Assessing the safety of del Nido cardioplegia solution in adult

congenital cases
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G Smigla, R Jaquiss, R Walczak, ...

First Published July 9, 2014 Research Article

https://doi.org/10.1177/0267659114543346

Article information 

Abstract

Purpose:

del Nido cardioplegia solution (CPS) has been successfully used for myocardial
protection in the pediatric population. We propose this solution can be used safely in
adult congenital patients. The proposed benefit of this solution is the avoidance of
the need for repetitive interruption of the operation to administer multiple doses of
standard cardioplegia.

Methods:

As part of a quality improvement initiative, 47 consecutive adult patients (mean age

40.9 years, range 18–71) undergoing congenital heart surgery were given del Nido
CPS. Cardiac function was assessed pre- and post-operatively by echocardiography
(ECHO). Inotrope use, troponin levels and restoration of cardiac rhythm were also
evaluated.

Results:

The average duration of the longest ischemic time was 52.5 minutes ± 15.57
minutes. In patients receiving a single dose (40%, n=19) of CPS, the average
 ischemic time was 49.8 minutes ± 18.8 minutes. No patients demonstrated any
ventricular electrical activity while the aorta was cross-clamped. Post-operative
ECHO showed that 94% (n=44) had no change in ejection fraction from the pre-
operative ECHO. Patients requiring inotropic support at the time of leaving the
operating room (OR) was 43% (n=20). The percentage of patients requiring inotropic
support twenty-four hours post-operatively was 17% (n=8). Spontaneous restoration
of cardiac rhythm (without the need for defibrillation) after cross-clamp removal
occurred in 91% (n=43) of patients. The average troponin T level post-op was 1.86 ±
2.9 µg/L.

Conclusions:

del Nido CPS can be used for myocardial protection during adult congenital cardiac
surgery without any apparent adverse effects. In addition, we were able to change
our re-dosing protocol to 45 minutes with del Nido CPS compared to 20 minutes with
our adult 4:1 blood CPS.

Keywords del Nido, cardioplegia, myocardial protection, adult congenital, ischemic time

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New insights on the use of del Nido cardioplegia in

the adult cardiac surgery
Paolo Nardi, Calogera Pisano, Fabio Bertoldo, Giovanni Ruvolo

Division of Cardiac Surgery, Tor Vergata University Hospital, Rome, Italy

Correspondence to: Paolo Nardi, MD, PhD. Tor Vergata University Hospital, Viale Oxford 81,
00133 Rome, Italy. Email: pa.nardi4@libero.it.
Comment on: Ad N, Holmes SD, Massimiano PS, et al. The use of del Nido cardioplegia in adult cardiac

surgery: A prospective randomized trial. J Thorac Cardiovasc Surg 2018;155:1011-8.

Submitted Jul 27, 2018. Accepted for publication Aug 15, 2018.

doi: 10.21037/jtd.2018.08.81

The use of cardioplegia solution represents the most important strategy to protect myocardial muscle during

cardiac surgery (1). Cold crystalloid cardioplegia associated with mild-to-moderate hypothermia has the

advantage to decrease the oxygen consumption, offers some degree of myocardial protection during period of

low flow or low perfusion pressure.

Blood was then found to be an important vehicle for delivery of potassium in the cardioplegic solution, either

with moderate hypothermia than at physiological temperature. Warm blood cardioplegia has been proposed as

a safe technique for myocardial protection based on the rationale that blood, as opposed to crystalloid solution,

could potentially improve postoperative cardiac outcomes, because it more closely approximates the normal

physiology, i.e., carrying oxygen to the myocardium or ensuring a less hemodilution.

Several studies published in the 80s and 90s have not showed substantial differences between type (crystalloid

versus blood), temperature of solution (cold, tepid, or warm), or via administration (antegrade versus

retrograde) of the cardioplegia, and therefore, it is still debated which type of cardioplegia is better for

myocardial protection during cardiac arrest (2-6). The more recently introduced del Nido cardioplegic solution

(7,8) has the rationale to preserve the intracellular phosphates concentration, the intracellular pH value, and to

reduce the intracellular damage by the calcium ion influx during ischemic arrest, especially during surgical

procedures requiring long time, i.e., for the treatment of congenital heart disease. The del Nido cardioplegia is

delivered with 20% by volume fully oxygenated patient blood, which supports aerobic metabolism for a finite

period of time and provides buffering properties to promote anaerobic glycolysis. Del Nido cardioplegia was

mainly developed for use in the pediatric population to address the inability of immature myocardium to

tolerate high levels of intracellular calcium following cardiac surgery (9,10). The main differences in the del
Nido solution in comparison with other types of cardioplegia are given by the presence of concentration of

mannitol, magnesium sulphate and, in particular, lidocaine. Ad and colleagues performed an interesting

multicentre randomized trial, involving six American cardiovascular and thoracic centers, aimed to evaluate if

the use of del Nido cardioplegia in comparison with blood-based cardioplegia is safe and effective also in adult

cardiac surgery (11).

They included 89 stable patients who underwent isolated coronary artery bypass grafting (CABG) surgery,

isolated single valve surgery, and concomitant CABG and single valve surgery. Forty-eight patients were

randomized to receive del Nido cardioplegia (del Nido group), 41 whole blood cardioplegia (control group).

Primary end-points included myocardial preservation by return to spontaneous rhythm, defibrillation

requirement, need for inotropes use, and troponin release at 4 time points: baseline at anaesthesia induction, 2

hours after cardiopulmonary bypass weaning, 12 and 24 hours after admission in intensive care unit,

respectively. Preoperative and intraoperative characteristics were similar in both groups. Patients enrolled in

the del Nido group received 1 L of the del Nido cardioplegic solution after aortic cross-clamp, with an

additional 500 mL in presence of left ventricular hypertrophy, at a temperature of 6–10 °C; The dose of whole

blood cardioplegia was 1–2 L, with subsequent doses administered every 20 minutes, at a temperature of 8–11

°C.

As compared with control group, the del Nido group had a greater number of patients who retuned in

spontaneous rhythm (97.7% vs. 81.6%), a lower number of defibrillations after coronary reperfusion

(4.7% vs. 13.2%), and fewer patients required inotropic support (65.1% vs. 84.2%), although these differences

did not reach a statistical significance, at a level of P value greater than 0.001. Aortic cross-clamp time was

shorter for del Nido group (70 vs. 83 minutes, P=0.018). Troponin I release was similar in both groups,

although a lower release was observed in the del Nido group at 12 and 24 hours after operation in comparison

with the control group (P=0.040).

On the contrary, as expected, the mean total volume of cardioplegia (1,746±852 vs. 5,077±2,457 mL) and the

number of cardioplegia doses per patient was higher in the control group (P<0.001, for both comparisons). The

incidence of morbidity was low, with no stroke, perioperative myocardial infarction, renal failure, operative

mortality. In light of these results, Ad and coworkers concluded that del Nido cardioplegia appears to be non-

inferior to the conventional strategy of myocardial protection in the setting of adult cardiac surgery, and that it
can be used safely, leading to comparable clinical outcomes. Similar results were observed in two studies

published by Li (12), and by Mishra (13) and coworkers. In the first study, in a meta-analysis comparing del

Nido cardioplegia with conventional cardioplegia in adult cardiac surgery, Li reported cardiopulmonary bypass

and cross-clamp times significantly shorter with the use of the del Nido cardioplegia, but no difference in

myocardial enzyme release, postoperative inotropic support, atrial fibrillation and in-hospital mortality was

found between the two groups (12). In the second study, as compared with St. Thomas’ cardioplegic solution,

the del Nido solution leaded to shorter cardiopulmonary and aortic cross-clamp times, reduced cardioplegia

doses, with a safety clinical profile comparable to St. Thomas’ solution (13).

