Systematic Review

Optimizing Myocardial Protection in Minimally Invasive

Cardiac Surgeries: A Network Comparison of Del Nido,
Histidine-Tryptophan-Ketoglutarate, and Blood Cardioplegia
Sadeq Al-Hasan-Al-Saegh 1,*,†, Sho Takemoto 2,†, Stefano Benenati 3, Saeed Shafiei 4, Senol Yavuz 5, Mattia Galli 6,
Florian Helms 1, Lukman Amanov 1, Nunzio Davide De Manna 1, Saeed Torabi 7, Jan Karsten 8,
Jan Dieter Schmitto 1, Fabio Ius 1, Tim Kaufeld 1, Jawad Salman 1, Aron-Frederik Popov 1, Bastian Schmack 1,
Arjang Ruhparwar 1, Alina Zubarevich 1,‡ and Alexander Weymann 1,‡

1 Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School,

30625 Hannover, Germany; [email protected] (A.W.)
2 Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard

Medical School, Boston, MA 02114, USA

3 Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino, IRCCS Italian Cardiology Network,

16132 Genova, Italy

4 Department of Cardiac and Thoracic Vascular Surgery, Marburg University Hospital,

35043 Marburg, Germany

5 Department of Cardiovascular Surgery, University of Health Sciences, Bursa Yuksek Ihtisas Training and

Research Hospital, 16310 Bursa, Turkey

6 Department of Cardiology, Maria Cecilia Hospital, GVM Care & Research, 48033 Cotignola, Italy

7 Department of Anesthesiology, University Hospital Cologne, 50931 Cologne, Germany

8 Department of Anaesthesiology and Intensive Care Medicine, Hannover Medical School,

30625 Hannover, Germany

* Correspondence: [email protected]; Tel.: +49-176-1532-4895
† These authors shared first authorship.
Citation: Al-Hasan-Al-Saegh, S.;
‡ These authors shared senior authorship.
Takemoto, S.; Benenati, S.; Shafiei, S.;
Yavuz, S.; Galli, M.; Helms, F.;
Amanov, L.; De Manna, N.D.;
Abstract: Background/Objectives: The optimal choice of cardioplegia solution in minimally inva-
Torabi, S.; et al. Optimizing sive cardiac surgeries (MICS) remains debated, as prolonged myocardial protection is essential to
Myocardial Protection in Minimally avoid interruptions to the surgical flow, which can prolong aortic cross-clamp time and cardiopul-
Invasive Cardiac Surgeries: A monary bypass time, especially in the constrained surgical field. We conducted a network meta-
Network Comparison of Del Nido, analysis to evaluate the safety and efficacy of the del Nido (DN), histidine-tryptophan-ketoglutarate
Histidine-Tryptophan-Ketoglutarate, (HTK), blood cardioplegia (BC), and St. Thomas’ (STH) solutions in MICS. Methods: Medical elec-
and Blood Cardioplegia. J. Clin. Med. tronic databases were thoroughly searched without time restrictions, including all types of studies
2024, 13, 6977. https://doi.org/ except for study protocols and animal research. The final search was completed in June 2024. Subse-
10.3390/jcm13226977
quently, a network meta-regression was performed on both primary and secondary endpoints, utiliz-
Academic Editor: Bernhard Rauch ing R (The R Foundation for Statistical Computing, version 3.6.2) for the analysis. Meta-analyses were
carried out using Review Manager software. Results: A total of 15 studies, enrolling 2282 patients,
Received: 19 October 2024
were included in the analysis. None of the comparisons showed statistically significant differences
Revised: 6 November 2024
Accepted: 12 November 2024
in in-hospital mortality between the four cardioplegia solutions (BC vs. HTK, OR: 3.21, 95% CI: 0.13–
Published: 19 November 2024 80.84; DN vs. HTK, OR: 1.42, 95% CI: 0.28–7.23; STH vs. HTK, OR: 1.25, 95% CI: 0.19–8.20). Conclu-
sions: In this network meta-analysis of cardioplegia solutions in MICS, no significant differences
were observed in major clinical outcomes across the solutions. Cardioplegia solutions that provide
Copyright: © 2024 by the authors. Li-
long-lasting myocardial protection with a single dose, such as DN and HTK, were found to be safely
censee MDPI, Basel, Switzerland. applied in MICS. DN was associated with shorter CPB times and HTK was associated with shorter
This article is an open access article hospital stays, though these differences may not have clinical implications.
distributed under the terms and con-
ditions of the Creative Commons At- Keywords: myocardial protection; cardioplegia; minimally invasive cardiac surgery; cardiac
tribution (CC BY) license (https://cre- surgery; del Nido; histidine-tryptophan-ketoglutarate; blood cardioplegia; meta-analysis
ativecommons.org/licenses/by/4.0/).

J. Clin. Med. 2024, 13, 6977. https://doi.org/10.3390/jcm13226977 www.mdpi.com/journal/jcm

J. Clin. Med. 2024, 13, 6977 2 of 17

1. Introduction
Cardiac arrest during cardiac surgery is typically achieved using cardioplegia under
cardiopulmonary bypass (CPB), which provides a bloodless surgical field and myocardial
protection [1]. Various cardioplegia formulations offer different durations of protection,
myocardial preservation, and clinical outcomes [1]. Minimally invasive cardiac surgery
(MICS) has gained increasing popularity due to its reduced invasiveness, blood loss, and
need for transfusion, as well as shorter required hospital stays compared to conventional
cardiac surgery [2,3]. However, the optimal choice of cardioplegia solution in MICS re-
mains debated, as prolonged myocardial protection is essential to avoid interruptions to
the surgical flow, which can prolong aortic cross-clamp time and CPB time, especially in
the constrained surgical field.
Since the first clinical use of Bretschneider’s solution in the 1960s, various solutions—
including crystalloid cardioplegia (CCP) solution, histidine-tryptophan-ketoglutarate
(HTK) solution, St. Thomas’ (STH) solution, and blood cardioplegia (BC) solution, which
combines Buckberg solution with oxygenated blood—have been widely used [1,4]. In
MICS, where long-lasting myocardial protection with a single dose is preferred, the use
of the del Nido (DN) cardioplegia solution, originally developed for pediatric cardiac sur-
gery and containing lidocaine, has rapidly expanded alongside HTK [1,5].
While some studies have compared cardioplegia solutions head-to-head, results have
often been inconsistent [1]. Moreover, there is limited data specifically focused on the
MICS setting. To address these gaps in knowledge, we conducted a network meta-analysis
to evaluate the safety and efficacy of DN, HTK, BC, and STH solutions in MICS. This anal-
ysis combined both direct and indirect evidence to provide clinical guidance on the opti-
mal choice of cardioplegia solution in minimally invasive cardiac surgery.

