What are some alternatives to Plasmalyte for del Nido cardioplegia solution?

What are some alternatives to Plasmalyte for del Nido cardioplegia solution?

Comment by InpharmD Researcher

Limited evidence exists comparing Plasmalyte versus suitable del Nido cardioplegia solution alternatives. Current guidelines do not specify any specific base solutions. One recent randomized trial from Asia found Plasmalyte A-based del Nido cardioplegia to be noninferior to plain Ringer’s based del Nido cardioplegia. A similar study comparing lactated Ringer’s-based del Nido cardioplegia and cold blood cardioplegia in congenital heart disease also found similar outcomes between the agents.

Background

Current practice guidelines do not provide recommendations regarding the use of a specific del Nido cardioplegia base solution. There appears to be a lack of studies detailing the advantages and disadvantages of available solutions in terms of myocardial protection. [1], [2]

A 2022 retrospective, single-center study in Thailand investigated patient risk profiles, operative details, mortality rates, care durations, inotrope use, blood transfusion, and complications in 116 patients with congenital heart disease undergoing operations with cardioplegic arrest. Lactated Ringer’s-based del Nido cardioplegia was used for 66 patients and cold blood cardioplegia for 50 patients. More patients in the del Nido group had a Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery score of 3 to 5 (24.2% vs. 10% in the cold blood group; p= 0.049). No significant difference was found between groups for median intubation duration, length of intensive care unit stay, use of vasoactive medications (both, immediately and 24 hours after the operation), and complications/adverse events. Four deaths were reported in the lactated Ringer’s del Nido group and zero in the cold blood group (p= 0.13). The lactated Ringer’s del Nido group required 70 to 100 mL less blood transfusion (p= 0.04). The authors concluded that outcomes were comparable between groups. A similar study completed in India with comparable outcomes can be found in Table 1. [3]

A clinical trial is currently underway to assess Custodiol (histidine- tryptophan- ketoglutarate) and modified del Nido cardioplegia (lactated Ringer's as a base solution). The study was tentatively completed in May 2022 but no publication has been released. [4], [5]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What are some alternatives to Plasmalyte for del Nido cardioplegia solution?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-2 for your response.