Over the past decades, the question of which solution, temperature or mode of administration of different types

of cardioplegia provides a better myocardial protection during cardiac surgery has been widely discussed.

Experimental studies have suggested a more favorable outcome with the use of blood cardioplegia in

comparison with cold crystalloid cardioplegia. Several clinical studies with or without randomization have

been performed to assess which cardioplegic solution guarantees a better myocardial protection, but some

studies have reported a favorable outcome of the blood (cold or warm) cardioplegia (2-5,14,15), others have

not been able to demonstrate any difference (16-18). In another study a worse outcome for patients receiving

cold blood cardioplegia has been reported (19). Finally, two studies on the del Nido solution failed to show

significant difference in serum troponin levels (20,21).

This debate perfectly includes the findings observed by Ad and coworkers, showing potential benefit of del

Nido solution that has the advantage in requiring shorter aortic cross-clamp and cardiopulmonary bypass times

in comparison with other types of cardioplegia intermittently administered.

In our institution we performed a retrospective, not randomized, study on the use of warm blood cardioplegia

or cold crystalloid cardioplegia antegrade intermittently administered in one hundred and ninety-one stable

patients undergoing aortic valve replacement with or without CABG. Serum levels of total CK (U/L), CK-MB

(ng/mL), and cardiac troponin I (ng/mL) were lower in the crystalloid cardioplegia group of patients in

comparison with warm blood cardioplegia group, in particular, at the time of the admission in intensive care

unit. The CK-MB/CK ratio >10% (5.9% vs. 7.8% of the patients; P<0.0001), was lower in the cold crystalloid

cardioplegia group. We concluded that a significant decrease of myocardial enzyme release can be observed

with the use of cold crystalloid cardioplegia, but this difference did not translate into clinical outcomes, that
were found similar in both types of cardioplegia. This made us hypothesize that in presence of left ventricular

hypertrophy, i.e., in presence of aortic valve disease, a better myocardial protection can be achieved with the

use of a cold rather than a warm cardioplegia (22).

An important aspect highlighted by Ad and colleagues is the potential benefit of del Nido solution in

preventing ventricular arrhythmias during coronary reperfusion after aortic clamp removal, thanks to the effect

that lidocaine has in better preserving the intracellular pH, in limiting the intracellular entry of calcium ion, and

to promote the release of nitric oxide. In fact, in their study they report a lower incidence of defibrillation after

aortic clamp removal (4.7% vs. 13.2%) compared to the control group (11). In their study, however, this

difference did not translate into a different clinical outcome, also because the study was conducted on patients

with a normal systolic function of the left ventricle. It can be hypothesized that in patients with systolic left

ventricular dysfunction or marked cardiac dilatation, a more rapid recovery of the cardiac rhythm after aortic

de-clamping, may reduce the risk of myocardial damage and therefore, the risk of postoperative low cardiac

output syndrome.

In conclusion, we congratulate the authors on the methodology approached in the study and on the obtained in-

hospital results, and also on the clarity with which the data of the randomized trial in question were presented.

From the data obtained in this study, due to the small sample size, we cannot try any definitive conclusion

about what is the best method of myocardial protection during adult cardiac surgery. The clinical bottom line

of the study is that del Nido cardioplegia can be used safely also in adult cardiac surgery, as well as for the

treatment of congenital heart disease, in the ambit of the different types of cardioplegia that are currently

available.

To test del Nido cardioplegia effectiveness on myocardial protection more broadly, studies that include larger

patient samples and interventions requiring very long aortic clamping times are necessarily warranted.

AcknowledgementsOther Section

None.
FootnoteOther Section

Conflicts of Interest: The authors have no conflicts of interest to declare.

ReferencesOther Section
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protection by cold or warm retrograde cardioplegia? J Heart Valve Dis 1996;5:273-80.
[PubMed]
6. Hendry PJ, Masters RG, Haspect A. Is there a place for cold crystalloid cardioplegia in
the 1990s? Ann Thorac Surg 1994;58:1690-4. [Crossref] [PubMed]
7. del Nido PJ, Wilson GJ, Mickle DAG, et al. The role of cardioplegic solution buffering in
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8. Matte GS, del Nido PJ. History and use of del Nido cardioplegia solution at Boston
Children's Hospital. J Extra Corpor Technol 2012;44:98-103. Erratum in: J Extra Corpor
Technol 2013;45:262. [PubMed]
9. Takeuchi K, Cao-Danh H, Kawai A, et al. Prolonged preservation of the blood-perfused
canine heart with glycolysis-promoting solution. Ann Thorac Surg 1999;68:903-7.
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10. Choi YH, Cowan DB, Wahlers TC, et al. Calcium sensitisation impairs diastolic
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cardiac surgery: A prospective randomized trial. J Thorac Cardiovasc Surg
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 Del Nido cardioplegia: A one stop shot for adult cardiac
surgery?
Derrick Y. Tam, MD

, 

Stephen E. Fremes, MD, MSc∗, Correspondence information about the author MD,

MSc Stephen E. Fremes Email the author MD, MSc Stephen E. Fremes

Division of Cardiac Surgery, Schulich Heart Centre, Department of Surgery, Sunnybrook Health
Sciences Centre, University of Toronto, Toronto, Ontario, Canada

PlumX Metrics

DOI: https://doi.org/10.1016/j.jtcvs.2017.10.066

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Stephen E. Fremes, MD, MSc (left), and Derrick Y. Tam, MD (right)

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Central Message
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See Article page 1011.

Although it was initially developed for congenital heart surgery, del Nido cardioplegia (DN) has recently

gained widespread attention in adult cardiac surgery.1 Its purported benefit in pediatric surgery include

its long duration of action with a single dose and its potential for improved myocardial protection

through reduced energy consumption and scavenging of inflammatory substrates. These potential

benefits have led DN to be evaluated further in adult cardiac surgery. Multiple studies have examined

DN in various settings in adult cardiac surgical populations, from complex valve surgery to coronary

artery bypass grafting for acute coronary syndrome.2, 3, 4, 5, 6, 7 All these studies, however, have been

observational and retrospective in nature.

In this issue of the Journal, Ad and colleagues8 present their findings from a randomized clinical trial

examining the efficacy and safety of DN versus whole blood cardioplegia in patients undergoing

nonemergency isolated coronary artery bypass grafting (CABG), isolated valve surgery, and combined

valve and CABG surgery. Patients were block randomized such that both baseline characteristics and

procedural type were well balanced between the arms. In this study, the primary outcome was

myocardial preservation, as assessed through 4 means: return to spontaneous rhythm, defibrillation

requirement, inotropic support, and serial troponin values. Important secondary outcomes included

mortality and morbidity, as defined by the Society of Thoracic Surgeons National Database.