2. Materials and Methods

2.1. Eligibility Criteria
This study was carried out following the Cochrane Collaboration published guide-
lines and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) guidelines (appendix) [6]. A network meta-analysis comparing the DN, HTK,
BC, and STH solutions in MICS was conducted. The other part of this study was focused
on providing reliable comparisons of outcomes and complications between the DN, HTK,
BC, and STH solutions in two-group direct comparisons.
Therefore, the research question was structured using the Population, Intervention,
Comparison, Outcome, and Study (PICOS) framework. Studies were included in the anal-
ysis based on the following criteria.
• Population: all patients underwent MICS
• Intervention: the DN, HTK, BC, and STH solutions as cardioplegia solutions
• Comparator: direct and indirect comparison with other solutions
• Outcome: postoperative clinical outcomes and complications
• Study design: Original articles were considered in the initial evaluation, while exper-
imental studies, case reports, conference abstracts, letters, editorials, reviews, and
general overviews were excluded.
J. Clin. Med. 2024, 13, 6977 3 of 17

2.2. Ethics
Since our study was based on existing literature and did not use information from
human subjects, there were no ethical issues related to medical ethics that needed to be
considered.

2.3. Literature Search

The Cochrane Library, Embase, PubMed, PubMed Central, OVID Medline, and Web
of Science databases were systematically searched using a combination of the following
search terms: “del Nido cardioplegia solution” OR “del Nido” OR “Bretschneider cardio-
plegic solution” OR “HTK solution” OR “Custodiol solution” OR “HTK solution of
Bretschneider” OR “Bretschneider solution” OR “histidine-tryptophan-ketoglutarate so-
lution” OR “St. Thomas’ Hospital cardioplegic solution” OR “STH solution” OR “cardio-
plegic solution STH” OR “Plegisol” OR “blood cardioplegia” OR “potassium cardioplegic
solution” OR “crystalloid cardioplegic solution” OR “University of Wisconsin-lactobi-
onate solution” OR “UW solution” OR “University of Wisconsin cardioplegic solution”
OR “Cardiosol” OR “Celsior” AND “minimally invasive” OR “minimally invasive cardiac
surgery” OR “cardiac surgery” OR “heart surgery”. There were no restrictions on the pub-
lication year during the literature search. The final search was conducted in June 2024.
Furthermore, the reference lists of the retrieved articles were thoroughly examined to
identify any additional relevant studies that might have been missed in the initial search.

2.4. Data Extraction

All titles and abstracts were screened independently by multiple authors (S.A.-H.-A.-
S., S.S., S.Y., and S.T.). Eligible full-text articles were subsequently and independently re-
viewed by five authors (S.S., S.B., S.Y., S.T., and S.A.-H.-A.-S.) to determine inclusion and
extract data. Any disagreements were resolved by the senior authors (A.Z. and A.W.). All
data were compiled into an Excel table.

2.5. Outcome Measures

The following information was extracted from the included studies: first author’s
name, year of publication, country of origin, sample size, study design, type of compari-
sons, propensity-matched design, demographic data and baseline characteristics of pa-
tients, procedural details, type of surgery, minimally invasive techniques, cardioplegia
solution used, method of administering cardioplegia, dosage and volume of cardioplegia,
duration of cardiopulmonary bypass (CPB), and aortic cross-clamping (ACC) time. Addi-
tionally, information on clinical outcomes and surgical complications following MICS was
recorded. This included any instances of in-hospital mortality, durations of ACC and CPB,
occurrences of new-onset atrial fibrillation (POAF), usage of intra-aortic balloon pumps
(IABP), administration of inotropes, incidence of stroke, acute kidney injury (AKI) with
need for dialysis, cases of low cardiac output syndrome, postoperative re-explorations,
prolonged ventilation, use of defibrillators, and the length of stay in the intensive care unit
(ICU) and hospital.

2.6. Statistical Analysis for Network Comparison

The impact of various cardioplegic solutions on primary and secondary endpoints
was analyzed using a Bayesian meta-analysis with a random-effects model, which inte-
grated both direct and indirect evidence while assuming consistency among the data.
Odds ratios (ORs) and 95% credible intervals (CrIs) were calculated using a Markov chain
Monte Carlo simulation. To evaluate publication bias, we utilized comparison-adjusted
funnel plots of effect size versus standard error, along with Egger’s tests. Smaller studies
often highlight treatment effectiveness, potentially skewing results in network meta-anal-
yses due to their focus on limited cohorts. To explore this, treatments were ranked from
most effective to least effective. The consistency of the evidence was assessed using the
J. Clin. Med. 2024, 13, 6977 4 of 17

node-splitting technique. Finally, a network meta-regression was conducted on the pri-

mary endpoint, with the analysis performed using R (The R Foundation for Statistical
Computing, version 3.6.2).

