The effects of del Nido cardioplegia combined with dexmedetomidine on cardiac surgery with cardiopulmonary bypass

Abstract

Objective

To evaluate the effects of dexmedetomidine administration and the use of del Nido cardioplegia in reducing the incidence of atrial fibrillation (AF) and delirium during the perioperative period.

Methods

448 patients were randomized into two groups: the treatment group received dexmedetomidine combined with del Nido cardioplegia, and the control group received normal saline placebo combined with Buckberg traditional cardioplegia. Each group included 224 patients. The occurrence of AF and delirium within 5 days after surgery, as well as other intraoperative and postoperative indicators, were noted.

Results

There were no significant differences in preoperative indicators between the two groups. The incidences of AF and delirium events were significantly higher in the control group than in the treatment group.

Conclusion

We found that del Nido cardioplegia combined with dexmedetomidine was safe in cardiac surgery with CPB and effectively reduced the incidence of postoperative AF and delirium.

Keywords

cardiac surgery cardiopulmonary bypass myocardial preservation postoperative delirium postoperative atrial fibrillation

Cardiopulmonary bypass (CPB) during cardiac surgery can activate the sympathetic nervous system, leading to atrial fibrillation (AF) and delirium. AF is the most common arrhythmia after cardiac surgery and is associated with prolonged intensive care unit (ICU) and hospital stays as well as increased mortality.¹ Delirium often is followed by poor cognitive recovery, functional decline, and even death.² Dexmedetomidine is a central alpha-2 adrenergic agonist that has the sympatholytic effects of reducing heart rate and improving myocardial oxygen supply.³ In addition, dexmedetomidine can inhibit sinoatrial and atrioventricular node function, making it a reasonable preventive medication for postoperative AF.⁴ Dexmedetomidine can maintain a sleep structure close to normal, which can help alleviate delirium symptoms commonly seen in ICU patients due to sleep deprivation. It can also reduce dependence on opioid and benzodiazepine drugs, both of which may contribute to delirium.⁴ Therefore, dexmedetomidine may help decrease the incidence of postoperative delirium. A meta-analysis involving 1301 patients who had cardiac surgery concluded that dexmedetomidine can reduce the occurrence of delirium.⁵ However, another cohort study on dexmedetomidine in cardiac surgery showed no significant reduction in AF or delirium compared with the rates in the control group.⁶ Thus, the effects of dexmedetomidine on AF and delirium in cardiac surgery remain controversial. In recent years, del Nido cardioplegia has become a widely used myocardial protection solution, and several studies have found that del Nido can prevent myocardial cell ischaemia–reperfusion injury and reduce the incidence of postoperative AF in adult cardiac surgery.^7–9 Furthermore, del Nido cardioplegia contains lidocaine, which has a stabilising effect on neuronal cell membranes and a protective effect against ischaemic hypoxic brain injury.¹⁰ Pre-treatment with dexmedetomidine can also mitigate myocardial ischemia/reperfusion injury by suppressing sympathetic nervous activity. Thus, dexmedetomidine and del Nido cardioplegia may exhibit a synergistic effect in protecting against myocardial ischemia-reperfusion injury and providing neuroprotection. Therefore, we hypothesized that administering dexmedetomidine and using del Nido cardioplegia during the perioperative period can reduce the incidence of new-onset AF and delirium.

Methods

Inclusion and exclusion criteria

This study was approved by the participating institution’s ethics committee, and all patients signed written informed consent. Inclusion criteria: Age 18–70 years; New York Heart Association functional class II–IV. Exclusion criteria: patients who refused to sign the informed consent form, planned to undergo deep hypothermic circulatory arrest surgery, had preoperative mechanical circulatory support, had concurrent AF ablation surgery, or had acute coronary syndrome or simultaneous coronary artery bypass grafting within 1 week before surgery. In the subgroup analysis, patients with a Euroscore II score ≥3 were classified as the high-risk group.¹¹

