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Table of Contents
Year : 2022  |  Volume : 6  |  Issue : 3  |  Page : 133-144

The use of blood versus crystalloid cardioplegia in adult open heart surgery: A systematic review

Department of Anesthesiology and Intensive Therapy, Universitas Sebelas Maret, Dr. Moewardi Hospital, Surakarta, Indonesia

Date of Submission19-Feb-2022
Date of Decision10-May-2022
Date of Acceptance12-May-2022
Date of Web Publication27-Jul-2022

Correspondence Address:
Eka Satrio Putra
Department of Anesthesiology and Intensive Therapy, Universitas Sebelas Maret, Dr. Moewardi Hospital, Kolonel Sutarto street No.132, Jebres, Surakarta, Central Java 57126
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bjoa.bjoa_62_22

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Myocardial ischemia can occur due to hypotension, shock, coronary heart disease, and aortic cross-clamping during open-heart surgery using a cardiopulmonary bypass machine. Cardioplegia is classified into the blood or crystalloid base as a cardioprotective method. This systematic review and meta-analysis aimed to describe the effectiveness of blood and crystalloids cardioplegic solutions in adult open-heart surgery by focusing on their effects on cardiac enzymes. This study investigated the effect of blood and crystalloid cardioplegia on troponin (cTn) and creatinine kinase myocardial bound (CKMB). The literature search was carried out on several Cochrane, PubMed, PMC, and Google Scholar databases from January 2014 to August 2020 using the medical subject heading keywords and Boolean operator. We obtained 346 articles and identified nine prospective randomized studies from five countries that met the eligibility criteria. The majority discussed the comparison of blood cardioplegia and crystalloids in coronary revascularization cardiac surgery (CABG). The cTn values (weighted mean difference [WMD] –2.67, confidence interval [CI] –4.18 to 1.17, P = 0.0005) and CKMB values (WMD –2.67, CI –4.18 to 1.17, P = 0.0005) 24 h operatively showed that the level of the cardiac enzymes increased in the crystalloids cardioplegia group more than the blood cardioplegia group. Overall, the articles used have a low risk of bias despite their high level of homogenicity. The current literature on cardioplegia in adults does not provide adequate advanced-phase trials. Both types of cardioplegia provide reasonable protection for the myocardium. However, several studies reveal that crystalloid cardioplegia increases cardiac enzymes more significantly than blood cardioplegia.

Keywords: Blood cardioplegia, cardiac enzyme crystalloid cardioplegia, cardiac surgery

How to cite this article:
Putro BN, Purwoko P, Supraptomo RT, Putra ES, Sunjoyo A. The use of blood versus crystalloid cardioplegia in adult open heart surgery: A systematic review. Bali J Anaesthesiol 2022;6:133-44

How to cite this URL:
Putro BN, Purwoko P, Supraptomo RT, Putra ES, Sunjoyo A. The use of blood versus crystalloid cardioplegia in adult open heart surgery: A systematic review. Bali J Anaesthesiol [serial online] 2022 [cited 2022 Aug 10];6:133-44. Available from: https://www.bjoaonline.com/text.asp?2022/6/3/133/352405

  Introduction Top

Cardiac surgery, especially those using a cardiopulmonary bypass (CPB) machine, can lead to myocardial ischemia due to ischemia-reperfusion, aortic cross-clamping, surgical trauma, and oxidative stress, which can result in myocyte death and myocardial damage. A 45-min-period of normothermic global ischemia may cause myocardial contractility dysfunction, whereas regional ischemia without infarction of just 15 min may lead to cardiac stunning. Myocardial damage should be prevented by using myocardial protection.[1]

Cardioplegia is one of the myocardial protectors that prevent iatrogenic injury due to extracorporeal circulation, aortic cross-clamping, ischemic segment revascularization, and cross-clamp release.[2] There are various kinds of cardioplegic compositions to carry out the needs of cardiac surgery techniques. They are usually characterized by a hypothermic and high-level-potassium solution or a crystalloid-blood combination.[3] Cardioplegia reduces ischemic injury by decreasing oxygen demand, excess calcium ions, and edema. It also increases material supply and utilization.[4]