2.7. Statistical Analysis for Two-Group Comparison

Meta-analyses were conducted using Review Manager software (RevMan version
5.3.5; The Cochrane Collaboration, The Nordic Cochrane Center, Copenhagen, Denmark).
Due to anticipated clinical heterogeneity among the included studies, the Mantel–
Haenszel random-effects model was employed. Dichotomous data were reported as odds
ratios (ORs), while continuous data were presented as weighted mean differences (MDs).
Summary effect measures included the corresponding 95% confidence intervals (CIs). Sta-
tistical heterogeneity was assessed using the I2 statistic, where values between 0% and 25%
indicated negligible heterogeneity, 26% and 50% indicated low heterogeneity, 51% and
75% indicated moderate heterogeneity, and 76% and 100% indicated high heterogeneity.
A fixed-effects model was applied when the I2 was less than 50%, while a random-effects
model was used for I2 values greater than 50%.

3. Results
A total of 15 studies, enrolling 2282 patients, were included in the analysis [7–21]
(Figure 1). Of these, two were prospective randomized studies, two were prospective non-
randomized studies, and eleven were retrospective observational studies, including ten
propensity-matched studies (Table 1). The network meta-analysis involved comparisons
between four cardioplegia solutions: DN vs. HTK (four studies), DN vs. BC (four studies),
HTK vs. BC (four studies), HTK vs. STH (two studies), and DN vs. STH (one study). De-
tailed characteristics of the included studies, patients’ baseline data, and procedural de-
tails are presented in Supplemental Tables S1–S3.

Figure 1. PRISMA flow diagram.

J. Clin. Med. 2024, 13, 6977 5 of 17

Table 1. List of included studies.

Propensity-
Author Year Study Period Comparison Country Study Type
Matched
Vistarini et al. Single-center, retrospective, obser-
2017 2012–2015 DN vs. BC Canada No
[12] vational study
Single-center, retrospective, com-
Lee et al. [9] 2020 2015–2019 DN vs. HTK South Korea Yes
parative study
Ziazadeh et al. Single-center, retrospective, non-
2017 2011–2016 DN vs. BC USA Yes
[14] randomized study
Single-center, retrospective, non-
Luo et al. [21] 2019 2017 DN vs. STH China Yes
randomized study
Single-center, retrospective, obser-
Mork et al. [19] 2019 2012–2019 HTK vs. STH Switzerland Yes
vational study
Barbero et al. Single-center, prospective, observa-
2023 2014–2018 STH vs. HTK Italy Yes
[20] tional study
Mohamed et al. Single-center, prospective, nonran-
2023 2021–2022 HTK vs. BC Egypt No
[15] domized, observational study
De Palo et al. [17] 2017 2012–2015 HTK vs. BC Italy Single-center, retrospective study No
Kang et al. [7] 2024 2018–2021 DN vs. HTK Germany Single-center, retrospective study Yes
Single-center, retrospective, case-
Gerber et al. [10] 2023 2016 DN vs. HTK Poland Yes
control study
Gunaydin et al. Single-center, prospective, random-
2020 2017–2019 DN vs. HTK Turkey No
[8] ized study
Hummel et al. Single-institution, retrospective,
2016 2011–2015 BC vs. HTK USA Yes
[16] case-control study
Koeckert et al. Single-center, retrospective, non-
2018 2013–2015 DN vs. BC USA Yes
[11] randomized study
Kammerer et al. Single-center, prospective, random-
2012 2008–2009 HTK vs. BC Germany No
[18] ized study
Single-center, retrospective, obser-
Pozzoli et al. [13] 2023 2005–2015 DN vs. BC Switzerland Yes
vational study
Abbreviations: DN: del Nido solution; HTK: histidine-tryptophan-ketoglutarate solution; STH: St.
Thomas’ solution; BC: blood cardioplegia solution.

3.1. Network Comparison

3.1.1. Primary Endpoint (In-Hospital Mortality)
The results of the primary endpoint are displayed in Figure 2. None of the compari-
sons showed statistically significant differences in in-hospital mortality between the four
cardioplegia solutions (BC vs. HTK—OR: 3.21, 95% CI: 0.13–80.84; DN vs. HTK—OR: 1.42,
95% CI: 0.28–7.23; STH vs. HTK—OR: 1.25, 95% CI: 0.19–8.20).
J. Clin. Med. 2024, 13, 6977 6 of 17

Figure 2. Forest plots for in-hospital mortality.

3.1.2. Secondary Endpoints

There was no significant difference in ACC time across the cardioplegia solutions
(Figure 3). However, DN was associated with a significantly shorter CPB time than HTK
(MD: −8.57 min, 95% CI: −17.09–0.04) (Figure 3). No significant differences were observed
in ICU stays between the groups (Figure 3).

Figure 3. Forest plots for the secondary outcomes (ACC: aortic cross-clamping; CPB: cardiopulmo-
nary bypass; ICU: intensive care unit).

On the other hand, DN was associated with a longer hospital stay compared with
HTK (MD: 0.62 days, 95% CI: 0.25–0.98) (Figure 4). There were no significant differences
in inotrope use, IABP use, low CO syndrome, renal failure, stroke, prolonged ventilation,
or defibrillator use (Figure 4).
J. Clin. Med. 2024, 13, 6977 7 of 17

Figure 4. Forest plots for the secondary outcomes (continued) (POAF: postoperative atrial fibrilla-
tion; low CO syndrome: low cardiac output syndrome; IABP: intra-aortic balloon pump).

The odds of re-exploration were significantly higher for both the BC and DN solu-
tions compared to HTK (BC vs. HTK—OR: 10.84, 95% CI: 2.11–55.59; DN vs. HTK—OR:
3.20, 95% CI: 1.30–7.85). In contrast, there was no significant difference in re-exploration
between STH and HTK (OR: 0.43, 95% CI: 0.06–3.33) (Figure 5).

Figure 5. Forest plot for the incidence of re-exploration.