Anaesthesia and CPB

Patients were induced with standard anaesthesia protocols at the participating institution. Standard monitoring included central venous or pulmonary artery catheterisation and transoesophageal echocardiography was used to assess the left-ventricular ejection fraction before and after surgery. To induce anaesthesia, midazolam at 0.04–0.05 mg/kg, sufentanil at 0.5 μg/kg, vecuronium bromide at 0.1 mg/kg, and etomidate at 0.2–0.3 mg/kg were intravenously administered. Tracheal intubation was performed after satisfactory muscle relaxation was achieved. During the operation, 1%–2% sevoflurane was inhaled, propofol was continuously pumped intravenously at a rate of 2–4 mg·kg⁻¹·h⁻¹, and sufentanil at 0.3–0.6 μg·kg⁻¹·h⁻¹ was administered to maintain anaesthesia. Vecuronium bromide was injected intermittently to maintain muscle relaxation. Intraoperative peripheral oxygen saturation (SpO₂) was maintained above 98%, and the bispectral index was maintained within the range of 45–55. Surgical approaches included full median sternotomy or minimally invasive upper sternotomy. A membrane oxygenator with an integrated arterial filter was used to achieve CPB. Roller pumps or centrifugal pumps were used to provide arterial flow >2 L/min/m² while maintaining mean arterial pressure >65 mmHg.

Operative procedure

Participants were allocated using a block randomization method, with computer-generated blocks of variable and undisclosed sizes (ranging from 10 to 30) to ensure balance. Within each block, subjects were randomly assigned to two groups at a 1:1 ratio, receiving either a combination of dexmedetomidine and del Nido cardioplegia (referred to as the treatment group) or a combination of saline placebo and Buckberg conventional cardioplegia (referred to as the control group). Randomisation for group assignments was generated by a computer. Randomization and blinding were implemented at the research center through the use of sealed envelopes, which were opened solely by a research assistant involved in the surgical phase. Although practitioners involved in the surgical intervention could not be blinded, the intensive care unit physicians responsible for outcome assessments remained unaware of the group assignments.

To prepare del Nido cardioplegia, we used international standard formulations mixed with blood (1 part blood to 4 parts del Nido solution) to form a 1:4 diluted del Nido solution, and a heat exchanger was used to infuse the solution during the procedure, with the temperature maintained at 4°C–8°C. Traditional Buckberg cardioplegia was based on the St Thomas II formula and mixed with blood (4 parts blood to 1 part St Thomas II solution) to form a 4:1 diluted blood cardioplegia (Table 1). A heat exchanger was used to maintain the temperature of the solution at 15°C.

Table 1.

Final ion concentration in cardioplegia solution.

Final administered solution	Del Nido cardioplegia (mmol/L)	Buckberg cardioplegia (mmol/L)
Na⁺	142–144	140–148
K+	21	36
Ca²⁺	0.22–0.27	1.8–2.2
Mg²⁺	6–8	0.9–1.25

Administration of dexmedetomidine hydrochloride was initiated before surgical incision at a dose of 0.1 μg/kg/h. After completing the CPB, the dose was increased to 0.2 μg/kg/h. The anaesthetist could appropriately reduce the dosage of the study drug as needed to maintain hemodynamic stability. During the procedure, opioid and benzodiazepine drugs were administered by the anaesthetist as necessary. Postoperatively, the dose of dexmedetomidine (or placebo) was increased to 0.4 μg/kg/h and maintained for 24 h after starting the infusion. The control group was administered a saline placebo of identical packaging for maintenance purposes. Similarly, the clinical physician could reduce the dosage of the study drug and control drug according to the actual situation and provide sedative and analgesic medications if needed. Prophylactic use of amiodarone was not permitted.

Outcome measures

The primary outcome measures were the incidence of AF or delirium events within 5 days after surgery. Any AF events were automatically recorded by the electrocardiographic telemetry system and independently assessed by two researchers. Delirium events were confirmed by doctors and independent nurses by review of patient records, and the Richmond Agitation–Sedation Scale was used to assess sedation before the delirium assessment.¹² Delirium was only evaluated when the score on the Richmond Agitation–Sedation Scale was not −4 or −5 (indicating insufficient wakefulness). Secondary outcomes included postoperative levels of cardiac troponin, temporary cardiac pacemaker use, cardiac death and all-cause mortality.

Statistical analysis

R version 4.0.0 (NIH, US) was used to perform all statistical analyses. Continuous normally distributed data are presented as the mean ± standard deviation (mean ± SD), non-normally distributed data are presented as the median (interquartile range) M (Q1, Q3) and categorical data are presented as frequencies (%). Missing data were managed using a multiple imputation approach. The chi-squared test was performed to compare categorical data, the t test was performed for normally distributed continuous data, and the Mann–Whitney U-test was performed for non-normally distributed continuous data. Survival curves were analyzed by applying the Kaplan–Meier method, and a Cox regression model was used to assess hazard ratios and perform subgroup analysis. The clinical significance of atrial fibrillation and delirium events was described and analyzed using the number needed to treat (NNT). All statistical tests were two-tailed, and values of p < .05 were accepted as indicating statistical significance. Subgroup analysis was conducted using a predefined subgroup approach.