Plasmalyte-A Based del Nido Cardioplegia Versus Plain Ringer Based del Nido Cardioplegia: Double-Blind Randomized Trial
Design	Prospective, double-blind, randomized trial N= 80
Objective	To compare the standard del Nido cardioplegia solution (SDN) with the modified del Nido cardioplegia solution (MDN) in which the base solution was the plain Ringer solution
Study Groups	SDN; Plasmalyte A (n= 39) MDN; Ringer solution (n= 41)
Inclusion Criteria	Children < 12 years undergoing intracardiac repair of Tetralogy of Fallot (TOF) with an estimated aortic cross-clamp time > 45 minutes
Exclusion Criteria	Patients > 12 years of age, co-existing morbidities, emergency surgery, and estimated aortic cross-clamp time < 45 minutes
Methods	Patients in the control group received SDN cardioplegia whose base solution is Plasmalyte-A giving a final cardioplegia with a pH of 7.55, concentrations of sodium: 135 mmol/L, potassium: 26 mmol/L, bicarbonate: 6.7 mmol/L, and calcium: 0.18 mmol/L, with the addition of mannitol: 3.26 g, lidocaine: 130 mg, and magnesium: 2 g, with a final osmolarity of 337 mOsm/L. In the MDN group, Plasmalyte-A was replaced with the plain Ringer solution giving a pH of 7.53, concentrations of sodium: 135.2 mmol/L, potassium: 24 mmol/L, bicarbonate: 7.3 mmol/L, and calcium: 1.29 mmol/L, with the addition of mannitol: 3.26 g, lidocaine: 130 mg, and magnesium: 2 g, with a final osmolarity of 328 mOsm/L. Four parts of this crystalloid component of either SDN or MDN were mixed with 1 part of the patient’s blood. After aortic cross-clamping, 20 mL/kg of cardioplegia solution (temperature 6°C-8°C) was administered into the aortic root. Repeat doses (10 mL/kg) were administered 90 min later, or on resumption of cardiac electro-mechanical activity, whichever was earlier.
Duration	February 2018 and September 2019
Outcome Measures	The primary outcome was a change in cardiac index (CI). Secondary outcomes were ventricular arrhythmias after the release of aortic-cross clamp, postoperative inotropic score (IS), time to peripheral rewarming, duration of mechanical ventilation, intensive care unit (ICU) length of stay, and hospital length of stay, and electron microscopic differences between groups
Baseline Characteristics		SDN (Plasmalyte A)	MSN (Ringer solution)
	Mean age, months	61.17 ± 40.90	53.90 ± 35.23
	Female	11 (28.2%)	12 (29.27%)
	Operative procedure ICR ICR + TAP ICR+TAP+PA plasty Conduit repair	12 (30.7%) 7 (17.9%) 17 (43.5%) 3 (7.69%)	13 (31.7%) 12 (29.2%) 14 (34.1%) 2 (4.87%)
	CPB time, min	101.79 ± 34.04	103.80 ± 38.12
	Mean aortic cross clamp time, min	65.87 ± 26.60	64.65 ± 27.38
	Amount of cardioplegia, mL	456.15 ± 174.04	455.6 ± 196.58
	Volume of ultrafiltrate, mL	746.66 ± 424.47	781.95 ± 385.52
	Hypothermia time, min	48.28 ± 19.15	54.29 ± 19.64
	Time for cardiac arrest, s	19.15 ± 9.57	15.90 ± 4.10
	Time for return of activity post clamp release, s	40.71 ±34.38	41.29 ± 33.78
	Time for a return to normal sinus rhythm post clamp release, s	80.17 ± 47.87	86.37 ± 36.43
	Active intraoperative rewarming time, min	34.71 ± 13.38	32.68 ± 11.99
	Activity during arrest	6 (15.38%)	4 (9.76%)
	VT/VF incidence post clamp release	7 (17.95%)	7 (17.07%)
	Defibrillation used	7 (17.95%)	7 (17.07%)
	Priming volume, mL	837.43 ± 287.82	910.97 ± 251.12
