This category included those receiving isolated coronary artery bypass grafting (CABG), isolated valve surgery, combined valve surgery or concomitant CABG and valve surgery. Exclusion criteria comprised a lidocaine allergy, the presence of preoperative inotropic pharmacologic support or mechanical circulatory support and patients undergoing cardiac surgical procedures that did not fall within the defined inclusion criteria categories.

Between August 2019 and December 2020, a total of 212 eligible patients were initially recruited. However, 12 patients were subsequently excluded because they required additional procedures that did not align with the study's inclusion criteria. Subsequently, the remaining 200 patients were randomized in a 1:1 ratio into 2 groups: the LRS group (referred to as the study group, n = 100) and the Plasma-Lyte A group (referred to as the control group, n = 100) as illustrated in Fig. 1. No patients withdrew from the study after randomization. In the LRS group, LRS served as the base solution for del Nido cardioplegia, while in the Plasma-Lyte A group, Plasma-Lyte A was utilized as the base solution for del Nido cardioplegia. This randomization process was executed through computerized random number generation and blocked randomization, with group sizes set at 4. The randomization order had been established before the commencement of patient enrolment and was then placed into sealed envelopes, each sequentially numbered. This task was carried out by a team member not involved in patient enrolment. Upon a patient's admission, a consecutive sealed envelope was opened, determining the patient's group assignment. The corresponding number was then communicated to our in-house pharmacist, who was aware of the designated numbers for the preparation of the del Nido cardioplegia. The del Nido cardioplegia, prepared according to the group assignment, was subsequently sent to the operating room in a sealed container. Throughout this process, it is important to note that the patients, surgeons, anaesthesiologists, care providers and data collectors remained blinded to the treatment allocation.

Primary outcomes

The primary outcomes focused on evaluating postoperative troponin-T level at 24 h. To collect data for this evaluation, we routinely obtained blood samples, which included measurements of troponin-T at several time points. Specifically, these samples were collected on the day of admission, immediately after surgery, at 12 h postoperatively and at 24 h postoperatively. In addition to troponin-T, we also collected blood samples to measure other relevant cardiac markers, such as creatinine kinase (CK) and creatinine kinase-myocardial band isoenzyme (CK-MB). These samples were collected immediately after surgery, at 12 h postoperatively and at 24 h postoperatively.

Secondary outcomes

Secondary outcomes encompassed assessments of additional measures related to myocardial protection, including the incidence of ventricular fibrillation after aortic cross-clamp removal, changes in postoperative left ventricular ejection fraction (LVEF), the duration of inotrope/vasopressor requirement, the need for intra-aortic balloon pump (IABP) support, as well as monitoring mortality and postoperative complications.

The evaluation of LVEF was conducted both before and after the procedure using intraoperative transoesophageal echocardiography. Postoperative changes in LVEF were calculated as the difference between postoperative LVEF and preoperative LVEF. Patient characteristics variables and perioperative outcomes, which included Society of Thoracic Surgeons risk score, mortality, renal failure, prolonged ventilation, stroke, deep sternal wound infection, reoperation and incidence of major morbidity or operative mortality were defined according to the criteria outlined in the Society of Thoracic Surgeons Adult Cardiac Surgical Database. The study assessed the incidence of several postoperative complications within a timeframe of up to 1 month following the surgical procedures. Postoperative stroke was defined as any confirmed neurological deficit with an abrupt onset, caused by a disturbance in blood supply to the brain, and persisting for >24 h. The occurrence of renal failure was determined by either an increase in serum creatinine to ≥4.0 with an increment of at least 0.5 mg/dl or 3 times the most recent preoperative creatinine level, or the initiation of new postoperative dialysis. Prolonged ventilation, exceeding 24 h, was identified as sustained pulmonary ventilation from the operating room exit until extubation, including any additional hours following reintubation.