3.1.3. Heterogeneity, Node-Split Analysis, and Publication Bias

Supplemental Table S4 displays the I2 statistics for individual comparisons for each
endpoint, with heterogeneity ranging from low to high. Node-split did not show signifi-
cant inconsistencies between direct and indirect evidence. Comparison-adjusted funnel
plots were not suggestive of significant publication bias (Figure 6).
J. Clin. Med. 2024, 13, 6977 8 of 17

Figure 6. Comparison-adjusted funnel plots (ACC: aortic cross-clamping; CPB: cardiopulmonary

bypass; ICU: intensive care unit; POAF: postoperative atrial fibrillation; low CO syndrome: low car-
diac output syndrome; IABP: intra-aortic balloon pump).

3.1.4. Ranking the Strategies

Among the four solutions, the DN solution was ranked first for ACC time, CPB time,
IABP use, low CO syndrome, renal failure, and stroke (Figure 7).
J. Clin. Med. 2024, 13, 6977 9 of 17

Figure 7. Rankogram of the four cardioplegia solutions for each outcome (ACC: aortic cross-clamp-
ing; CPB: cardiopulmonary bypass; ICU: intensive care unit; POAF: postoperative atrial fibrillation;
low CO syndrome: low cardiac output syndrome; IABP: intra-aortic balloon pump).

3.2. Two-Group Comparison

3.2.1. Group 1: DN vs. HTK
Early outcomes were reported in four studies, with a total of 517 patients. CPB time
was significantly shorter in DN compared to HTK, while no significant difference was
observed in ACC time (CPB time—MD: −3.87 min, 95% CI: −5.97–1.77; ACC time—MD:
−0.15 min, 95% CI: −1.68–1.38; Figure 8). Significantly longer hospital stays and higher
odds of re-exploration were observed in HTK (MD: 0.55 days, 95% CI: 0.15–0.94; OR: 3.26,
95% CI: 1.34–7.96, respectively; Figure 8). There were no significant differences in ICU
stay, IABP use, in-hospital mortality, low CO syndrome, POAF, stroke, or prolonged ven-
tilation (Figure 8).
J. Clin. Med. 2024, 13, 6977 10 of 17

Figure 8. Results of the random-effects model: DN vs. HTK (ACC: aortic cross-clamping; CPB: car-
diopulmonary bypass; ICU: intensive care unit; POAF: postoperative atrial fibrillation; low CO syn-
drome: low cardiac output syndrome; IABP: intra-aortic balloon pump) [7–10].

3.2.2. Group 2: DN vs. BC

Outcomes were reported in four studies, with a total of 202 patients. There were no
significant differences in ACC time, CPB time, or 30-day mortality. The BC solution was
associated with higher odds of inotrope use (OR: 2.21, 95% CI: 1.14–4.28; Figure 9), while
there was no significant difference in postoperative LVEF. The BC solution was also asso-
ciated with higher odds of POAF (OR: 1.59, 95% CI: 1.02–2.50; Figure 9).
J. Clin. Med. 2024, 13, 6977 11 of 17

Figure 9. Results of the random-effects model: DN vs. BC (ACC: aortic cross-clamping; CPB: cardi-
opulmonary bypass; ICU: intensive care unit; POAF: postoperative atrial fibrillation; LVEF: left ven-
tricle ejection fraction) [11–14].

3.2.3. Group 3: HTK vs. BC

Four studies and a total of 101 patients were included in the HTK vs. BC group. Both
cardioplegia solutions were comparable with respect to ACC and CPB time, low CO syn-
drome, and POAF (Figure 10).

Figure 10. Results of the random-effects model: HTK vs. BC (ACC: aortic cross-clamping; CPB: car-
diopulmonary bypass; POAF: postoperative atrial fibrillation; low CO syndrome: low cardiac out-
put syndrome) [15–18].
J. Clin. Med. 2024, 13, 6977 12 of 17

3.2.4. Group 4: HTK vs. STH

CPB time was an only measured outcome that showed a significant difference, which
was longer in HTK (MD: 9.19 min, 95% CI: 0.93–17.45; Figure 11). No significant differ-
ences were observed in ACC time, hospital stay, in-hospital mortality, stroke, prolonged
ventilation, or re-exploration (Figure 11).

Figure 11. Results of the random-effects model: HTK vs. STH (ACC: aortic cross-clamping; CPB:
cardiopulmonary bypass) [19,20].

4. Discussion
In the present network meta-analysis, we evaluated the outcomes of different cardi-
oplegia solutions, including DN, BC, HTK, and STH, across various clinical endpoints.
The main findings of our analysis can be summarized as follows (1) DN was associated
with a significantly shorter CPB time compared with HTK, although no significant differ-
ences were found in ACC time across the cardioplegia solutions; (2) DN was linked to a
longer hospital stay compared with HTK, while no significant differences were observed
in ICU stay between the groups; (3) re-exploration was significantly more frequent with
both BC and DN compared to HTK, while STH showed no significant difference in this
outcome; and (4) there were no significant differences among the cardioplegia solutions
in terms of other key clinical outcomes, such as low cardiac output syndrome, renal fail-
ure, stroke, inotrope use, IABP use, prolonged ventilation, or defibrillator use.
HTK, known for its ability to provide myocardial protection for more than 120 min
with a single dose, has been shown to offer comparable safety and myocardial protection
to BC in randomized controlled trials (RCTs) [22,23]. The DN solution has gained rapid
popularity in adult cardiac surgery following its initial use in pediatric cardiac surgery
[5]. An RCT conducted by Talwar et al. reported that the DN solution demonstrated better
preservation of the cardiac index, shorter ventilation times, shorter ICU and hospital stays,
lower inotropic scores, reduced myocardial edema, and lower troponin-I release com-
pared to HTK in pediatric cardiac surgery patients [24]. As of August 2024, only two RCTs
compare the DN and HTK solutions in adult cardiac surgery, including one in MICS
[8,25]. One of these RCTs, included in our analysis, reported comparable clinical outcomes
J. Clin. Med. 2024, 13, 6977 13 of 17