Although it was initially designed as a noninferiority trial with a planned analysis of 250 patients per

group, the study was stopped very early after an interim analysis showed superiority in one of the

primary outcomes in the DN group. The trial enrolled a total of 89 patients between the arms. Given

that an interim analysis took place and that there were four primary outcomes, a new P value for

superiority was calculated (P < .001). As none of the 4 primary outcome variables approached the new

statistical threshold, we can only conclude from this trial that DN is noninferior and not superior to

blood cardioplegia. Interestingly, there was no difference in cardiopulmonary bypass time (97 vs

103 minutes; P = .288), although aortic crossclamp time was reduced (70 vs 83 minutes; P = .018)

with DN relative to whole blood cardioplegia. These findings are relevant, because both

cardiopulmonary bypass time and aortic crossclamp time have shown to be independent risk factors

for postoperative death.9, 10

Nonetheless, findings from this study must be interpreted in the context of some limitations. The

surgical team was unblinded, and there was no standardization for the use of inotropic support; this

represents a potential source of bias. Furthermore, the clinical significance of the surrogate outcomes

used in this study, such as the return of spontaneous rhythm or the need for defibrillation, remains

unclear. Troponin values continued to rise in the control group, such that a peak could not be

demonstrated. That said, the prognostic significance of small rises in postoperative troponin levels
after cardiac surgery in the absence of electrocardiographic and echocardiographic findings is

uncertain and controversial.11 The study findings are only generalizable to patients in stable condition

who required either isolated CABG, isolated single valve, or single valve and CABG. The investigators

specifically excluded high-risk patients, including those requiring preoperative inotropic support and

preoperative mechanical circulatory support. Most of the cases were elective; the safety of single-shot

cardioplegia for CABG after acute coronary syndrome could be affected by the compromised coronary

circulation. In a propensity matched study of 40 patient pairs undergoing high-risk CABG after an acute

myocardial infarction, no differences in early mortality, inotropy requirement, or intra-aortic balloon

pump requirement were noted.6 Furthermore, the results reported by Ad and colleagues 8 were derived

from a single center of excellence, with an institution-specific protocol used for the delivery and

composition of both conventional and DN cardioplegia that may be different from that in other centers.

The most important point to stress is that this trial was initially designed to assess noninferiority

between DN and whole blood cardioplegia but was stopped early because of the benefits seen in the

DN group. The decision to end clinical trials prematurely is difficult and remains

controversial.12, 13, 14 Patient protection is paramount in trials, and studies are stopped prematurely, in

general, for excess harm rather than benefit. Still, a meta-analysis and metaregression of early

truncated clinical trials suggest that these trials often overestimate the true effect size relative to

nontruncated studies.15 In this case, Ad and colleagues 8 justified the early termination of this trial,

because one of their primary outcomes, spontaneous return of rhythm, was found to be not only

noninferior but superior at the interim analysis. Other important outcomes, however, such as inotropic

requirements, cardiopulmonary bypass time, crossclamp time, and the composite of Society of

Thoracic Surgeons–defined complications trended lower in the DN group but were not statistically

significantly different at the revised α threshold for superiority. The continuation of the trial to a higher
recruitment level might have provided the power necessary to detect important differences on

clinically relevant outcomes. Also, a larger sample size might have allowed for some subgroup

analyses. Overall, this article reaffirms and highlights the challenge in designing and completing

adequately powered studies in cardiac surgery for clinically relevant outcomes that reflect myocardial

protection. Recent large clinical trials in cardiac surgery that examined the rate of perioperative

myocardial infarction or low cardiac output syndrome have enrolled totals of 800 to 4000

patients.16, 17, 18

Again, Ad and colleagues8 are to be commended for conducting a relevant study and shedding light on

this important topic critical to performing safe cardiac surgery. DN may be particularly advantageous

in mitral valve operations because the valvular correction does not need to be interrupted by frequent

readministration of cardioplegia, thereby improving surgical workflow. Although multiple strategies of

 protection are sufficient for most cardiac operations, there remains an unmet need for a simple

approach that can reliably preserve the myocardium for very lengthy, complex procedures. The

findings from this randomized, controlled trial8 confirm those of a recently published meta-analysis of

observational studies; the aortic cross-clamp time was lower with DN, and there were no differences in

mortality, cardiac enzyme release, or the need for inotropic support. 19 Nonetheless, there remains a

need for further investigation in the form of a much larger multicenter clinical trial to prove the

generalizability of these results. Although DN may not be the one-stop shot for all adult cardiac

surgery, it has certainty proved its benefit for coronary artery bypass grafting and single-valve surgery

in this small randomized, controlled trial.

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Del Nido cardioplegia: from an infant conceive to an adult life - a
brief review of the current evidence in adult patients
Claudio Pragliola1,2 , Essam Hassan1,3 , Abdulaziz Al Hossan1 , Khaled Al Otaibi1 , Juan J. T. Alfonso1 , Afnan Al
Khalaf1 , Khalid D. Al Garni1,4 
1
Prince Sultan Military Cardiac Centre, Riyadh 11564, Saudi Arabia.
2
Dipartimento Scienze Cardiovascolari, Università Cattolica, Roma 00198, Italy.
3
Department of Cardiac Surgery, Tanta University, Tanta 31527, Egypt.
4
Department of Cardiac Sciences, King Saud University, Riyadh 12372, Saudi Arabia.
Correspondence Address: Dr. Claudio Pragliola, Consultant Cardiac Surgeon, Prince Sultan Military Cardiac
Centre, Building 6 Makka Makkarrama Road 12323 Al Sulimanyah, Riyadh 11564, Saudi Arabia. E-mail:
mailto:claudio.pragliola@libero.it ; mailto:cpragliola@pscc.med.sa 
Received: 24 Mar 2019 | First Decision: 18 Apr 2019 | Revised: 26 Apr 2019 | Accepted: 24 May 2019
| Published: 18 Jun 2019

Science Editor: Mario F. L. Gaudino | Copy Editor: Cai-Hong Wang | Production Editor: Jing Yu

© The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing,
adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as
long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative
Commons license, and indicate if changes were made.
Abstract
The increasing number of minimally invasive procedures prompted the quest for a simple and effective single
shot cardioplegia to allow the surgeons to focus on their workflow. The originally pediatric Del Nido solution
was successfully tested in several centers and gradually extended to regular coronary and valvular cases. In the
present review we report the current evidence on the use of the Del Nido solution in adult patients.

Keywords
Del Nido cardioplegia, adult cardioplegia, myocardial protection, blood cardioplegia, single shot cardioplegia

Introduction
Adult cardiac surgery has changed in the last decade. In the 2018 the STS[1] database reports that about 75%
of the patients submitted to myocardial revascularization had 3 or more grafts with an increasing number of
non-elective procedures, diabetic and heart failure patients. At the same time 23% of the all the isolated
mitral procedures performed in 2016 were minimally invasive and the isolated aortic valve procedures, the
second most common cardiac operation, undergoing key-hole surgery have a steady increase. Clearly we are
facing more complex procedures and worse clinical characteristics of our patients. This can imply longer cross
clamp times which is a well-known risk factor in cardiac surgery. On the other hand the available cardioplegic
solutions to protect the heart need to be repeated every 10 to 20 min or continuously infused in a retrograde
fashion through the coronary sinus. Although the results with the current cardioplegias are consistently good,
some surgeons, in particular those who have focused in minimally invasive procedures, are searching for a
“solution” which could combine effective and consistent long lasting myocardial protection with easy of
deliver.