The perioperative safety and workflow also involved the observation of various factors, which included the total volume of administered cardioplegia, the number of doses, total cardiopulmonary bypass (CPB) time, aortic cross-clamping time, differences in the composition of delivered cardioplegia and postoperative red cell transfusion. Intraoperative chemical analyses of the delivered cardioplegia, including assessments of temperature, calcium levels and pH, were conducted using the i-STAT system (Abbott Point-of-Care, Princeton, NJ, USA).

Cardioplegia preparation and delivery protocol

Table 1 provides a comprehensive overview of the compositions of both our modified del Nido cardioplegia and the original del Nido cardioplegia. Plasma-Lyte A was imported from Hong Kong in compliance with hospital regulations for research and treatment purposes. Our in-house pharmacist meticulously prepares the del Nido cardioplegia within a cleanroom class 100 (ISO class 5) environment to ensure stringent sterility standards are met. This precisely prepared solution is then stored under refrigeration, maintaining a controlled temperature range of 2–8°C, and is consistently utilized within a 24-h timeframe [9, 10].

Upon delivery, the solution undergoes a specific blending process, following a precise 1:4 ratio that combines 1 part of oxygenated pump blood with 4 parts of the cardioplegia solution. As it traverses through our CPB circuit, the cardioplegia flows through a custom non-recirculating cardioplegia set equipped with a coil heat exchanger, which helps maintain a constant delivery temperature of 4°C.

Our standardized protocol typically initiates with an initial single-dose equivalent to 20 ml/kg for patients, with a maximum limit of 1000 ml for individuals weighing over 50 kg. This infusion is administered over a carefully monitored duration of 1–2 min, with close observation of system pressure, which typically falls within the range of 100–200 mmHg. Decisions regarding the need for redosing and the subsequent dosage amount after 90 min of aortic cross-clamping time are made based on the surgeon's discretion [1–2, 9–10].

The method of delivery is thoughtfully tailored to the specific surgical procedure and the unique degree of aortic valve insufficiency presented by each patient. In most scenarios, del Nido cardioplegia is introduced antegrade through an aortic root catheter. However, for patients with significant aortic valve insufficiency, a more direct route is employed, with the cardioplegia delivered directly through the coronary ostia. In cases requiring coronary bypass grafting, a smaller quantity of del Nido cardioplegia—usually between 5 and 10 ml—is injected via either the saphenous vein graft or the radial artery graft to evaluate the distal anastomosis.

Sample size calculation

The sample size calculation was based on the difference in the 24-h postoperative troponin levels between the del Nido cardioplegia and blood cardioplegia groups, as obtained from a previous study conducted by Ad et al. [8]. These troponin levels were reported as 2.3 [standard deviation (SD) = 2.1] and 7.0 (SD = 14.7) ng/ml, respectively (P = 0.053). Our preceding observational study also yielded comparable outcomes between the modified del Nido cardioplegia and blood cardioplegia [9]. In this randomized study, we aimed to achieve a statistical power of 80% at a significance level (alpha, α) of 0.05 and a Type II error probability (beta, β) of 0.2 in a two-sided, equivalence test. Guided by these considerations, a required sample size of 160 randomized patients (with 80 patients in each group) was estimated. To account for potential attrition, a sample size of 100 was selected for each group.

Statistical analyses

Continuous data were presented using measures of central tendency such as mean (SD) or median (interquartile range), and their comparison was carried out employing either the independent sample Student's t-test or the Mann–Whitney U-test, chosen according to the distributional properties of the data. Categorical variables were represented as frequencies (%) and were subject to rigorous examination using either the chi-squared test or Fisher’s exact test, contingent upon the inherent characteristics of the data. The statistical analyses were conducted utilizing STATA version 14 (StataCorp, College Station, TX). A threshold of P < 0.05 was established to demarcate statistical significance within the study.

RESULTS

Patients’ characteristics

Patient characteristics, including age, body surface area, Society of Thoracic Surgeons risk score, preoperative LVEF, type of procedure and comorbidities, were similar between the groups. The only difference observed was in the proportion of male patients (60 vs 75%, P = 0.024) (Table 2). The mixed effect linear regression analysis indicated no correlation between sex and troponin levels (see Supplementary Material, Table S1).