There are two types of cardioplegia: crystalloid and blood cardioplegia solution.[5] Both of them have their advantages and disadvantages. Crystalloid Cardioplegia leads to mild to moderate hypothermia, reduces oxygen consumption, and provides a better view of the distal coronary artery anastomoses. Still, it is associated with myocardial edema resulting in low cardiac output syndrome (LCOS).[5] Blood cardioplegia nourishes the endothelium and myocardium, has efficient transport of oxygen and nutrients, increases buffering ability, has oncotic variations reducing cellular lesions, and reduces the free radicals providing a better effect on ischemic injury. However, it may cause temperature-related perfusion disturbances, increase the risk of excess sodium and calcium ions, lead to complex fabrication, and need to add complementary circuits to the CPB machine, thereby encouraging additional priming.[5],[6]

The cardiac enzyme can be a sensitive marker in myocardial injury. A cohort study by Greenberg et al. reported that postoperative cardiac enzyme elevations were associated with the risk of LCOS, atrial fibrillation, arrhythmias, prolonged intensive care unit (ICU) stays, and 30-day postoperative mortality.[7],[8] Stahel et al.[9] and Mey et al.[10] in their retrospective study, stated that there was an increase in troponin T and creatinine kinase myocardial bound (CKMB) after surgery using a CPB machine.

Troponin T has been identified as a myocardial muscle damage marker. Its inhomogeneous myocardial protection feature is sensitive to detecting minor injuries, thus effectively assessing the impact of different cardioplegia procedures. Controversy regarding the protective effect of the myocardium using blood cardioplegia over crystalloids has long existed. A meta-analysis comparing the effects of blood cardioplegia and crystalloid cardioplegia on cardiac enzyme elevation in the pediatric population has been carried out by Mylonas et al.[11] Many random control trial (RCT) studies on blood cardioplegia and crystalloids are conducted to address this controversy. However, none of them reported conclusive in the adult population. Therefore, we performed a study to investigate the myocardium protective effectiveness of blood and crystalloids cardioplegic solutions in adult open-heart surgical procedures.

  Materials and Methods Top

Protocol, The Preferred Reporting Items for Systematic Reviews, and Meta-Analyses (PRISMA) guidelines were used to delimit the processes of this review. PRISMA was used as the guiding protocol to ensure credibility and guide the systematic analysis and meta-analysis to assess the research question. Two independent reviewers performed searching and reviewing. Another independent reviewer extracted the eligible articles meeting the inclusion criteria into a table. In case of disagreement, the author resolved as the sole decision-maker.

Search Strategy The search process was carried out in the Cochrane Library, Pubmed/Medline, PMC, and Google Scholar electronic databases. We included full-text cross-sectional and experimental research articles on adult patients undergoing first open-heart surgery written in English involving the cardiac enzyme as the primary outcome and atrial fibrillation, myocardial infarction, length of stay at ICU, the use of inotropic support, and mortality as the secondary outcome. The database was selected using the medical subject heading-related English words: “cardioplegic,” “cardioplegic solution,” “cardioplegia,” and “cardiac surgery” with a combination of Boolean operators (AND, OR). The other keywords used in the search included troponin, troponin-t, troponin-I, cardiac enzymes, and CKMB. Relevant articles were obtained from the reference list systematically with the “snowball” procedure. The articles written in non-English, involving pediatric patients, in vivo, or in vitro experiments, were excluded from the study. The irrelevant article, including literature review, editorial letter, and editorial perspective, were also excluded. The data collected include the author’s name, year of publication, location, sample size, method, and primary and secondary outcome. The data were reported in a descriptive method using Microsoft Excel 2013 software.

Eligibility criteria: The studies that could potentially be used in this systematic review and meta-analysis were reviewed by two independent investigators. Based on the discussions between the investigators, the eligibility criteria for the inclusion of studies in the systematic review and meta-analysis were agreed upon. The inclusion criteria focused on randomized control trials that evaluated the comparative effect of blood and crystalloids cardioplegic procedures on the levels of troponin and CKMB. The included studies examined the postoperative levels of the cardiac enzymes in 24 h. The study also included troponin-T (cTn-T) and troponin-I (cTn-I). Full-text analysis was conducted to ensure that the included studies met the desired goals given the eligibility criteria.

Data extraction risk of bias (RoB) analysis was performed on the included studies before extraction. The studies were assessed using a Microsoft Excel spreadsheet in areas aligned with the systematic review and meta-analysis. Equal weights were assigned to the studies and measured across different characteristics. The characteristics included in the RoB analysis were the randomization process, deviations from intended intervention, missing outcome data, measurement of the outcome, and selection of the reported result. The overall outcome of each study was estimated based on these characteristics to determine the RoB.