In the last few years, when its original the patent expired, the paediatric del Nido cardioplegia (DNC) has
been increasingly used in adult patients[2]. This cardioplegia allows for an interval between infusions up to 90
min and has some unique features that appear to be promising to the adult cardiac surgeons.

The DNC is a 1:4 blood cardioplegia which can be classified as a modified depolarizing cardioplegia,
containing Lidocaine and Magnesium. Clinically it has been validated in valve surgery[3] and at the moment, in
low risk coronary patients[4]. We hereby are summarizing the basic concepts behind its formulation and use,
along with the available evidence in the adult patients.

Development of DNC
For long time paediatric cardiac surgeons had to rely on the common adult cardioplegic solutions to operate
on their patients. However, the crystalloid solutions in use in the 80’s and early 90’s had controversial results
in young populations with, for instance, the St Thomas solution being reported either effective [5] or
ineffective[6]. Although infant and paediatric hearts have some distinctive histologic and metabolic features, a
“dedicated” cardioplegia was missing. Histologically the paediatric heart has a poorly developed
sarcoplasmatic reticulum[7], fewer mitochondria, a higher concentration of poly unsaturated fatty acids[8] in the
cell membrane and a deficient free radical scavenge system with less active superoxide dismutase, catalase
and glutathione reductase[9]. In addition these hearts depends more on the extracellular calcium for
contraction. At Pittsburgh University Hospital the team led by Pedro J. del Nido focused on many of these
aspects and developed a solution preventing the intracellular accumulation of Calcium, providing effective
free radicals scavenge whit maintenance of the anaerobic glycolysis and assuring effective buffering during
prolonged periods of cardiac arrest. A detailed description of the development of the cardioplegia is available
in the literature[10].

Components
The DNC is a 1:4 Blood to Crystalloid solution with additional components to achieve depolarized arrest and
mitigate the effects of temporary myocardial ischemia [Table 1].
Table 1

Composition of the del Nido cardioplegia

Del Nido formulation Plasma-Lyte a solution 1000 mL

Plasma Lyte A Solution 1 L              Sodium 140 mEq

Mannitol 20 % (16.3 mL)              Potassium 5 mEq

Magnesium Sulfate 50% (4 mL)              Magnesium 3 mEq

Sodium Bicarbonate 8.4% (13 mL)              Cloride 98 mEq

Potassium Cloride 2 mEq/L (13              Gluconate 23 mEq

mL)

Lidocaine 1% (13 mL)              Acetate 27 mEq

Blood : Crystalloid 1:4

Plasmalyte a solution
The Plasma Lyte A (Baxter Health Care Corp. Deerfield, IL USA) solution forms the crystalloid base of the DNC.
It is an extracellular (Na+ 140 mEq, K+ 5 mEq/L) solution with a final pH of 7.4 and an osmolarity of 294
mOsm/L. It is commonly used as a fluid volume replacement infusion in many clinical conditions. Noticeably it
does not contain glucose.

Potassium
Similarly to other common depolarizing solutions, the final content of K+ ions in the DNC is about 24 mEq/L
which is obtained from the basal content of Plasma-Lyte (5 mEq) plus the added 26 mEq and an assumed 4.5
mEq/L from the patient’s blood.

As known Potassium increases the resting potential of myocytes to about -46 mV, well above the
depolarization threshold of – 65 mV. In doing so it leaves the cells in a state of arrest. Hence, indirectly
potassium blocks the inward current of Na+ during the phase 0 of the myocardial action potential

Lidocaine
Lidocaine is a class I antiarrhythmic drug that directly blocks the Na+ channels in phase 0. Its half-life is
relatively long and is obviously increased by the absence of coronary circulation. It also blocks the so called
“window” channels which remain open during the depolarized arrest and allow some Na+ and Ca2+ inward
current in the cell. Lidocaine therefore allows for prolonged periods of cardiac arrest and participates in the
control of intracellular accumulation of calcium during the ischemic period.

Magnesium
Magnesium is a natural Calcium channels blocker. Contrary to the skeletal muscle, the cardiac myocyte is
largely dependent from extracellular calcium for its contraction. Calcium ions enter the cardiac myocyte
during phase 2 plateau of the action potential through L-Type channels which are blocked by Magnesium
ions. In doing so Magnesium prevents the contraction of the myocytes and accumulation of Calcium in the
cell. Interestingly both paediatric and “aged” cardiomyocytes have an altered homeostasis of Calcium which
can be modulated by Magnesium

Mannitol
Mannitol is a common additive to cardioplegia solutions. Its usage prevents cellular oedema and scavenges
free radicals. The cell membrane of immature myocardium has high concentration of poly unsaturated fatty
acids providing more sites for oxidative damage, on the other hand oxidative stress is believed to be potent
promoter of myocardial aging.

1:4 Blood ratio

The addition of blood to crystalloid cardioplegia is far beyond the simple concept of substrates and oxygen
deliver to the arrested heart. As the haemoglobin dissociation curves are altered during hypothermia, the
oxygen deliver is minimal and dependent from the gas dissolved in the solution. However, blood proteins and
the other components have several potential benefits which include buffering from proteins and carbonic
anhydrase contained in red cells, free radicals scavenge and more favourable rheological properties. In
addition, as a result of the lower haematocrit compared to the classic solution with a 4:1 ratio, the DNC has a
very low Calcium content which enhances the effects of Lidocaine and Magnesium.

Deliver and technical aspects

With the widespread use of blood cardioplegias the perfusionist can easily arrange a circuit to deliver the
DNC basic crystalloids components in a 4:1 ration with the patient’s derived oxygenated blood (> 150 mmH
pO2). Sample circuits drawings are available in the literature from the original Boston Children Hospital and
the Cleaveland Clinic[11]. Table 1 depicts the current setting in use in our Centre. The DNC is usually delivered
in the aortic root at a dose of 20 mL/kg with a maximum dose of 1000 mL. Rate of infusion is usually between
150 mL/min to 300 mL/min for a pressure of 100 mmHg in 2 to 4 minutes. The cardioplegia’s circuits include
a heat exchanger to deliver the solution at 4 °C for a final myocardial temperature of less of 15 °C. As known
the myocardium Oxygen consumption decreases of 50% for any 10 °C reduction of temperature, at 10 °C the
oxygen requirements should be in the 15% to 20% range of the baseline. Hence ice slush for local
temperature control is added by the surgeon in the pericardium at the aortic cross clamp time. However,
continuous myocardial temperature is not routinely used.

