2Dipartimento Scienze Cardiovascolari,
3Department of Cardiac Surgery,
4Department of Cardiac Sciences,
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:email@example.com ; mailto:firstname.lastname@example.org
© 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.
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.
Del Nido cardioplegia, adult cardioplegia, myocardial protection, blood cardioplegia, single shot cardioplegia
Adult cardiac surgery has changed in the last decade. In the 2018 the STS 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. 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 and at the moment, in low risk coronary patients. We hereby are summarizing the basic concepts behind its formulation and use, along with the available evidence in the adult patients.
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 or ineffective. 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, fewer mitochondria, a higher concentration of poly unsaturated fatty acids in the cell membrane and a deficient free radical scavenge system with less active superoxide dismutase, catalase and glutathione reductase. 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.
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].
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 mL)||Gluconate 23 mEq|
|Lidocaine 1% (13 mL)||Acetate 27 mEq|
|Blood : Crystalloid 1:4|
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.
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 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 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 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.
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.
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. 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.
|Reference||Population (n)||Study design||Significant results in DNC group||No differences|
|Yerebakan et al.||Acute MI CABG
DNC = 48
WCBC = 40
↓ X- Clamp
|Enzyme relese EF% Postperative support Mortality|
|Sorabella et al.||Reoperative AVR DNC = 52 Blood = 61||DNC vs. blood
|↓Cardioplegia volume||CPB, X-clamp time Complication rate|
|Mick et al.||Isolated Valve Aortic = 85/85
Mitral = 110/110
|Retrospective 1:1 Propensity score Matched||Aortic
↓ CPB, ↓ XC lamp, ↓Glucose ↓ Insuline
↓ Insuline ↓ Glucose
|Ensyme Release EF% Clinical results|
|Ota et al.||AVR (240)
DNC = 178
Blood = 62
|DNC vs. blood Retrospective Propensity matched 54 pairs||↓CPB, ↓ X-clamp
↓Use of retrograde
|Mishra et al.||CABG or double valve
DNC = 50
Blood = 50
|DNC vs. blood
|↓CPB, ↓ X-clamp ↓Redosing
|Timek et al.||CABG
DNC = 82
CB = 82
|DNC vs. CB Rterospective
Propensity score matched pairs
|↓ Glucose||Cross Clamp Inotropes Enzyme Release EF%|
|Guajardo et al.||CABG (408)
DNC = 159
Blood = 249
|DNC vs. blood Retrospective||↓ Need defibrillation
↓Transfusion (P < 0.08)
|CPB, X-clamp time Length of stay Mortality|
|Vistarini et al.||Min. invasive AVR
DNC = 25
Blood = 21
|DNC vs. blood
|↓ Need defibrillation
↓CK-MB ↓Insulin use
|Complication rate Mortality|
|Kim et al.||Valve
DNC = 149
Blood = 892
|DNC vs. blood
Retrospective Propensity matched 111 pairs
|Inotropic support Mortality Complication rates|
|Hamad et al.||AVR/CABG
DNC = 25
Blood = 25
|DNC vs. blood
|↓CK-MB, troponin T
|Inotropic support Operative time Length of stay Complication rates|
|Ziazadeh et al.||Min invasive AVR
DNC = 77
Blood = 101
|DNC vs. blood
Retrospective Propensity matched 63 pairs
|**↓CPB, X-clamp ↓Glucose levels||Troponin T Ejection fraction Complication rates|
|Koeckert et al.||Min. invasive AVR
DNC = 59
Blood = 122
|DNC vs. blood
Retrospective Propensity matched 59 pairs
↓Use of retrograde
|CPB, X-clamp time Inotropic support Transfusion Length of stay Complication rates|
|Ad et al.||CABG ± valve
DNC = 48
Blood = 41
|Randomized, controlled||↓ A.Fib Postop (*)
↓ Troponine (*)
|CPB, X-clamp time Complication rates Inotropic support Need defibrillation|
|UCAK et al.||CABG elective
DNC = 112
|DNC vs. IWBC
|↓ CPB ↓ X-clamp
|Enzyme release Clinical events|
|O’Donnel et al.||CABG
BC = 27
|DNC vs. BC
|↓ CPB ↓ X-clamp
|No difference in clinical outcomes|
|Pragliola et al.||All kinds of adult surgery including emergencies
IWBC = 102
|DNC vs. IWBC
Retrospective Propensity score matched pairs
|↓Ejection fraction in low EF subgroup||No differences overall|
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 according to the literature. Unlikely other blood cardioplegias, we strongly advise not to use a continuous infusion. This can result either in an excess of volume or Lidocaine and magnesium. Najjar et al. in a series of 14 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. 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.
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.
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. 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.
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., describing the development of the DNC reports the regular use in Adult Congenital cases at Boston Children Hospital. Ota et al. and Sorabella et al. published their experiences with first time and re-operative Aortic Valve surgery, all with safe and comparable results. Mongero 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. 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 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 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® 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. 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. 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. 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. 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. 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.
Understandably Lazar 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. 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.
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
NoneConflicts of interest
All authors declare that there are no conflicts of interest.Ethical approval and consent to participate
Not applicable.Consent for publication
© The Authors 2019.
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