Data analysis after collecting the data: a narrative data analysis was conducted on the effect of blood cardioplegia and crystalloid cardioplegia on cardiac enzyme elevation in adults undergoing open-heart surgery. In addition, a statistical analysis was carried out to determine the significance of the elevation of cardiac enzymes when the two methods were used in heart surgery. Forest plots were used to present the pooled summary measures of the nine studies considered in this analysis. The I2 statistic generated from the pooling was used to determine the heterogeneity of the studies included in the analysis. Review Manager Software version 5.4 (RevMan 5.4) was used to calculate and plot the pooled effects of the included studies.

This study had been registered in PROSPERO with the number CRD42022306352.

  Results Top

Study selection

A total of 306 studies were selected for this study from different databases. Forty-four of these studies were selected for screening title and abstract. Eleven were excluded since they focused on pediatric patients. The full-text version of 36 studies was retrieved at this point and screened to determine if they fit the study. The next stage involved excluding the studies that were not RCTs. This led to the exclusion of 27 nonrandomized and retrospective studies.[12],[13],[14],[15] With the remaining articles left fit for inclusion, the study used nine studies, as illustrated in [Figure 1] PRISMA diagram.
Figure 1: PRISMA diagram

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Study characteristics

Of the 346 articles that we obtained, we identified nine prospective randomized studies from 2014 to 2020 [Figure 1], with a total of 1014 subjects undergoing open heart surgery (coronary artery bypass grafting [CABG], valve surgery, and heart transplantation). Of these subjects, 510 received blood cardioplegia treatment, whereas the other 444 subjects had crystalloid cardioplegic treatment. [Table 1] depicts the characteristics of the study subjects. The 60 that went through other procedures were excluded from this analysis.
Table 1: Characteristic of article study

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The number of study subjects per article varies from a minimum of 30 to a maximum of 297 subjects. Most articles compared blood cardioplegia to crystalloids in CABG [Table 1]. Overall, the articles had a low risk of bias [Figure 2]. All studies included in the systematic review were RCTs that were published between 2004 and 2019 in six countries, with the USA (3, 33.33%), Egypt (2, 22.22%), and Turkey (2, 22.22%) being the most frequent and Norway and Poland offering one (11.11%) each. [Table 1] provides a summary of the characteristics of the analyzed RCTs.
Figure 2: Risk of bias (RoB) result

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Outcome measures

Eight trials (88.89%) had at least two cardiac enzymes as the primary outcomes with CKMB measured and Troponin T or Troponin I [Table 2]. Four studies (44.44%) measured Troponin T. In contrast, the other five (55.56%) measured Troponin I. These primary endpoints were assessed, and other secondary clinical. Non-clinical outcome measures such as atrial fibrillation (3, 3.33%), myocardial infarction (5, 55.56%), inotropic use (3, 33.33%), and mortality (4, 44.44%), and length of ICU stay (3, 33.33%). Despite all trials measuring CKMB and cardiac troponin (cTn-I or cTn-T), there was heterogeneity in the metrics of assessments across the RCTs. One trial expressed its continuous data as medians with interquartile ranges (IQRs), whereas the rest used mean measures to express the data. The levels of cTn-I and cTn-T were measured using the pictograms per milliliter (pg/mL) in two trials (22.22%), nanograms per milliliter (ng/mL) in four studies (44.44%), microgram per milliliter (µg/mL) in one study (11.11%) and microgram per liter (µg/L) in two trials (22.22%).
Table 2: Primary and secondary outcome

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The CKMB was measured using the international unit (IU/L) in all trials except two that used µg/L and ng/mL each. All studies had preoperative and postoperative measures, whereas two (22.22%) had intraoperative measurements.

Quality of trials

The assessment of the quality of the RCTs is essential in evaluating their usefulness in this systematic analysis. An independent data monitoring committee did not oversee any of the nine trials. However, no trial was extended or stopped early. Only one trial (11.11%) had an enrolment flow diagram. The RoB was analyzed with the RoB tool of the Cochrane Library to evaluate the studies’ methodological quality and internal validity. It classifies into a high, low, or uncertain RoB. The applied criteria were as follows: Generation of the randomization sequence; Confidentiality of allocation; Concealment of allocation; Masking (blinding) of participants and the team of researchers; Masking (blinding) in the evaluation of outcomes; Incomplete data of outcomes; Selective report of outcomes, and other sources of bias identified by reviewer.[16]