Table 2

Literature summary

Significant results
Reference Population (n) Study design No differences
in DNC group

Yerebakan e Acute MI CABG Retrospective ↓ CPB Enzyme relese EF%

t al.[24] DNC = 48 ↓ X- Clamp Postperative support
 Significant results
Reference Population (n) Study design No differences
in DNC group

WCBC = 40 Mortality

Sorabella et Reoperative AVR DNC vs. blood ↓Cardioplegia CPB, X-clamp time

al.[18] DNC = 52 Blood = Retrospective volume Complication rate
61

Mick et al.[3] Isolated Valve Retrospective 1:1 Aortic Ensyme Release EF%
Aortic = 85/85 Propensity score ↓ CPB, ↓ XC Clinical results
Mitral = 110/110 Matched lamp, ↓Glucose
↓ Insuline
Mitral
↓ Insuline ↓
Glucose

Ota et al.[17] AVR (240) DNC vs. blood ↓CPB, ↓ X-clamp Inotropic support

DNC = 178 Retrospective ↓Use of
Blood = 62 Propensity matched retrograde
54 pairs

Mishra et al. CABG or double DNC vs. blood ↓CPB, ↓ X-clamp Complication rates

[31]
valve Retrospective ↓Redosing
DNC = 50 ↓Ejection fraction
Blood = 50

Timek et al. CABG DNC vs. CB ↓ Glucose Cross Clamp Inotropes

[23]
DNC = 82 Rterospective Enzyme Release EF%
CB = 82 Propensity score
matched pairs

Guajardo et CABG (408) DNC vs. blood ↓ Need CPB, X-clamp time

al.[4] DNC = 159 Retrospective defibrillation Length of stay Mortality
Blood = 249 ↓Transfusion (P <
0.08)

Vistarini et Min. invasive AVR DNC vs. blood ↓ Need Complication rate

al.[27] DNC = 25 Retrospective defibrillation Mortality
Blood = 21 ↓CK-MB ↓Insulin
use

Kim et al.[21] Valve DNC vs. blood ↓CPB, X-clamp Inotropic support

DNC = 149 Retrospective ↓Troponin Mortality Complication
Blood = 892 Propensity matched ↓Transfusion rates
111 pairs

Hamad et AVR/CABG DNC vs. blood ↓CK-MB, Inotropic support

 Significant results
Reference Population (n) Study design No differences
in DNC group

al.[28] DNC = 25 Retrospective troponin T Operative time Length

Blood = 25 ↓CPB, X-clamp of stay Complication
rates

Ziazadeh et Min invasive AVR DNC vs. blood **↓CPB, X-clamp Troponin T Ejection

al.[29] DNC = 77 Retrospective ↓Glucose levels fraction Complication
Blood = 101 Propensity matched rates
63 pairs

Koeckert et Min. invasive AVR DNC vs. blood ↓Redosing CPB, X-clamp time

al.[30] DNC = 59 Retrospective ↓Cardioplegia Inotropic support
Blood = 122 Propensity matched volume Transfusion Length of
59 pairs ↓Use of stay Complication rates
retrograde

Ad et al.[26] CABG ± valve Randomized, ↓ A.Fib Postop (*) CPB, X-clamp time
DNC = 48 controlled ↓ Troponine (*) Complication rates
Blood = 41 Inotropic support Need
defibrillation

UCAK et al. CABG elective DNC vs. IWBC ↓ CPB ↓ X-clamp Enzyme release Clinical
[25]
DNC = 112 Randomized ↓ Glucose events
IWBC =185 Controlled

O’Donnel et CABG DNC vs. BC ↓ CPB ↓ X-clamp No difference in clinical

al.[20] DNC=54 Retrospective ↓ Defibrillations outcomes
BC = 27

Pragliola et All kinds of adult DNC vs. IWBC ↓Ejection fraction No differences overall

al.[33] surgery including Retrospective in low EF
emergencies Propensity score subgroup
DNC =102 matched pairs
IWBC = 102

AVR: aortic valve replacement; CABG: coronary artery bypass graft; CPB: cardiopulmonary bypass time; DNC: del Nido
cardioplegia; X-clamp: cross-clamp time; IWBC Intermittent warm blood cardioplegia CC Cold Cardioplegia BC Blood
Cardioplegia. *(see text for details) Note that alpha value for statistical significance was P < 0.001, thus nonsignificant trends
exist.
The cardioplegia can also be infused directly into the coronary arteries in case of severe Aortic regurgitation,
as can be infused retrogradely at the some doses used in the aortic root although this is not common practice

advise not to use

according to the literature. Unlikely other blood cardioplegias, we strongly

a continuous infusion. This can result either in an excess

of volume or Lidocaine and magnesium. Najjar et al.  in a series of 14 [12]
patients undergoing re-operative surgery and continuous infusion reported a mean total volume of 4367 mL
± 751 mL for an aortic cross clamp time of 81 min ± 35 min. With retrograde continuous infusion in patients
submitted to aortic valve reimplantation, Jiang et al.[13] reported a 26% incidence of postoperative heart
block resulting in 6.7% incidence of permanent heart block. Due to the limited number of patients and the
inherent surgery they were submitted to, it is not possible to reach a definite conclusion, but caution is
advised.

Experimental studies
The conflicting evidences on the premature myocardium metabolism which were evident at the time the DNC
was developed at Boston Children Hospital have been stressed by Matte in his report. In brief the Del Nido
was conceived as a hyperpolarizing (K+), extracellular (Na+) glucose free (Plasmalyte), hyperosmolar
(Mannitol), buffered (Bicarbonate, blood proteins) solution controlling the calcium influx into the cells
(Magnesium and Lidocaine). The presence of lidocaine in an unperfused coronary bed (slowly wiped off by
the collateral coronary flow) allows for long intervals between the infusion of the solution. This is as
important as the maintenance of a low myocardial temperature and the use of the cold cardioplegic solution
when manually testing the anastomosis during CABG surgery. These details are collateral, but not less
important parts of the technique in adults[14].

However, there are at least two experimental studies supporting the use of the DNC in aged hearts. During
cardioplegic arrest induced by DNC in an isolated cells model from senescent rats, the intracellular Calcium
content was lower and the cells were not reactive to electric filed stimulation as well as they did not develop
hypercontraction at reperfusion contrary to the same model treated with conventional cardioplegias. The
Authors concluded that according to these results, the DNC had the potential to better protect senescent
hearts preventing electromechanical activity during the arrest and hypercontraction at the time of
reperfusion[15]. Similarly, in an isolated working model of senescent hearts, the treatment group that
underwent 60 min of cardiac arrest induced by DNC had better contractility and lower enzyme release
compared to the group treated with conventional cardioplegia[16].

Experiences in adult patients

Interestingly, although it is now clear that major cardiothoracic units are regularly using the DNC solution,
available studies deal only with limited subpopulations.

Matte et al.[10], describing the development of the DNC reports the regular use in Adult Congenital cases at
Boston Children Hospital. Ota et al.[17] and Sorabella et al.[18] published their experiences with first time and
re-operative Aortic Valve surgery, all with safe and comparable results. Mongero[19] state that the DN
cardioplegia is the only solution in use in their Centre, the Columbia University Presbiterian Hospital NY, since
2011 and call for a broader use of it in adults. O’Donnell et al.[20] reports that the DNC is the cardioplegia of
choice in CABG since 2015.

In many institutions, including ours, the del Nido was initially used in minimally invasive Mitral cases and then
gradually extended to cover all procedures. This path, though not openly stated, was probably started at the
Columbia University and followed in Cleaveland[21] where the Del Nido was propensity matched with good
results to the Buckberg solution in minimally invasive or robotic valvular cases and showed better glucose
control, reduced cross-clamp and operative times.

As the field of minimally invasive and robotic surgery is rapidly expanding, teams dealing with these
techniques are looking for a simple and effective cardioplegia. Amongst the available alternative solutions,
the Buckeberg[19] entails a staged deliver in different phases and shorter intervals of ischemia (15 m to 20 m)
which can slow down the surgical workflow. Besides, the retrograde infusion in minimally invasive surgery is
a sophisticated and sometime difficult technique to control in a limited surgical field. The
Custodiol®[22] solution for long time has been the only single shot cardioplegia. Initially introduced for the
donor hearts that usually are exposed to long ischemic times during organ procurements, it achieves a long-
lasting myocardial protection. However, this solution requires the infusion of a large volume of hyponatremic
crystalloid which is usually drained during the donor heart harvest but can be problematic in patients
operated with a minimally invasive approach. Although ultrafiltration can help solve this problem, the volume
overload and the hyponatremia can complicate the postoperative period.