Primary outcomes

The postoperative troponin-T levels at 24 h showed no significant differences between the groups [0.482 (0.272, 0.871) vs 0.524 (0.307, 0.904) ng/ml, P = 0.464] as illustrated in Fig. 2. Additionally, the levels of troponin-T and other cardiac markers remained consistently similar across all measured time points as presented in Table 3.

Secondary outcomes

Intraoperative outcomes

The total cardioplegia volume, the number of doses given, the delivery temperature, aortic cross-clamp time, total CPB time, incidence of ventricular fibrillation after aortic cross-clamp removal and postoperative LVEF change were similar between the groups. Notably, in the delivered cardioplegia, the LRS group exhibited a lower pH (7.228 vs 7.246; P = 0.005) and higher calcium levels (0.908 vs 0.358 mmol/l; P < 0.001). Intraoperative outcomes are detailed in Table 4.

Postoperative outcomes

No instances of mortality were observed. Postoperative complications, duration of inotrope/vasopressor requirement, the incidence of postoperative atrial fibrillation or flutter with rapid ventricular response, the requirement for IABP support, intensive care unit stay, hospital stay and postoperative red cell transfusion were similar between the groups (Table 5). Subgroup analysis of primary and secondary outcomes was demonstrated in Supplementary Material Tables S2–S7.

DISCUSSION

The present prospective randomized controlled trial study sheds light on the use of LRS as an alternative base solution for del Nido cardioplegia in adult cardiac surgery, particularly in settings where the availability of Plasma-Lyte A may be limited. Primary outcomes, focused on troponin-T levels at 24 h postoperative, revealed no significant differences, indicating comparable myocardial preservation. Secondary outcomes, covering intraoperative measures and postoperative parameters, consistently demonstrated remarkable equivalence between LRS and Plasma-Lyte A groups. Mortality was absent in both groups underscored the safety and success of the procedures conducted. Postoperative complications, inotrope requirement, atrial fibrillation incidence, IABP support, intensive care unit stay, hospital duration and red cell transfusion were similar. It is noteworthy that while the overall outcomes indicate similarity, a detailed examination of the delivered cardioplegia revealed slightly lower pH levels and elevated calcium levels in the LRS group.

The recent exploration of modifications to del Nido cardioplegia, particularly the use of alternative base solutions, has yielded promising findings. Sevuk et al. introduced modifications involving the use of plain Ringer solution or normal saline as the base solution for their tepid modified del Nido cardioplegia. Their findings revealed that this modification yielded outcomes comparable to those achieved with cold blood cardioplegia in adults undergoing cardiac surgical procedures [5]. Similarly, Talwar et al. conducted a study in which plain Ringer solution served as the base solution for del Nido cardioplegia, with a comparison to the standard Plasma-Lyte A-based del Nido cardioplegia. This investigation focused on paediatric patients undergoing intracardiac repair of Tetralogy of Fallot. Through their randomized trial, the author concluded that that this modification was noninferior to the conventional del Nido cardioplegia in terms of preserving the cardiac index and other important metrics [11]. Additionally, Sithiamnuai et al. reported that clinical outcomes associated with lactated Ringer-based del Nido cardioplegia were comparable to those achieved with blood cardioplegia in congenital cardiac surgery [12]. These modifications have demonstrated comparable or noninferior outcomes in both adult and paediatric populations undergoing cardiac surgical procedures. This accumulating evidence suggests that alternative base solutions can be employed without compromising clinical effectiveness, which aligns with the results observed in our study.