Averagely, the standard mean difference for the overall performance is –2.67 (CI –4.18 to 1.17, P = 0.0005). The unit of measurement for the average is excluded from the analysis since the different studies; different methodologies were used. The subgroup analysis that was conducted indicated that the concentrations of troponin (cTn-I and cTn-T) at 24 h postoperatively were significantly higher in patients in the crystalloids cardioplegia group compared to those in the blood cardioplegia group (weighed mean difference [WMD] –2.67, confidence interval [CI] –4.18 to 1.17, P = 0.0005) as shown in [Figure 3]. [Figure 4] shows the WMD of CKMB values 24 h operatively for the crystalloids cardioplegia and the blood cardioplegia groups.
Figure 3: Forest plot: weighted mean difference of cardiac troponin (cTn-I and cTn-T) values for 24 h postoperatively

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Figure 4: Forest plot: weighted mean difference of CKMB values for 24 h postoperatively

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Averagely, the standard mean difference for the overall performance is –2.17 (CI –3.00 to 1.35, P = 0.00001). The unit of measurement for the average is excluded from the analysis since the different studies; different methodologies were used. The subgroup analysis that was conducted indicated that the concentrations of CKMB at 24 h postoperatively were significantly higher in patients in the crystalloids cardioplegia group compared to those in the blood cardioplegia group (WMD–2.17 [CI –3.00 to 1.35, P = 0.00001]), as shown in [Figure 4].

  Discussion Top

The risk minimization and rigor of RCTs imply that they are the most effective ways of assessing the effectiveness of healthcare interventions. Despite their efficacy, robustness can be increased by incorporating multiple canters, using large patient samples, prospectively registering trials, and independent oversight. These features were difficult to identify in the 346 trials that were examined and nine that were incorporated in this systematic analysis. In addition, patient, intervention, and metric heterogeneity imply limited evidence base in individual trials to support clinical decision-making. This systematic review aimed to bridge this gap by looking at the outcomes of nine RCTs.

This systematic review investigated the comparative effectiveness of blood versus crystalloid cardioplegic solutions in adult open-heart surgical procedures. A heart-lung bypass machine causes more red blood cells than the regular human cardiovascular system. The trauma from using this machine is structural and can be functional. Stress–strain: The impact of exposure of blood cells to the extracorporeal machine hose system, and the turbulent flow in them can cause hemolysis or shorten the lifespan of blood cells. However, the use of blood as cardioplegia is considered safe and effective for cardioplegia with more cardioprotective effects when compared to crystalloids. Nine randomized controlled studies comparing the effectiveness of blood cardioplegia to crystalloids in open-heart surgery were included in this review.

The cardiac enzyme is a sensitive marker for myocardial injury. Elevation of myocardial enzymes was the primary outcome of our study. Myocardial injury is significantly associated with cardiac troponin levels.[7] Two out of five studies examined the effect of blood versus crystalloid cardioplegia on enzyme Troponin I; significantly higher levels of Troponin-I were reported in patients who received crystalloid compared to blood cardioplegia.[2],[6] A similar pattern of higher levels of CKMB was observed in two studies for patients who received crystalloids.[2],[6] The Troponin T has been reported in four studies. There were significantly higher levels among the patients who received crystalloid than those with blood cardioplegia in three studies (33.33%). One study did not find a significant difference among the patients who received crystalloid or blood.[1]

Four of the six studies which employed warm blood cardioplegia reported significantly lower release of CKMB and Troponin I in comparison to crystalloid cardioplegia. In addition to this, higher use of inotropic and increased length of ICU stay was observed in patients who received crystalloid cardioplegia compared to warm blood cardioplegia.[2],[6] These findings are consistent with early meta-analyses on warm blood cardioplegia and crystalloid cardioplegia. In their meta-analysis of thirty-four studies, Guru et al.[17] reported that blood cardioplegia significantly reduced the incidence of LCOS and CKMB release. Owing to better oxygen-carrying capacity, buffer capacity, and physiological oncotic properties, the use of blood as cardioplegia is considered safe and effective for cardioplegia compared to crystalloids.[17]

We also sought to explore whether the theoretical benefits of blood over crystalloid cardioplegia translate into better clinical outcomes. Atrial fibrillation, myocardial infarction, length of stay at ICU, the use of inotropic support, and mortality were the secondary outcomes of our review. Surprisingly, an insignificant difference between both groups of cardioplegia was reported for atrial fibrillation, myocardial infarction, and mortality.[1],[2],[3],[4],[6] Similar findings were also reported by Mylonas et al.[11] in their meta-analysis, where both cardioplegia modalities showed comparative clinical effectiveness in pediatric patients.