There are also several studies testing the DNC in coronary revascularization. Timek et al.[23] reported on a
group of CABG patients receiving the DNC, propensity score matched to a population operated with usual
Cold Blood Cardioplegia infused at 15-20 min intervals. Not surprisingly the DNC resulted in a lower volume
infused and a lower peak glucose level during cardiopulmonary bypass compared to the matched population.
No clinical differences were noted in the outcomes.

The DNC has also been tested in high risk coronary cases with Acute Myocardial infarction by Yerebakan et
al.[24] in 2014 with excellent clinical results. Two recently published Randomized Controlled Trials (RCT)
compared the use of the DNC to the intermittent whole blood cardioplegia in CABG or CABG plus valve
surgery. Ucak et al.[25] could observe shorter aortic cross-clamp and CPBP times and better glucose control in
the DNC group, without meaningful clinical differences in a population with an average Euroscore of 4.1.
Similarly, Ad et al.[26] conducted the single registered RCT (NCT02442050) for the DNC in adults. The
randomized patients had an average STS score of 1.3. Initially designed as a non-inferiority study to include
500 patients, it was prematurely interrupted because the DNC patients had a better rhythm recovery after
surgery. The study was then turned into a superiority study with a required level of evidence of P < 0.001.
With these new parameters there were no clinical differences in the outcome although the peak T troponin
level was lesser in the DNC group at P < 0.04 without sufficient power to achieve statistical differences. Table
1 summarizes the available studies. Many of them where also included in an extensive metanalysis which
favoured the del Nido in reducing the volume of cardioplegia infused, shortening the cardio-pulmonary
bypass and cross clamp times and hade comparable results in terms of troponine and CKmb release. All the
studies had comparable clinical results[27,32].

In the available literature, the common criticisms to the use of the DNC in adults are two: the limited number
of patients included in the studies, usually with a single pathology and the low risk of these groups of
patients.
In his elegant statistical study, Kim et al.[21] matched two similar groups of 104 patients treated with the DNC
or Blood Cardioplegia out of 1041 consecutive patients. Again the DNC showed an advantage in the
postoperative peak troponin release and shorter cross-clamp times. Noticeably all kind of procedures were
done in these groups, including multiple complex valves and aortic arch surgery. However, the logistic
Euroscore II for the DNC group was 2.9 ± 3.3.

Comments and conclusion

Understandably Lazar[14] put forward a few questions about the use of the DNC in high-risk cases with low EF
%, high Euroscore or high Pulmonary Artery Pressures; adult patients in whom the solution has not been
extensively tested.

We do not have a definite answer to these questions. In our Centre the DNC quickly took over the IWBC to be
the standard solution in use[33]. Over the last 1000 consecutive cases in 2017-2018 we could propensity score
match 102 pairs including two groups with a high Euroscore II (mean ESII 10) and one with low EF (EF 30%) in
whom the DNC provided sufficient protection without major differences with the IWBC and allowed the
surgeon to focus on the his surgical workflow (data in press). There are not clear guidelines on cardioplegic
solutions and the debate whether it should be warm or cold, blood or asanguineous, antegrade or
retrograde, intermittent, single shot or continuous flooded the surgical literature. Clearly the perfect
myocardial protection is the result of a complex interaction of the surgical team with the procedure
performed, the patient characteristics, the cardioplegic solution and the technique of delivery. This is coming
from practice, consistence and excellence as certainly occurred in all the centres where the DNC was adopted
routinely in adult cases.

A large randomized superiority trial enrolling only high risk cases will be difficult to complete and poses
several potential problems : some ethical and some very practical. To date, as a result, there are not similar
trials registered in the Clinical Trials website.

In conclusion, there is sufficient evidence to engage with the single shot DNC in all the routine cases either
valvular or coronary, especially in minimally invasive procedures. Whether this will expand into the moderate
and high risk cases will depend from the surgical team preferences.

Declarations
Authors’ contributions

Made substantial contributions to conception and design of the study: Pragliola C, Hassan E
Performed data analysis and interpretation: Pragliola C, Hassan E, Al Gharni KD
Performed data acquisition, as well as provided administrative, technical, and material support: Alfonso JJT,
Al Hossan A, Al Otaibi K, Al Khalaf A.
Availability of data and materials

Not applicable.
Financial support and sponsorship
 None
Conflicts of interest

All authors declare that there are no conflicts of interest.

Ethical approval and consent to participate

Not applicable.
Consent for publication

Not applicable.
Copyright

© The Authors 2019.

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Myocardial protection following del Nido cardioplegia in pediatric

cardiac surgery
Show all authors
Debasish Panigrahi, Saibal Roychowdhury, Rahul Guhabiswas, ...

First Published April 18, 2018 Research Article

https://doi.org/10.1177/0218492318773589

Article information 

Abstract

Background
 This study was designed to compare myocardial protection with del Nido cardioplegia
and conventional blood cardioplegia in children undergoing cardiac surgery in Risk
Adjustment for Congenital Heart Surgery categories 1 and 2.

Methods

Sixty patients were randomized into 2 groups receiving del Nido cardioplegia solution
or conventional blood cardioplegia. Myocardial injury was assessed using
biochemical markers (troponin I and creatine kinase-MB). Vasoactive-inotropic
scores were calculated to compare inotropic requirements.

Results

Demographic characteristics, cardiopulmonary bypass time, and aortic crossclamp

time were comparable in the 2 groups. Time-related changes in troponin I and
creatine kinase-MB were similar in both groups. Statistically significant differences
were seen in total cardioplegia volume requirement (p < 0.0001), number of
cardioplegia doses given (p < 0.0001), packed red cell volume usage during
cardiopulmonary bypass (p < 0.02), and time taken to restore spontaneous regular
rhythm (p < 0.0001). Vasoactive-inotropic scores on transfer to the intensive care unit
(p < 0.040) and at 24 h (p < 0.030) were significantly lower in the del Nido group.
Duration of mechanical ventilation, intensive care unit stay, and hospital stay were
comparable in the 2 groups.

Conclusions

Our results show that del Nido cardioplegia solution is as safe as conventional blood
cardioplegia. Moreover, it provides the benefits of reduced dose requirement, lower
consumption of allogenic blood on cardiopulmonary bypass, quicker resumption of
spontaneous regular cardiac rhythm, and less inotropic support requirement on
transfer to the intensive care unit and at 24 h, compared to conventional blood
cardioplegia.