In addition to the previously discussed findings, it is crucial to address a critical aspect concerning the calcium concentration within del Nido cardioplegia. The original del Nido cardioplegia formulation was designed with a calcium-free base solution. However, in practical application, the final calcium concentration in the delivered cardioplegia is minimal due to the mixing of one-part oxygenated pump blood to 4 parts crystalloid component [1]. Our modification, involving the use of LRS as the base, introduced variations in calcium concentrations in the delivered cardioplegia. LRS inherently contains calcium within a reported range of 1.5–3 mEq/l [13]. In our modified del Nido cardioplegia, the final calcium concentration was measured at 0.908 (±0.08) mmol/l. This contrasts with the calcium concentration in the original del Nido cardioplegia, which was ∼0.358 (±0.20) mmol/l (Table 4). While the altered calcium concentration was a consideration in our study, it is noteworthy that no evidence of impaired outcomes was observed with our approach. Theoretically, elevated extracellular calcium levels could potentially hinder the sodium-calcium exchanger's ability to pump calcium out of the cell. This may result in increased intracellular calcium accumulation, potentially affecting myocardial relaxation and recovery. However, it is important to acknowledge that the presence of magnesium, acting as a competitive antagonist for calcium, along with the sodium channel blocking properties of lidocaine, likely played a role in mitigating these effects. We hypothesize that these additional components compensated for the elevated calcium levels observed in the lactated Ringer's-based del Nido cardioplegia when compared to the Plasma-Lyte version.

While the concentrations of sodium, potassium and chloride were notably similar, distinctions in composition between LRS and Plasma-Lyte A are noteworthy. LRS, distinguished by its lactate content, is juxtaposed with Plasma-Lyte A, which incorporates acetate and gluconate. The selection of electrolyte components in cardioplegic solutions is critical, exerting influence on cellular function, metabolism and, consequently, clinical outcomes. Notably, lactate acts as both an energy substrate and pH buffer, potentially impacting myocardial metabolism and acid–base equilibrium. In contrast, acetate and gluconate may impart distinct metabolic effects. Acetate in Plasma-Lyte A contributes to the body's bicarbonate pool, aiding in acid–base balance, while gluconate serves as an anion source. Both contribute to maintaining electrolyte and acid–base equilibrium when administered intravenously. Additionally, variations in magnesium levels could affect myocardial contractility and cellular functions, although this distinction is considered minor as magnesium will be added in the final del Nido solution.

The variance in pH levels between LRS and Plasma-Lyte A introduces a significant parameter that merits consideration. LRS possesses a pH of 6.5, whereas Plasma-Lyte A exhibits a pH of 7.4 (6.5–8.0). This difference in pH can have ramifications for myocardial protection and overall cardiac surgical outcomes. The pH of a cardioplegic solution is a critical factor that influences cellular metabolism, ion channel activity and the overall function of myocardial cells. A higher pH, such as that of Plasma-Lyte A, tends to promote a more physiological environment for the myocardium. It may offer improved preservation of cellular function, minimize the impact of ischaemic–reperfusion injury and facilitate better postoperative recovery. The relatively lower pH of LRS might theoretically lead to suboptimal cellular functioning and could potentially affect the efficacy of myocardial protection. However, the findings of this study, where the modified del Nido cardioplegia using LRS demonstrated comparable outcomes to the original formulation. It's important to consider the mitigating factors that contribute to the overall pH environment in del Nido cardioplegia. Sodium bicarbonate, a known acid–base buffer, is one of the components of the del Nido solution. This buffer capacity could counteract the potential negative impact of the lower pH and help maintain a more optimal intracellular pH. Additionally, the introduction of oxygenated blood during the mixing process serves as a natural acid–base buffer, further contributing to the maintenance of a balanced pH environment. Furthermore, the mildly acidotic pH range of both LRS-based and Plasma-Lyte-based del Nido cardioplegia might offer protective effects to ischaemic or hypoxic myocardium by reducing metabolic demands during arrest and limiting intracellular calcium overload. This protective effect was likely stemming from the competition between hydrogen ions and calcium ions at various cellular sites, with acidosis playing a key role in limiting calcium overload, a major contributor to myocardial ischaemic injury [14, 15].