However, a significant increase in the length of ICU stay was reported in only one study out of three studies that examined this parameter.[2],[4],[6] Similarly, among the three studies that examined inotropic support,[1],[2],[3] Mourad et al.[4] observed significantly higher use of inotropic support in the crystalloid group. In line with our review findings, a significantly lower concentration of cTn and CKMB in patients who underwent cardiac surgery by employing warm blood cardioplegia was reported by Fan et al.[18] in their meta-analysis of 41 RCTs.

The study used the forest plots as part of the Meta-analysis to determine the overall performance across the included cardiac enzyme studies. The meta-analysis is important in pooling together the studies to get a significant overall sample size to estimate the effect of crystalloids Cardioplegia and blood Cardioplegia on cardiac enzymes. The large bottom diamond signifies the overall performance of the included individual studies in the forest plots in [Figures 3] and [4]. Despite Ucak et al.[19] showing no variation in the levels of the cardiac enzymes between the crystalloids cardioplegia group and the blood cardioplegia groups, the overall performance confirms the WMD. Both bottom diamonds are on the left side, thus indicating that the levels of CKMB and troponin (cTn-I and cTn-T) are significantly increased in the crystalloids cardioplegia group compared to those in the blood cardioplegia group [Figure 3] and [Figure 4].

There are several limitations to this systematic review. One of the limitations of this review is the variation of cardioplegic temperature, composition, and the route among the included studies, which can affect the clinical outcomes. Secondly, the majority of the studies included in this review were performed on patients with CABG surgery, and these findings cannot be extrapolated to the adult patients undergoing other types of cardiac surgeries. The studies included were RCTs with small sample size and primarily single-center trials. With one having a sample size as small as 30, there is the need for larger samples to reduce errors and increase the validity and reliability of findings—the studies used in the systematic analysis also have inconsistent endpoints and measurement metrics. Standardized and validated endpoints will make it easier to assess these trials and perform a meta-analysis of pooled data.

The reliance on the journal databases as the sources of the included studies left the study exposed to publication bias. With only half of studies ever published with studies with non-significant findings failing to be published, the study missed out on other potential studies that met the inclusion criteria due to non-publication.[20] The forest plot showed a high publication bias. The search was also restricted to the four databases due to the ease of accessibility. The study did not, therefore, include studies from other databases that might have more studies with fewer publication bias. The exclusion of non-English studies also reduced the poll of potential studies that were included in the analysis.

  Conclusion Top

The findings of our systematic review revealed that both types of cardioplegia provide reasonable protection for the myocardium. It is still unclear which cardioplegic solution provides the best myocardial protection. However, several studies suggested that crystalloid cardioplegia increases cardiac enzymes (CKMB and Troponin I) more than blood cardioplegia does.

The limited sample size and different outcome measures elicit a limited evidence base to inform everyday clinical practice. It must be noted that, in general, clinical outcomes are also affected by many factors such as the severity of heart problems, comorbidities, duration of CPB use, difficulty in surgical procedure, and infection process. The studies are highly heterogeneous, with both the forest plots reporting heterogeneity of over 50% (98% for troponin and 97% for CKMB) [Figure 3] and [Figure 4]. This makes the systematic analysis a more fitting approach for examining the effect of crystalloids cardioplegia and blood cardioplegia on cardiac enzymes compared to meta-analysis. Further research to assess myocardial protection in adults should improve the open-heart surgery’s outcome. A clearer understanding of these perioperative conditions is the key to enhancing myocardial protection during open-heart surgery. As the standard error increases, the funnel plot representing individual studies should be more horizontally scattered. As with this analysis, the funnel plots with horizontally spread studies suggest high publication bias.[20]


Not applicable.

Financial support and sponsorship

Not applicable.

Conflicts of interest

There are no conflicts of interest.