with a single dose [8]. Still, the DN solution demonstrated a significantly higher incidence
of atrioventricular block and longer ICU and hospital stays when comparing multiple
doses of DN or HTK solutions [8]. Clinically small but statistically significantly shorter
CPB time was consistent in our two-group comparison between the DN and HTK solu-
tions.
In comparing the DN and BC solutions, no significant differences in perioperative
outcomes were observed, except for a higher incidence of POAF in the DN solution among
patients undergoing coronary artery bypass grafting with or without valve surgery [26],
which was inversely observed in our two-group analysis of DN vs. BC (OR: 1.59, 95% CI:
1.02–2.50). However, there were no RCTs evaluating DN and BC specifically in MICS. No-
tably, an existing network meta-analysis that included all categories of patients and car-
diac surgery types reported that the DN solution may be associated with lower perioper-
ative mortality compared to the HTK or BC solutions, while the risk of POAF may be
lower with HTK than with the BC or DN solutions in adults [1].
In contrast to the findings reported by Tan et al., both our network meta-analysis and
two-group analysis did not demonstrate a mortality benefit with the DN solution com-
pared to other cardioplegia solutions [1]. This discrepancy may be attributed to the fact
that our analysis focused exclusively on MICS, which typically involves less complex sur-
gical procedures.
In the context of MICS, minimizing interruptions during surgery is critical, particu-
larly regarding cardioplegia administration. Repeated doses of cardioplegia can interrupt
the flow of the surgical procedure and lead to prolonged ACC and CPB times. Therefore,
a single dose of cardioplegia solution that provides prolonged myocardial protection is
ideal. While Nagashima et al. reported the safety and efficacy of 60-minute dosing inter-
vals with a STH-based crystalloid cardioplegia solution, the DN solution can provide my-
ocardial protection for up to 90 min and HTK for up to 120 min with a single dose [27]. In
cases with no significant differences in major clinical outcomes, selecting a cardioplegia
solution that offers longer myocardial protection is reasonable, although HTK showed a
slightly longer CPB time than STH in the two-group comparison (MD: 9.19 min, 95% CI:
0.93–17.45), and DN vs. STH has not yet been well investigated. However, in cases where
the ACC time exceeded 180 min, a comparison between nine patients who received DN
and fifteen patients who received BC (with low-dose lidocaine) showed significantly
higher postoperative CK-MB levels in the DN group (75.1 µg/L vs. 60.5 µg/L) [28]. These
results suggest that the longer dosing interval associated with the DN solution may con-
tribute to myocardial injury in cases with a prolonged ACC time. Therefore, in more com-
plex and prolonged surgeries, it may be necessary to shorten the dosing interval of DN
solutions to minimize the risk of myocardial damage.
In our results, although there was no significant difference in the ACC time between
the cardioplegia solutions, CPB time was significantly shorter with the DN solution. How-
ever, many of the included studies involved relatively simple procedures that did not re-
quire prolonged ACC. Additionally, while statistically significant, the reported MD of
−8.57 min in CPB time may not have a clinically meaningful impact. Similarly, while HTK
was associated with a significantly shorter hospital stay compared to DN (MD: −0.62
days), the clinical relevance of this difference is limited.
One of the key features of the DN solution is the addition of lidocaine, a sodium
channel blocker that suppresses membrane excitation. The membrane-stabilizing effect of
lidocaine has been reported to result in a lower incidence of POAF and a reduced need for
defibrillation after the release of the ACC [29–32]. However, in our analysis, no significant
differences were observed in POAF or defibrillator use among the four groups. Regarding
defibrillator use, each of the four comparison pairs was based on only one study. There-
fore, further research is needed to investigate the restoration of spontaneous cardiac ac-
tivity after ACC release and postoperative arrhythmia in MICS. In terms of re-exploration,
the DN solution showed a statistically significant increase in re-exploration rates com-
pared to HTK (OR: 3.2). Despite this finding, the absolute event counts were relatively low
J. Clin. Med. 2024, 13, 6977 14 of 17

across studies (e.g., 10 re-explorations out of 228 in Lee et al. [9]), raising questions about
the clinical relevance of this difference. Furthermore, MICS outcomes can be influenced
by surgeon expertise and technique, which were not uniformly controlled across studies.
Therefore, while the DN solution’s composition may provide some theoretical benefits in
myocardial protection, its association with re-exploration requires validation through
large, multi-center RCTs that account for surgical expertise, patient risk profiles, and pro-
cedural variables.
The significantly lower incidence of re-exploration observed with HTK in our analy-
sis is unlikely to be attributed to the composition of the cardioplegia solutions, as there
have been no reports suggesting that differences in cardioplegia formulations increase
bleeding. Given that our study included multiple propensity-matched studies, differences
in patient backgrounds and surgical procedures between groups were largely adjusted
for. However, further investigation with larger sample sizes, standardized surgical tech-
niques, and consistent surgical teams is required to validate this finding.
A systematic review and meta-analysis conducted by Chan et al. examined studies
available in various databases up until April 2021. Given the increasing number of publi-
cations on minimally invasive cardiac surgery in recent years, an updated analysis was
warranted, incorporating additional studies. Chan et al. found no significant differences
between blood and crystalloid cardioplegia solutions in adult patients undergoing mini-
mally invasive cardiac surgery. They concluded that the choice of cardioplegia solution in
these procedures ultimately depends on the surgeon’s individual preferences and deci-
sions [33]. Russell and colleagues highlighted that the selection of cardioplegia solution in
MICS is primarily influenced by the surgeon’s individual preference. They found that so-
lutions that enable longer cardiac arrest periods during infusion are often preferred, as
they contribute to a more straightforward surgical process [34]. The study by Misra et al.
did not identify any mortality benefits associated with the del Nido cardioplegia solution.
However, they found that intraoperative glucose homeostasis was better maintained in
the del Nido solution group. Additionally, this group experienced lower postoperative
cardiac troponin T release and required fewer transfusions. The authors concluded that
the del Nido cardioplegia solution is a safe and advantageous alternative to the blood
cardioplegia solution in adult cardiac surgery [35].
There are several limitations to this study. First, the number of studies included in
the network meta-analysis was relatively small, particularly for specific cardioplegia com-
parisons, which may have limited the statistical power of our findings. Second, most in-
cluded studies were observational or propensity-matched rather than RCTs, which may
introduce potential biases despite efforts to adjust for confounding factors. This lack of
high-quality RCT data may impact the robustness and generalizability of our conclusions.
Additionally, certain comparisons included small sample sizes, which further limited sta-
tistical power and our ability to detect clinically meaningful differences. Third, the heter-
ogeneity in surgical techniques and endpoints across the included studies made it chal-
lenging to draw definitive conclusions. Finally, the lack of consistent reporting on specific
outcomes, such as defibrillator use, further limited our ability to assess the full clinical
impact of different cardioplegia solutions.