	Total intravenous fluid volume, mL	449.61 ± 227.38	459.14 ± 163.72
	Blood transfused, mL	453.07 ± 144.06	418.17 ± 131.88
	Least intraoperative hematocrit, %	34.58 ± 5.43	34.54 ± 6.28
	Abbreviations: ICR: intracardiac repair; TAP: transannular patch; PA: pulmonary artery No significant demographic or intraoperative differences between groups
Results	Endpoint	SDN (Plasmalyte A)	MSN (Ringer solution)	p-Value
	Mean peripheral rewarming time, h	9.05 ± 6.47	11.28 ± 24.58	0.58
	Mean mechanical ventilation, h	12.15 ± 6.79	14.89 ± 27.28	0.27
	LCOS	14 (35.9%)	11 (26.83%)	0.38
	Mean postoperative 24 h lactate level, mg/dL	3.52 ± 1.91	3.07 ± 1.58	0.24
	Mean postoperative ICU stay, days	2.52 ± 1.11	2.52 ± 1.54	0.50
	Mean postoperative hospital stay, days	6.46 ± 2.98	6.32 ± 2.94	0.57
	Pre-CPB CI-0 Post-CPB CI-1 Postoperative 6 h CI-2 Postoperative 24 h CI-3	3.05 ± 0.96 3.16 ± 1.03 3.09 ± 0.75 3.28 ± 0.97	3.35 ± 0.94 3.44 ± 1.22 3.32 ± 0.95 3.49 ± 0.90	0.15 0.27 0.23 0.32
	Preop-TAPSE-0 Immediate postoperative period TAPSE-1 Post op 6 h TAPSE-2 Post op 24 h TAPSE-3	16.15 ± 1.15 11.79 ± 1.89 12.87 ± 2.17 13.94 ± 2.68	16.26 ± 1.22 11.53 ± 1.80 12.70 ± 2.14 14.14 ± 2.41	0.66 0.53 0.73 0.72
	IS POD0 IS POD1 IS POD2 IS POD3	12.89 ± 12.82 9.77 ± 4.83 6.66 ± 5.16 3.07 ± 4.41	9.72 ± 4.69 8.75 ± 5.88 6.28 ± 7.16 3.65 ± 6.79	0.14 0.39 0.78 0.64
	Trop-I ng/dL Pre-CPB Post-CPB Trop-I Postoperative 24h-Trop-I IL-6 pg/dL Postoperative 24 h TNF-α	3.10 ± 1.33 5853.24 ± 3737.01 4761.33 ± 2071.86 5.97 ± 2.71 11.03 ± 7.70	3.66 ± 1.42 5420.61 ± 3370.41 4225.46 ± 2479.75 5.60 ± 2.53 11.72 ± 6.26	0.07 0.58 0.29 0.53 0.66
	Applying the noninferiority confidence interval approach, the difference between the changes in CI between the 2 groups was −0.093 L/min/m² (95% CI: −0.46-0.27 L/min/m²) which was within the noninferiority threshold of −0.5 indicating that CI was similar in both SDN and MDN.
Adverse Events	Common Adverse Events: N/A
Study Author Conclusions	Plain Ringer based del Nido cardioplegia solution is noninferior to the standard Plasmalyte-A based del Nido cardioplegia solution in terms of preservation of CI. In addition, for the following secondary outcome metrics, no significant differences were observed between the SDN (Plasmalyte-A) and MDN (Plain Ringer) groups based on two-sided testing: postoperative inotropic scores, duration of mechanical ventilation, serum markers of myocardial injury, inflammatory markers, and ICU and hospital length of stay. Electron microscopic features of myocardial injury were similar in both groups. Plain Ringer based del Nido cardioplegia solution offered a definite cost advantage in these patients and should be considered as an alternative base solution for del Nido cardioplegia in resource limited set-ups.
InpharmD Researcher Critique	The study population is comprised of only patients with TOF and does not include patients with more complex cardiac diagnoses. Additionally, this patient cohort is comprised of older patients which are different from those encountered in the Western world where surgical repair in neonates and early in infancy are more common. Finally, this study was designed to test non-inferiority rather than superiority or equivalence between tested solutions.