  References Top

Sef D, Szavits-Nossan J, Predrijevac M, Golubic R, Sipic T, Stambuk K, et al. Management of perioperative myocardial ischaemia after isolated coronary artery bypass graft surgery. Open Heart 2019;6:e001027.  Back to cited text no. 1
Whittaker A, Aboughdir M, Mahbub S, Ahmed A, Harky A Myocardial protection in cardiac surgery: How limited are the options? A comprehensive literature review. Perfusion 2021;36:338-51.  Back to cited text no. 2
Drury NE, Yim I, Patel AJ, Oswald NK, Chong CR, Stickley J, et al. Cardioplegia in paediatric cardiac surgery: A systematic review of randomized controlled trials. Interact Cardiovasc Thorac Surg 2019;28:144-50.  Back to cited text no. 3
Mourad FA, Fadala MA, Ibrahim AA, Ammar AM, Elnahas YM, Elghanam MA, et al. Myocardial protection during CABG: Warm blood versus cold crystalloid cardioplegia, is there any difference? J Egypt Soc Cardio-Thoracic Surg 2016;24:215-22.  Back to cited text no. 4
Nardi P, Pisano C, Bertoldo F, Vacirca SR, Saitto G, Costantino A, et al. Warm blood cardioplegia versus cold crystalloid cardioplegia for myocardial protection during coronary artery bypass grafting surgery. Cell Death Discov 2018;4:23.  Back to cited text no. 5
James TM, Nores M, Rousou JA, Lin N, Stamou SC Warm blood cardioplegia for myocardial protection: Concepts and controversies. Tex Heart Inst J 2020;47:108-16.  Back to cited text no. 6
Greenberg JW, Lancaster TS, Schuessler RB, Melby SJ Postoperative atrial fibrillation following cardiac surgery: A persistent complication. Eur J Cardiothorac Surg 2017;52:665-72.  Back to cited text no. 7
Rashid S, Malik A, Khurshid R, Faryal U, Qazi S The diagnostic value of biochemical cardiac markers in acute myocardial infarction. Myocard Infarct 2019;23:23-34.  Back to cited text no. 8
Tevaearai Stahel HT, Do PD, Klaus JB, Gahl B, Locca D, Göber V, et al. Clinical relevance of troponin T profile following cardiac surgery. Front Cardiovasc Med 2018;5:182.  Back to cited text no. 9
De Mey N, Cammu G, Brandt I, Belmans A, Van Mieghem C, Foubert L, et al. High-sensitivity cardiac troponin release after conventional and minimally invasive cardiac surgery. Anaesth Intensive Care 2019;47:255-66.  Back to cited text no. 10
Mylonas KS, Tzani A, Metaxas P, Schizas D, Boikou V, Economopoulos KP Blood versus crystalloid cardioplegia in pediatric cardiac surgery: A systematic review and meta-analysis. Pediatr Cardiol 2017;38:1527-39.  Back to cited text no. 11
Braathen B, Tønnessen T Cold blood cardioplegia reduces the increase in cardiac enzyme levels compared with cold crystalloid cardioplegia in patients undergoing aortic valve replacement for isolated aortic stenosis. J Thorac Cardiovasc Surg 2010;139:874-80.  Back to cited text no. 12
Sirvinskas E, Nasvytis L, Raliene L, Vaskelyte J, Toleikis A, Trumbeckaite S Myocardial protective effect of warm blood, tepid blood, and cold crystalloid cardioplegia in coronary artery bypass grafting surgery. Croat Med J 2005;46:879-88.  Back to cited text no. 13
Dar MI Cold crystalloid versus warm blood cardioplegia for coronary artery bypass surgery. Ann Thorac Cardiovasc Surg 2005;11:382-5.  Back to cited text no. 14
Sanetra K, Gerber W, Shrestha R, Domaradzki W, Krzych Ł, Zembala M, et al. The del nido versus cold blood cardioplegia in aortic valve replacement: A randomized trial. J Thorac Cardiovasc Surg 2020;159:2275-83.e1.  Back to cited text no. 15
Higgins J, Thomas J, Chandler J, Cumpston M Cochrane Handbook for Systematic Reviews of Interventions. 6.0. West Sussex: Cochrane Library; 2019.  Back to cited text no. 16
Guru V, Omura J, Alghamdi AA, Weisel R, Fremes SE Is blood superior to crystalloid cardioplegia? A meta-analysis of randomized clinical trials. Circulation 2006;114:I331-8.  Back to cited text no. 17
Fan Y, Zhang AM, Xiao YB, Weng YG, Hetzer R Warm versus cold cardioplegia for heart surgery: A meta-analysis. Eur J Cardiothorac Surg 2010;37:912-9.  Back to cited text no. 18
Ucak HA, Uncu H Comparison of del nido and intermittent warm blood cardioplegia in coronary artery bypass grafting surgery. Ann Thorac Cardiovasc Surg 2019;25:39-45.  Back to cited text no. 19
Drucker AM, Fleming P, Chan AW Research techniques made simple: Assessing risk of bias in systematic reviews. J Invest Dermatol 2016;136:e109-14.  Back to cited text no. 20


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2]


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