5. Conclusions
In this network meta-analysis of cardioplegia solutions in MICS, no significant dif-
ferences were observed in major clinical outcomes across the solutions. Single-dose car-
dioplegia solutions such as the DN and HTK solutions were found to be safely applicable
in MICS, with the DN solution associated with shorter CPB times and HTK with shorter
hospital stays. Although these differences may not have substantial clinical implications,
the findings suggest that both solutions provide effective myocardial protection in this
context. Future research should focus on conducting larger, multi-center RCTs with stand-
ardized surgical protocols to validate these results. Additionally, exploring the use of sin-
gle-dose cardioplegia solutions in more complex cardiac procedures may broaden the
J. Clin. Med. 2024, 13, 6977 15 of 17

applicability of these findings. These directions could ultimately help to establish the op-
timal cardioplegia strategy for MICS and potentially extend its benefits to a wider range
of cardiac surgeries.

Supplementary Materials: The following supporting information can be downloaded at:

https://www.mdpi.com/article/10.3390/jcm13226977/s1, Supplemental Table S1: Baseline patients’
characteristics; Supplemental Table S2: Procedural characteristics; Supplemental Table S3: Proce-
dural characteristics (continued); Supplemental Table S4: Heterogeneity across analyses.
Author Contributions: All authors contributed to the collection of data, manuscript development
and final approval. Conceptualization, A.Z., A.W., J.D.S. and S.A.-H.-A.-S.; methodology, S.A.-H.-
A.-S., M.G., S.B., L.A., N.D.D.M., F.H. and F.I.; software, S.A.-H.-A.-S., S.B., M.G., N.D.D.M., L.A.,
F.H., S.S., S.Y. and J.K.; formal analysis, S.A.-H.-A.-S., S.B., M.G., S.T. (Saeed Torabi), F.H., N.D.D.M.,
and L.A.; validation, J.S., J.D.S., A.W., T.K., A.-F.P., B.S., A.Z. and A.R.; investigation, J.S., S.A.-H.-
A.-S., S.S., S.Y., S.T. (Sho Takemoto), J.D.S., F.I., J.K. and T.K.; writing—original draft preparation,
S.A.-H.-A.-S., S.T. (Sho Takemoto), B.S., A.-F.P., A.Z. and A.W.; funding; T.K. and A.R.; writing—
review and editing, A.W., J.D.S., S.A.-H.-A.-S., S.T. (Sho Takemoto), J.S., A.Z. and B.S.; supervision,
F.I., J.D.S., J.S., A.-F.P., A.W., B.S. and A.R. All authors have read and agreed to the published version
of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Since our study is based on previously published literature
and did not involve any interactions with human subjects, there were no medical ethics issues that
needed to be addressed.
Informed Consent Statement: Not applicable.
Data Availability Statement: Data are available from the corresponding author upon reasonable request.
Conflicts of Interest: The authors declare no conflicts of interest.

References
1. Tan, J.; Bi, S.; Li, J.; Gu, J.; Wang, Y.; Xiong, J.; Yu, X.; Du, L. Comparative effects of different types of cardioplegia in cardiac
surgery: A network meta-analysis. Front. Cardiovasc. Med. 2022, 9, 996744. https://doi.org/10.3389/fcvm.2022.996744.
2. Eqbal, A.J.; Gupta, S.; Basha, A.; Qiu, Y.; Wu, N.; Rega, F.; Chu, F.V.; Belley-Cote, E.P.; Whitlock, R.P. Minimally invasive mitral
valve surgery versus conventional sternotomy mitral valve surgery: A systematic review and meta-analysis of 119 studies. J.
Card. Surg. 2022, 37, 1319–1327. https://doi.org/10.1111/jocs.16314.
3. Whiteley, J.; Toolan, C.; Shaw, M.; Perin, G.; Palmer, K.; Al-Rawi, O.; Modi, P. Patient-reported outcome measures after mitral
valve repair: A comparison between minimally invasive and sternotomy. Interact. Cardiovasc. Thorac. Surg. 2021, 32, 433–440.
https://doi.org/10.1093/icvts/ivaa276.
4. Bretschneider, H.J. Survival time and recuperative time of the heart in normothermia and hypothermia. Verh. Dtsch. Ges. Kreis-
laufforsch. 1964, 30, 11–34.
5. Matte, G.S.; Del Nido, P.J. History and Use of del Nido Cardioplegia Solution at Boston Children’s Hospital. J. Extracorpor.
Technol. 2012, 44, 98–103. https://doi.org/10.1051/ject/201244098.
6. Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.;
Brennan, S.E.; et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021, 372, n71.
https://doi.org/10.1136/bmj.n71.
7. Kang, J.; Hoyer, A.; Dieterlen, M.T.; Oetzel, H.; Otto, W.; Ginther, A.; Pfannmüller, B.; Misfeld, M.; Noack, T.; Kiefer, P.; et al.
Comparison of modified Del Nido and Custodiol® cardioplegia in minimally invasive mitral valve surgery. Eur. J. Cardiothorac.
Surg. 2024, 65, ezae161. https://doi.org/10.1093/ejcts/ezae161.
8. Gunaydin, S.; Akbay, E.; Gunertem, O.E.; McCusker, K.; Kunt, A.T.; Onur, M.A.; Ozisik, K. Comparative Effects of Single-Dose
Cardioplegic Solutions Especially in Repeated Doses During Minimally Invasive Aortic Valve Surgery. Innov. Technol. Tech.
Cardiothorac. Vasc. Surg. 2021, 16, 80–89. https://doi.org/10.1177/1556984520967119.
9. Lee, C.-h.; Kwon, Y.; Park, S.J.; Lee, J.W.; Kim, J.B. Comparison of del Nido and histidine-tryptophan-ketoglutarate cardioplegic
solutions in minimally invasive cardiac surgery. J. Thorac. Cardiovasc. Surg. 2022, 164, e161–e171.
https://doi.org/10.1016/j.jtcvs.2020.11.163.
10. Gerber, W.; Sanetra, K.; Gerber, A.D.; Jankowska-Sanetra, J.; Kuczera, M.; Białek, K.; Buszman, P.P.; Bochenek, A. One-shot
cardioplegia for minimally invasive mitral valve repair-a comparison of del Nido and Bretschneider Histidine-Tryptophan-
Ketoglutarate solutions. Perfusion 2023, 38, 763–770. https://doi.org/10.1177/02676591221080653.
J. Clin. Med. 2024, 13, 6977 16 of 17