Limitations

This study emanated from a single institution, introducing a degree of institutional bias, and limiting the generalizability of the findings to broader populations and diverse healthcare settings. Furthermore, the study exclusively focused on the comparison between LRS and Plasma-Lyte A as base solutions for del Nido cardioplegia. Other potential base solutions, their impacts and variations were not explored within the purview of this investigation. Additionally, this study included low-risk patients who underwent their first-time elective cardiac surgeries. Consequently, the results may not be directly applicable to higher-risk patients or those requiring emergency procedures. Moreover, the study's scope remained centred on surgeries related to acquired heart disease, thus the findings had limited relevance to different types of cardiac surgical procedures. The study's underpowered nature to detect differences in postoperative outcomes and the absence of precise cardiac indices measurements are acknowledged limitations. Incorporating tools like a Swan Ganz catheter in future studies could provide a more comprehensive understanding of myocardial preservation and overall cardiac function. While the findings demonstrated encouraging similarities in primary and secondary outcomes, the observed differences in pH and calcium levels underscored the complexity of this approach. Further study, potentially encompassing larger sample sizes and diverse patient cohorts, is essential to substantiate these initial insights and discern the broader implications of integrating LRS into the del Nido cardioplegia technique.

CONCLUSION

This prospective randomized controlled trial supports the use of LRS as a viable alternative for del Nido cardioplegia in adult cardiac surgery involving low-risk elective patients when the anticipated cross-clamp time is <120 min. LRS demonstrated comparable outcomes in myocardial preservation, intraoperative performance and postoperative results. These findings suggest that LRS can enhance accessibility to the del Nido technique without compromising patient safety or efficacy, making it a valuable option in regions with limited access to Plasma-Lyte A. However, further investigation is warranted to explore the implications of differences in cardioplegia composition. Moreover, it is crucial to acknowledge the study's focus on low-risk patients undergoing elective surgeries related to acquired heart disease. To broaden the generalizability of these findings, future research should consider expanding the study to include urgent cases with decreased left ventricular function, potentially limiting the patient cohort to specific diagnoses, such as only CABG or aortic valve procedures. This approach could provide valuable insights into the applicability and effectiveness of LRS-based del Nido cardioplegia in more challenging patient populations.

Presented at the 37th European Association for Cardio-Thoracic Surgery (EACTS) Annual Meeting, Vienna, Austria, 7 October 2023.

SUPPLEMENTARY MATERIAL

Supplementary material is available at EJCTS online.

ACKNOWLEDGEMENTS

We would like to express our gratitude to Suraida Aeesoa and Yada Phengsalae for their invaluable contributions to the statistical analysis of this study.

FUNDING

This study was supported by the Faculty of Medicine, Ramathibodi Hospital, Mahidol University. (Grant ID: RF_62040).

Conflict of interest: none declared.

DATA AVAILABILITY

The data underlying this article will be shared on reasonable request to the corresponding author.

Author contributions

Narongrit Kantathut: Conceptualization; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Validation; Writing—original draft; Writing—review & editing. Pimchanok Krathong: Data curation; Formal analysis; Investigation; Writing—review & editing. Siam Khajarern: Formal analysis; Writing—review & editing. Parinya Leelayana: Formal analysis; Writing—review & editing. Piya Cherntanomwong: Formal analysis; Writing—review & editing.

Reviewer information

European Journal of Cardio-Thoracic Surgery thanks Bilal Haneef Kirmani, Sachin Talwar and the other anonymous reviewers for their contribution to the peer review process of this article.

REFERENCES

ABBREVIATIONS

ABBREVIATIONS
 
• CABG

  Coronary artery bypass grafting

 
• CK

  Creatinine kinase

 
• CPB

  Cardiopulmonary bypass

 
• IABP

  Intra-aortic balloon pump

 
• LRS

  Lactated Ringer's solution

 
• LVEF

  Left ventricular ejection fraction

 
• SD

  Standard deviation