Results

From January 2020 to January 2024, a total of 462 patients who underwent cardiac surgery with CPB were enrolled in the study (Figure 1). Ultimately, 448 patients were included in the randomized groups, with 224 patients in each group. There were no significant differences in the baseline characteristics, including age, body surface area, troponin T, and CK-MB cardiac injury markers between the two groups (Table 2). The rates of the primary outcome measures, incidence of AF events, and delirium events within 5 days postoperatively were significantly higher in the control group than in the treatment group (Figure 2). The number needed to treat (NNT) for atrial fibrillation events was 5, while for delirium events, it was 10.

Table 2.

Baseline patient characteristics.

	Control	Treat	p
N	224	224
Age, years	54.00 [44.50, 61.00]	50.00 [42.00, 60.00]	.12
Gender, M	109 (48.7%)	117 (52.2%)	.508
Operation			.457
Aortic root reconstruction	73 (32.6%)	72 (32.1%)
Combined valve replace repair	97 (43.3%)	87 (38.8%)
Redo valve replace repair	54 (24.1%)	65 (29.1%)
BSA, m²	1.89 ± 0.15	1.89 ± 0.15	.919
Creatinine, mg/dL	1.00 [0.80, 1.00]	1.00 [0.79, 1.00]	.95
CK-MB, ng/ml	2.00 [1.00, 4.33]	1.82 [1.00, 4.15]	.391
Troponin T, pg/ml	1.00 [0.90, 5.44]	1.00 [0.90, 4.50]	.739
HCT, %	42.50 [39.98, 45.90]	42.55 [38.50, 46.45]	.387
LVEF, %	38.00 [34.00, 46.00]	39.00 [34.00, 46.00]	.666
Coronary artery disease	25 (11.2%)	35 (15.6%)	.212

Categorical data are presented as number (percentage). Continuous data conforming to a normal distribution is presented as “mean ± standard” deviation. A non-normal distribution is presented as “medium [quartile1, quartile3]” deviation.

BSA: body surface area; LVEF: left ventricular ejection fraction; CK-MB: creatine kinase (MB isoenzyme).

Comparisons of the intraoperative indicators showed that calcium-ion concentrations in the arterial blood gas analysis were higher in the control group than in the treatment group, whereas red blood cell haematocrit after aortic opening was lower in the treatment group than in the control group (Table 3). Comparisons of the postoperative indicators revealed the rate of temporary pacemaker use was higher in the treatment group than in the control group (Table 4).

Table 3.

Comparison of artery blood gas during CPB.

	Control	Treat	p
n	224	224
Artery blood gas after 5 min of cross-clamp the aorta
pH	7.39 [7.35, 7.43]	7.39 [7.35, 7.43]	.149
Na⁺, mmol/L	138.00 [135.00, 140.00]	138.00 [135.00, 140.25]	.835
K⁺, mmol/L	5.04 ± 0.71	4.85 ± 0.65	.003
Ca²⁺, mmol/L	1.04 ± 0.12	0.95 ± 0.11	<.001
HCT, %	29.00 [27.00, 31.25]	29.00 [27.00, 32.00]	.404
Glu, mmol/L	8.89 ± 2.02	8.76 ± 2.25	.544
Lac, mmol/L	1.96 ± 0.50	1.88 ± 0.54	.112
Artery blood gas after 5 min of declamping the aorta
pH	7.35 ± 0.05	7.36 ± 0.06	.046
Na⁺, mmol/L	137.00 [135.00, 139.00]	138.00 [135.00, 140.00]	.104
K⁺, mmol/L	5.04 [4.62, 5.48]	5.14 [4.48, 5.78]	.175
Ca²⁺, mmol/L	0.95 ± 0.11	0.77 ± 0.10	<.001
HCT, %	28.00 [27.00, 29.00]	26.00 [24.00, 28.00]	<.001
Glu, mmol/L	9.98 [8.60, 11.01]	10.34 [8.81, 11.56]	.097
Lac, mmol/L	2.73 ± 0.62	2.74 ± 0.60	.837

Na⁺: sodium; K⁺: potassium; Ca²⁺: calcium; Glu: glucose; HCT: hematocrit.