Keywords Cardioplegic solutions, Cardiopulmonary bypass, Child, preschool, Heart

arrest, induced, Heart defects, congenital, Postoperative complications
Introduction

Cardioplegia is an essential method of myocardial protection for patients of all ages

requiring cardiac surgery in which the heart must be stopped. 1 The immature
myocardium of infants and children is different to that of adults in a number of
ways.2 Therefore, a cardioplegia solution that more specifically addresses the needs
of the immature heart has been the subject of constant research. Promotion of
anaerobic glycolysis, scavenging of oxygen-free radicals, and prevention of
intracellular calcium accumulation are probably the keys to myocardial protection
during the period of arrest.3–5 del Nido cardioplegia solution is a unique formulation of
4 parts crystalloid to one part whole blood, which is generally used in a single-dose
fashion.6 Because of its unique properties, aortic crossclamping for up to 3 h has
been achieved safely without any ventricular electrical activity. 6 In contrast,
conventional blood cardioplegia has to be repeated at approximately 20-min
intervals, causing temporary interruption of the surgical procedure. Additional del
Nido cardioplegia may be given for hypertrophied hearts or those with aortic
insufficiency, based on the effectiveness of the initial dose. Subsequent doses are
not normally given except in the rare occurrence of ventricular activity during aortic
crossclamping or for exceptionally long crossclamp times (>3 h), at the surgeon’s
discretion. Studies published so far support the fact that this solution provides good
myocardial preservation in addition to reduction of the surgical time involved in
repeating cardioplegia doses.7 There are not many prospective randomized trials
available in which the safety and efficacy of del Nido cardioplegia has been
compared to the conventional blood cardioplegia used in pediatric congenital heart
surgery. In this study, we aimed to compare the safety and efficacy of del Nido
cardioplegia and conventional blood cardioplegia in low-risk pediatric patients
undergoing congenital cardiac surgery. The Risk Adjustment for Congenital Heart
Surgery (RACHS) score compares the data of surgical outcome for pediatric patients
undergoing cardiac surgery, and categories 1 and 2 are considered low risk. 8

Patients and methods

This study was a single-blind, parallel, single-center, randomized control trial

involving 60 patients undergoing corrective cardiac surgery. Children undergoing
corrective surgery were screened for eligibility. RACHS scores were calculated and
those in RACHS category 1 and 2 were identified. The RACHS score stratifies the
anatomic diversity into 6 categories based on age, type of surgery performed, and
the hospital mortality rate. This score is easily applicable and provides a linear
correlation between categories and mortality rates. 8 The parents of the 60 patients
were approached to participate in the study, and written informed consent was
obtained. The patients were randomized into 2 groups-Group A ( del Nido
cardioplegia group) and Group B (conventional cardioplegia group). Randomization
was performed using a sealed envelope strategy. One group received del Nido
cardioplegia and the other (control) group received conventional blood cardioplegia.
We excluded patients with complex anatomy belonging to a higher RACHS category.
We also decided at the outset to exclude any patient who required going back on
cardiopulmonary bypass (CPB) for any residual lesion detected after the initial repair.

Table 1. Demographics and operative variables in 60 pediatric

patients undergoing cardiac surgery with del Nido or
conventional cardioplegia.

Table 1. Demographics and operative variables in 60 pediatric patients undergoing

cardiac surgery with del Nido or conventional cardioplegia.

View larger version

General anesthesia was induced with midazolam, fentanyl and sevoflurane.

Pancuronium was used as the muscle relaxant. Anesthesia was maintained with
isoflurane and intermittent doses of fentanyl. All patients were operated through a
median sternotomy. CPB was established with aortocaval cannulation after adequate
heparinization (activated clotting time >400 s). Surgical correction was carried out
with appropriate hypothermic CPB support, using either of the cardioplegia solutions.
After achieving adequate rewarming, CPB was terminated, and various parameters
during the intraoperative and postoperative periods were recorded and analyzed.
The crystalloid composition of del Nido cardioplegia was 1000 mL of Plasmalyte A
base solution to which the following were added: 20% mannitol (16.3 mL), 50%
magnesium sulfate (4 mL), 8.4% sodium bicarbonate (13 mL), potassium chloride (2
meq·L−1), and 6.5 mL of 2% lidocaine. del Nido solution (800 mL) was mixed with 200 
mL of oxygenated blood (4:1 ratio) to produce a final electrolyte concentration of
sodium 150 mmol·L−1, chloride 132 mmol·L−1, potassium 24 mmol·L−1, magnesium 6 
mmol·L−1, calcium 0.4 mmol·L−1, lidocaine 140 mg·L−1, mannitol 2.6 g·L−1, and sodium
bicarbonate. Conventional blood cardioplegia was prepared using a mixture of
crystalloid cardioplegia and blood in a ratio of 1:4. The composition of the crystalloid
component was: Ringer’s lactate solution (160 mL), 20% mannitol (10 mL), sodium
bicarbonate (10 mL), and 20 mL of Plegiocard solution containing 16 mmol of
potassium chloride. A crystalloid volume of 200 mL was mixed with 800 mL of
oxygenated blood.

The cardioplegia delivery system consisted of a disposable tubing set, cardioplegia

bag, cardioplegia reservoir, pump loop, and cooling coil along with a temperature and
pressure monitoring site. Cardioplegia delivery was predominantly antegrade through
an aortic root needle. Cardioplegia was given in a dose of 20 mL·kg −1 for adults and
30 mL·kg−1 for children at a temperature between 8℃ and 12℃. Our strategy was to
repeat the dose beyond an ischemic time of 90 min for del Nido cardioplegia and
after 20 min for conventional blood cardioplegia.

Data were recorded for crossclamp and cardiopulmonary bypass times, volume and
dosage of cardioplegia administered, blood transfusion, time to regain spontaneous
regular rhythm after crossclamp release, pacing requirement, and inotropic support
as measured by the vasoactive-inotropic score (VIS). 9 The VIS uses the Inotrope
Score [dopamine dose (µg·kg−1·min−1) + dobutamine dose (µg·kg−1·min−1) + 100 × 
epinephrine dose (µg·kg−1·min−1)] and is defined as: VIS = Inotrope Score + 10 × 
milrinone dose (µg·kg−1·min−1) + 10,000 × vasopressin dose (units·kg−1·min−1) + 100 × 
norepinephrine dose (µg·kg−1·min−1) The primary outcome measures were the
biochemical markers of myocardial injury: troponin I and creatine kinase-MB. 10,11 Both
markers were measured at 6, 24, and 48 h. VIS was calculated at 0, 24, 48, and 72 h
 postoperatively. Epinephrine, norepinephrine, dobutamine, and milrinone were the
inotropic drugs used either alone or in combination, as per institutional practice.

All continuous variables are expressed as mean ± standard deviation, and qualitative

variables are expressed as numbers. Comparison of continuous variables between
groups was performed using the independent-sample t test (parametric data) or
Mann-Whitney U test (nonparametric data), as appropriate. Qualitative variables
were compared using the chi-square test or Fischer’s exact test, as appropriate.
Nonparametric tests for continuous variables were used when data violated
assumptions for parametric tests, such as normality and homogeneity. A p value
<0.05 was taken as statistically significant.

Results

Baseline demographic characteristics were comparable in the 2 groups (Table 1).