11. Koeckert, M.S.; Smith, D.E.; Vining, P.F.; Ranganath, N.K.; Beaulieu, T.; Loulmet, D.F.; Zias, E.; Galloway, A.C.; Grossi, E.A. Del
Nido cardioplegia for minimally invasive aortic valve replacement. J. Card. Surg. 2018, 33, 64–68.
https://doi.org/10.1111/jocs.13536.
12. Vistarini, N.; Laliberté, E.; Beauchamp, P.; Bouhout, I.; Lamarche, Y.; Cartier, R.; Carrier, M.; Perrault, L.; Bouchard, D.; El-
Hamamsy, I.; et al. Del Nido cardioplegia in the setting of minimally invasive aortic valve surgery. Perfusion 2017, 32, 112–117.
https://doi.org/10.1177/0267659116662701.
13. Pozzoli, A.; Torre, T.; Bagnato, P.; Gallo, M.; Toto, F.; Ferrari, E.; Demertzis, S. del Nido versus hematic cardioplegia in minimally
invasive aortic valve surgery. Asian Cardiovasc. Thorac. Ann. 2023, 31, 795–801. https://doi.org/10.1177/02184923231209858.
14. Ziazadeh, D.; Mater, R.; Himelhoch, B.; Borgman, A.; Parker, J.L.; Willekes, C.L.; Timek, T.A. Single-dose del Nido Cardioplegia
in Minimally Invasive Aortic Valve Surgery. Semin. Thorac. Cardiovasc. Surg. 2017, 29, 471–476. https://doi.org/10.1053/j.sem-
tcvs.2017.10.001.
15. Mohamed, M.N.; Shady, M.A.M.I.; Fadala, M.A.E.; Moustafa, M.G.E.D. Custodiol over cold blood cardioplegia in minimal in-
vasive cardiac valve surgery. Egypt. J. Surg. 2023, 42, 554–558. https://doi.org/10.4103/ejs.ejs_110_23.
16. Hummel, B.W.; Buss, R.W.; DiGiorgi, P.L.; Laviano, B.N.; Yaeger, N.A.; Lucas, M.L.; Comas, G.M. Myocardial Protection and
Financial Considerations of Custodiol Cardioplegia in Minimally Invasive and Open Valve Surgery. Innovations 2016, 11, 420–
424.
17. De Palo, M.; Guida, P.; Mastro, F.; Nanna, D.; Quagliara, T.A.; Rociola, R.; Lionetti, G.; Paparella, D. Myocardial protection
during minimally invasive cardiac surgery through right mini-thoracotomy. Perfusion 2017, 32, 245–252.
https://doi.org/10.1177/0267659116679249.
18. Kammerer, I.; Nagib, R.; Hipp, G.; Premar, M.; Hansen, M.; Franke, U. Myocardial Protection in Minimally Invasive Mitral
Valve Surgery: Comparison of the Cold-Blood Cardioplegia of the Bretschneider Solution and the Warm-Blood Cardioplegia of
the Calafiore Protocol. Arch. Clin. Exp. Surg. ACES 2012, 1, 14. https://doi.org/10.5455/aces.20120220022958.
19. Mork, C.; Koechlin, L.; Schaeffer, T.; Schoemig, L.; Zenklusen, U.; Gahl, B.; Reuthebuch, O.; Eckstein, F.S.; Grapow, M.T.R.
Bretschneider (Custodiol®) and St. Thomas 2 Cardioplegia Solution in Mitral Valve Repair via Anterolateral Right Thoracotomy:
A Propensity-Modelled Comparison. Mediat. Inflamm. 2019, 2019, 5648051. https://doi.org/10.1155/2019/5648051.
20. Barbero, C.; Pocar, M.; Marchetto, G.; Cura Stura, E.; Calia, C.; Dalbesio, B.; Filippini, C.; Salizzoni, S.; Boffini, M.; Rinaldi, M.;
et al. Single-Dose St. Thomas Versus Custodiol® Cardioplegia for Right Mini-thoracotomy Mitral Valve Surgery. J. Cardiovasc.
Transl. Res. 2023, 16, 192–198. https://doi.org/10.1007/s12265-022-10296-z.
21. Luo, H.; Qi, X.; Shi, H.; Zhao, H.; Liu, C.; Chen, H.; Peng, R.; Yu, Z.; Hu, K.; Wang, C.; et al. Single-dose del Nido cardioplegia
used in adult minimally invasive valve surgery. J. Thorac. Dis. 2019, 11, 2373–2382. https://doi.org/10.21037/jtd.2019.05.78.
22. Braathen, B.; Jeppsson, A.; Scherstén, H.; Hagen, O.M.; Vengen, Ø.; Rexius, H.; Lepore, V.; Tønnessen, T. One single dose of
histidine–tryptophan–ketoglutarate solution gives equally good myocardial protection in elective mitral valve surgery as repet-
itive cold blood cardioplegia: A prospective randomized study. J. Thorac. Cardiovasc. Surg. 2011, 141, 995–1001.
https://doi.org/10.1016/j.jtcvs.2010.07.011.
23. Vivacqua, A.; Robinson, J.; Abbas, A.E.; Altshuler, J.M.; Shannon, F.L.; Podolsky, R.H.; Sakwa, M.P. Single-dose cardioplegia
protects myocardium as well as traditional repetitive dosing: A noninferiority randomized study. J. Thorac. Cardiovasc. Surg.
2020, 159, 1857–1863.e1. https://doi.org/10.1016/j.jtcvs.2019.03.125.
24. Talwar, S.; Chatterjee, S.; Sreenivas, V.; Makhija, N.; Kapoor, P.M.; Choudhary, S.K.; Airan, B. Comparison of del Nido and
histidine-tryptophan-ketoglutarate cardioplegia solutions in pediatric patients undergoing open heart surgery: A prospective
randomized clinical trial. J. Thorac. Cardiovasc. Surg. 2019, 157, 1182–1192.e1. https://doi.org/10.1016/j.jtcvs.2018.09.140.
25. Mehrabanian, M.J.; Dehghani Firoozabadi, M.; Ahmadi Tafti, S.H.; Forouzan, N.S.K.; Najafi, A.; Mortazian, M.; Zeraatian,
N.D.S.; Soltaninia, H.; GHiasi, A.; Gorjipour, F.; et al. Clinical Outcomes and Electrolyte Balance Factors in Complex Cardiac
Operations in Adults; Del Nido® Versus Custodiol® Cardioplegia Solutions: A Randomized Controlled Clinical Trial. Iran. Red.
Crescent Med. J. 2018, 20, 1–8. https://doi.org/10.5812/ircmj.64648.
26. Timek, T.A.; Beute, T.; Robinson, J.A.; Zalizadeh, D.; Mater, R.; Parker, J.L.; Lypka, M.; Willekes, C.L. Del Nido cardioplegia in
isolated adult coronary artery bypass surgery. J. Thorac. Cardiovasc. Surg. 2020, 160, 1479–1485.e5.
https://doi.org/10.1016/j.jtcvs.2019.09.027.
27. Nagashima, K.; Inoue, T.; Nakanaga, H.; Matsuyama, S.; Geshi, E.; Tabata, M. Impact of the Cardioplegia Interval on Myocardial
Protection Using the Modified St. Thomas Solution in Minimally Invasive Mitral Valve Surgery: A Double-Center Study. J.
Extracorpor. Technol. 2022, 54, 135–141. https://doi.org/10.1051/ject/202254135.
28. Lenoir, M.; Bouhout, I.; Jelassi, A.; Cartier, R.; Poirier, N.; El-Hamamsy, I.; Demers, P. Del Nido cardioplegia versus blood car-
dioplegia in adult aortic root surgery. J. Thorac. Cardiovasc. Surg. 2021, 162, 514–522.e2. https://doi.org/10.1016/j.jtcvs.2020.01.022.
29. Comentale, G.; Parisi, V.; Fontana, V.; Manzo, R.; Conte, M.; Nunziata, A.; Bevilacqua,G.; Buono, M.; Hamameh, S.; Pilato, E.
The role of Del Nido Cardioplegia in reducing postoperative atrial fibrillation after cardiac surgery in patients with impaired
cardiac function. Heart Lung J. Crit. Care 2023, 60, 108–115. https://doi.org/10.1016/j.hrtlng.2023.03.003.
30. Sanetra, K.; Gerber, W.; Shrestha, R.; Domaradzki, W.; Krzych, Ł.; Zembala, M.; Cisowski, M. The del Nido versus cold blood
cardioplegia in aortic valve replacement: A randomized trial. J. Thorac. Cardiovasc. Surg. 2020, 159, 2275–2283.e1.
https://doi.org/10.1016/j.jtcvs.2019.05.083.
31. Ucak, H.A.; Ucak, D. Single-Dose Del Nido Cardioplegia vs. Blood Cardioplegia in Aortic Valve Replacement Surgery. Braz. J.
Cardiovasc. Surg. 2021, 36, 229–236. https://doi.org/10.21470/1678-9741-2020-0063.
J. Clin. Med. 2024, 13, 6977 17 of 17

