Del Nido cardioplegia: from an infant conceive to an adult life - a brief review of the current evidence in adult patients

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].

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.

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.^[12] 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.^[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.