Intraoperative variables were similar in both groups, but due to repeated
administration of cardioplegia in the conventional cardioplegia group, the dosage and
volume required were significantly higher (Table 1). No patient in the del Nido group
required a second dose of cardioplegia. The time taken for return of spontaneous
regular rhythm was significantly longer in the conventional cardioplegia group (Table
1). Temporary pacing was required for a brief period in one patient in each group
when coming off bypass. No residual lesions were detected after the initial repair in
either group, and no patient needed to go back on CPB for further correction; thus
post-randomization, no patient was excluded from the study. In the postoperative
period, time-related changes in troponin I were similar in both groups (Figure 1), and
the return to baseline was also similar. However, at 12 h, there was a trend towards a
significantly greater release of troponin I in the conventional cardioplegia group. VIS
was significantly higher during the first 24 h in the control group (Table 2). Total
duration of mechanical ventilation (12.4 ± 7.9 vs. 11.3 ± 7.9 h, p = 0.60), intensive care
unit stay (77.3 ± 22.8 vs. 66.5 ± 24.2 h, p = 0.08), and hospital stay (7.2 ± 1.7 vs. 7.7 ± 
1.7 days) were similar. The postoperative complication rate was comparable in both
groups. No incidence of delayed chest closure, reexploration, sepsis, peritoneal
dialysis, or prolonged mechanical ventilation (>72 h) were found. One (3.3%) patient
in each group was reintubated due to respiratory issues. Pre- and post-repair
 echocardiography was used to evaluate the adequacy of surgical repair, any change
in cardiac function, and any new finding. Both groups had satisfactory results as far
as surgical repair was concerned. No residual lesion was found, and no deterioration
of cardiac function was noted in any patient. Intensive care unit stay was shorter in
the del Nido group but the difference was not significant. Total duration of mechanical
ventilation was similar in both groups.

Figure 1. Time-related release of troponin I in 60 pediatric patients given del Nido

cardioplegia (group A) or conventional cardioplegia (group B).

Table 2. Biochemical markers and vasoactive-inotropic score in

60 pediatric patients undergoing cardiac surgery with del Nido
or conventional cardioplegia.

Table 2. Biochemical markers and vasoactive-inotropic score in 60 pediatric patients

undergoing cardiac surgery with del Nido or conventional cardioplegia.

View larger version

Discussion

In this prospective randomized study on patients with RACHS scores in category 1

and 2, undergoing elective congenital cardiac surgery, we found that myocardial
protection was generally similar in both groups. This was suggested by the similar
pattern of release of troponin I and creatine kinase-MB. VIS was better in the del
Nido group in the early period. However, there was no difference in postoperative
outcomes including intensive care unit or hospital stay. While the total CPB and
aortic crossclamp times were comparable in both groups, there were definitely fewer
interruptions for cardioplegia administration in the del Nido group, which is certainly
more desirable. Our finding is in keeping with other studies that reported similar
crossclamp and CPB times in children as well as adults.12,13

The single-dose administration, while convenient on one hand, has led to speculation
about the return of cardiac activity during crossclamping and the need for further
administration of cardioplegia. In our study, no patient demonstrated any ventricular
electrical activity while the aorta was crossclamped after administration of del Nido
cardioplegia, thus obviating the need for further doses, as found in other
studies.6,13 In has been shown in rat models that compared to conventional
cardioplegia, spontaneous activity is significantly less common with del Nido
cardioplegia. Also, use of del Nido cardioplegia results in less myocardial damage
and lower coronary vascular resistance during reperfusion, and it is associated with
superior functional recovery after cardioplegic arrest. 14 However, it has to be borne in
mind that most of these studies showing the superiority of del Nido cardioplegia over
blood cardioplegia had short crossclamp and cardiopulmonary bypass
times.7,13,14 Evidence of improved cardiac performance, functional and hemodynamic
recovery, and enzyme release after prolonged myocardial ischemia with del Nido
cardioplegia is limited.

Troponin I release and VIS have been established as markers of myocardial function
or preservation.15–17 Troponin I has been shown to be a reliable marker of cardiac
ischemia during cardiac operations.15 The release of troponin I was essentially similar
in both groups in our study. However at 12 h, the release of troponin I was almost
30% higher in the conventional cardioplegia group, with a trend towards significance.
This suggests that del Nido solution provides at least similar myocardial protection to
conventional cardioplegia in the pediatric cardiac surgical population. The
association between VIS and clinical outcomes after pediatric cardiac surgery has
confirmed VIS as an important variable in a risk-adjustment or risk-prediction model
during the intensive care period.16,17 Maximum VIS ≥ 20 in the first 24 h predicts
increased likelihood of poor clinical outcome and is consistent in analyses stratified
by age and surgical complexity.16,17 In our study, at no point was the VIS greater than
20, but it was significantly higher in the conventional cardioplegia group until 48 h
after surgery, suggesting that del Nido cardioplegia may offer slightly better
myocardial protection than conventional cardioplegia in pediatric congenital cardiac
surgery patients. The reduced inotropic support required in the del Nido group was
probably due to a number of factors.18 Similar to other cardioplegia solutions, the
arrest achieved with del Nido cardioplegia results from increased extracellular levels
of potassium, but the base solution (Plasmalyte) and lidocaine are perhaps
responsible for the beneficial action. The electrolyte composition of del Nido solution
correlates closely with that of plasma, being isoosmolar with a physiological pH;
sodium gluconate, through its alkalinizing effect, might serve to modulate myocardial
pH. Also, the relatively calcium-depleted base solution decreases the calcium load in
the coronary arteries during reperfusion, thereby preventing diastolic stiffness during
recovery.19 del Nido cardioplegia promotes anaerobic glycolysis during arrest and
also reduces energy consumption, blocks calcium entry into the intracellular
environment, scavenges hydrogen ions, and preserves high-energy
phosphates.6 The lidocaine content serves to increase Na + channel blockade and
minimize the potential for an Na+ window current during arrest, causing polarization
of cardiomyocytes. This property has been hypothesized to be the main
cytoprotective feature of del Nido cardioplegia, which is notably absent in blood
cardioplegia.

The volume of packed red blood cells needed during CPB was significantly lower in
the del Nido group compared to the conventional cardioplegia group, in agreement
with other studies. Transfusion requirements were lower in the del Nido group,
possibly due to the lower total cardioplegia volume. In contrast to other studies, we
found that the time taken to recover spontaneous regular rhythm after release of the
aortic crossclamp was significantly shorter in the del Nido group. One issue with del
Nido solution is that it contains more crystalloid than conventional blood cardioplegia,
and thus a theoretical risk of dilutional anemia exists, but this can be easily tackled,
as in our study, by modified ultrafiltration after termination of CPB. On the other hand,
the blood volume required in the conventional cardioplegia group in our study was
significantly higher, possibly due to the higher total cardioplegia volume required.
This finding has been supported by other studies that reported an increase in blood
transfusion requirements in conventional cardioplegia groups compared to del Nido
groups in children as well as adults.13,20
 The study was powered for detecting a difference in the biochemical markers, but it
was not sufficiently powered for clinical outcomes. Therefore, while the results show
that del Nido cardiopleiga is as safe as conventional blood cardioplegia it was not
powered to assess clinical superiority. Perhaps, as the study was underpowered for
clinical outcomes despite a lower VIS and trends towards significantly lower troponin
I release, no difference in clinical outcomes was seen. The other important limitation
of the study was the lack of more complex patients with higher RACHS scores. While
one would intuitively think that del Nido cardioplegia might be more useful in patients
with higher RACHS scores, this study did not address the issue of outcome in
patients with higher RACHS scores. Therefore, caution has to be exercised in
generalizing the findings or applying them to the high-risk pediatric population. A
larger prospective, randomized, multicenter study, powered to detect differences in
clinical outcomes, is required to establish the efficacy of del Nido cardioplegia.
Nevertheless, our results show that del Nido cardioplegia solution is as safe as
conventional blood cardioplegia in low-risk (RACHS 1 and 2) pediatric congenital
cardiac surgery cases.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research,
authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or
publication of this article.

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