32. Cayir, M.C.; Yuksel, A. The Use of del Nido Cardioplegia for Myocardial Protection in Isolated Coronary Artery Bypass Surgery.
Heart Lung Circ. 2020, 29, 301–307. https://doi.org/10.1016/j.hlc.2018.12.006.
33. Chan, J.; Oo, S.; Butt, S.; Benedetto, U.; Caputo, M.; Angelini, G.D.; Vohra, H.A. Network meta-analysis comparing blood cardi-
oplegia, Del Nido cardioplegia and custodiol cardioplegia in minimally invasive cardiac surgery. Perfusion 2023, 38, 464–472.
https://doi.org/10.1177/02676591221075522.
34. Russell, S.; Butt, S.; Vohra, H.A. In search of optimal cardioplegia for minimally invasive valve surgery. Perfusion 2022, 37, 668–
674. https://doi.org/10.1177/02676591211012554.
35. Misra, S.; Srinivasan, A.; Jena, S.S.; Bellapukonda, S. Myocardial Protection in Adult Cardiac Surgery With del Nido versus
Blood Cardioplegia: A Systematic Review and Meta-Analysis. Heart Lung Circ. 2021, 30, 642–655.
https://doi.org/10.1016/j.hlc.2020.10.016.

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual au-
thor(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to
people or property resulting from any ideas, methods, instructions or products referred to in the content.