Table 1 References:
[6] Talwar S, Harshavardhan N, Kapoor PM, et al. Plasmalyte-A Based del Nido Cardioplegia Versus Plain Ringer Based del Nido Cardioplegia: Double-Blind Randomized Trial. World J Pediatr Congenit Heart Surg. 2022;13(2):187-195. doi:10.1177/21501351211073610

Lactated Ringer’s as a Base Solution for del Nido Cardioplegia
Design	Prospective observational study N= 89
Objective	To evaluate myocardial preservation and clinical outcomes when using lactated Ringer’s solution as the base solution for del Nido cardioplegia as compared with institutional standard blood cardioplegia strategy
Study Groups	del Nido cardioplegia (n= 44) Blood cardioplegia (n= 45)
Inclusion Criteria	Aged ≥ 18 years; undergoing cardiac surgery for acquired heart disease, including isolated coronary artery bypass grafting (CABG), isolated valve surgery, combined valve surgery, or concomitant CABG and valve surgery
Exclusion Criteria	Lidocaine allergy; patient refusal
Methods	At the study institution, pharmacists compound del Nido cardioplegia with following ingredients: lactated Ringer’s solution 1,000 mL, sodium bicarbonate 1 mEq/mL, 20% mannitol 16.3 mL, 50% magnesium sulfate 4 mL, 1% lidocaine 13 mL, and potassium chloride 2 mEq/mL 13 mL and stored at 2–8°C before administration within 24 hours. Patients received a single dose 20 mL/kg with a maximum dose of 1,000 mL for those weighing > 50 kg, with a 1:4 with one part of oxygenated pump blood to four parts of cardioplegia solution. Subsequent doses were decided by the surgeon and patients who underwent coronary bypass grating would receive 5–10 mL of del Nido cardioplegia via the saphenous vein graft or the radial artery graft to test the distal anastomosis. On the other hand, blood cardioplegia is delivered 4:1 with four parts of oxygenated pump blood to one part of cardioplegia solution with an initial dose of 20 mL/kg and maintenance dose of 10 mL/kg over 1–2 minutes with system pressure 100–200 mmHg.
Duration	From February 2017 to November 2017 Follow-up: 2 days postoperatively
Outcome Measures	Primary: assessments of myocardial injury, including the troponin-T level at immediate postoperative, postoperative day 1, and postoperative day 2 Secondary: additional measures of myocardial protection; incidence of ventricular fibrillation after aortic cross-clamp removal and postoperative left ventricular ejection fraction (LVEF) change; requirement for intra-aortic balloon pump (IABP) support; intraoperative and clinical outcomes
Baseline Characteristics		del Nido (n= 44)	Blood Cardioplegia (n= 45)
	Median age, years	64.5	67
	Female	45.45%	28.89%
	Median Society of Thoracic Surgery Risk Score, %	1.629	1.206
	Median preoperative LVEF, %	60	55
	New York Heart Association Class I Class II Class III Class IV	11.36% 63.64% 15.91% 9.09%	22.22% 64.44% 13.33% 0
	Operation Isolated CABG CABG + valve Aortic valve Mitral valve Combine valve	56.82% 15.91% 6.82% 11.36% 9.09%	51.11% 17.78% 11.11% 15.56% 4.44%
	No significant differences between the two groups were noted in baseline characteristics.
Results	Endpoint	del Nido (n= 44)	Blood Cardioplegia (n= 45)	p-value
	Troponin levels, ng/mL (interquartile range [IQR]) Immediate postoperative Postoperative day 1 Postoperative day 2	0.541 (0.376 to 0.899) 0.632 (0.437 to 0.907) 0.363 (0.250 to 0.451)	0.821 (0.479 to 1.065) 0.827 (0.599 to 1.388) 0.549 (0.340 to 0.897)	0.63 0.009 0.002
	Intraoperative outcomes Ventricular fibrillation, % Postoperative LVEF changes, % (IQR)	9.09% 0 (0 to 1.70)	31.11% 0 (–8 to 5)	0.01 0.515
	Intraoperative outcomes Total cardioplegia volume, mL (IQR) Number of doses	1,075 (1,000 to 1,250) 1.6 ± 0.7	3,400 (2,700 to 3,750) 4.6 ±1.3	< 0.001 < 0.001
	No significant differences were noted in other cardiac markers of interest (creatinine kinase and CK-MB isoenzyme), intraoperative outcomes, requirement for IABP support, and red blood cell transfusion. The median (IQR) duration of inotrope/vasopressor requirement was lower in the del Nido group (1 [1, 1] vs. 1 [1, 2] days, p< 0.001). Incidence of postoperative atrial fibrillation or flutter with rapid ventricular response was lower in the del Nido group (25 vs 46.7%, p= 0.033). The del Nido group had a shorter ICU stay (2 vs 3 days, p< 0.001) and hospital stay (7 vs 9 days, p< 0.001).
Adverse Events	del Nido vs blood cardioplegia (not significant): none renal failure, stroke (4.55% vs 0), prolonged ventilation > 24 hours (6.82% vs 11.11%), reoperation for bleeding/tamponade (6.82% vs 2.22%), none hospital death
Study Author Conclusions	The use of traditional del Nido cardioplegia ingredients added to lactated Ringer’s as the base solution provided either similar or superior myocardial protection to the blood cardioplegia strategy depending on the outcome measure analyzed. The use of lactated Ringer’s as a base solution may be an option for centers that do not have access to Plasma-Lyte. Further investigation and follow-up are warranted after this observational study.
InpharmD Researcher Critique	The study is limited by its small sample size and nonrandomized nature where the choice of agents was mainly based on surgeons' preferences. Additionally, while the study showed the feasibility of using lactated Ringer’s solution as the base solution, a direct comparison with Plasma-Lyte A is not available from the study to decide the interchangeability between the two vehicles.

Table 2 References:
[7] Kantathut N, Cherntanomwong P, Khajarern S, Leelayana P. Lactated Ringer's as a Base Solution for del Nido Cardioplegia. J Extra Corpor Technol. 2019;51(3):153-159.