Table 4.

Comparisons of secondary outcomes and complications.

	Control	Treat	p
n	224	224
Defibrillation for VF	54 (24.1%)	28 (12.5%)	.002
Transfusion >2 units of RBC	89 (39.7%)	74 (33.0%)	.169
Chest revision	7 (3.1%)	11 (4.9%)	.47
Troponin T after operation 24 h, pg/ml	641.50 [501.84, 859.52]	596.72 [481.56, 794.48]	.431
Troponin T after operation 48 h, pg/ml	436.27 [311.22, 574.56]	435.41 [327.40, 533.42]	.862
CK-MB after operation 24 h, ng/ml	38.83 [28.44, 54.76]	36.08 [26.45, 53.87]	.519
CK-MB after operation 48 h, ng/ml	32.70 [22.38, 49.44]	31.08 [22.22, 50.59]	.859
Total drainage, mL	619.50 [511.00, 763.00]	629.00 [490.00, 767.50]	.796
Postoperative EF, %	52.00 [46.00, 57.00]	50.00 [45.00, 56.00]	.162
EF decline >5%	29 (12.9%)	35 (15.6%)	.5
Temporary pacemaker	22 (9.8%)	56 (25.0%)	<.001
Permanent complete AV-block	0 (0.0%)	4 (1.8%)	.132
Creatinine increase >25%	43 (19.2%)	43 (19.2%)	1
Greatest creatinine measured, mg/dL	1.39 ± 0.55	1.42 ± 0.54	.584
ICU stay, d			.682
1	134 (59.8%)	127 (56.7%)
2	39 (17.4%)	46 (20.5%)
≥3	51 (22.8%)	51 (22.8%)
Cardiac death	0 (0.0%)	3 (1.3%)	.247
Overall death	4 (1.8%)	3 (1.3%)	1

VF: ventricular fibrillation; AV-block: atrioventricular block; CK-MB: creatine kinase (MB isoenzyme); EF: ejection fraction; RBC: red blood cell.

Subgroup analysis showed that for patients who experienced AF events, the treatment had a protective effect in subgroups with CPB ≤180 min, cross-clamp time ≤120 min, low-risk Euroscore II, aortic root formation and combined valve replacement or repair. There were no significant differences among the other subgroups. For patients who experienced delirium events, treatment had a protective effect in subgroups with CPB >180 min, cross-clamp time >120 min and low-risk Euroscore II. There were no significant differences among the other subgroups (Figures 3 and 4).

Discussion

The most common arrhythmia following cardiac surgery is AF. Patients who develop AF after cardiac surgery are at increased risk of stroke, congestive heart failure, and haemodynamic instability. Additionally, rhythm disturbances can delay postoperative recovery and significantly increase ICU stay, hospitalisation time, and medical costs.^13,14 A study by Comentale¹⁵ on the incidence of postoperative AF in patients undergoing coronary artery bypass grafting using del Nido cardioplegia showed a significant reduction in AF occurrence in the del Nido-administered group. The results of those studies suggest that del Nido cardioplegia has a positive effect on reducing postoperative AF in cardiac surgery. On the other hand, alpha-2 adrenergic agonists, by increasing cAMP levels and enhancing adenosine-induced coronary vasodilation, have a protective effect against myocardial ischaemia.^16–18 Preconditioning with dexmedetomidine has been shown to attenuate myocardial ischaemia/reperfusion injury by activating pro-survival kinases.¹⁹ Lancaster et al.²⁰ reported a retrospective analysis of postoperative data from >1700 patients that indicated an association between increased incidence of postoperative AF and decreased serum magnesium-ion concentration and increased potassium-ion concentration.^21,22 Our study showed that the potassium-ion concentration during surgery was lower in the treatment group than in the control group, which may have contributed to the reduced incidence of postoperative AF. However, there was no significant reduction in AF occurrence when dexmedetomidine combined with del Nido cardioplegia was administered to patients with prolonged aortic cross-clamp time. This finding can be attributed to the accumulation of excessive oxygen-free radicals due to myocardial ischaemia and hypoxia in the patients with prolonged aortic cross-clamp time, resulting in more severe ischaemia–reperfusion injury.^23–25

Surgery and trauma activate the sympathetic nervous system, which can affect central nervous system function. Pro-inflammatory cytokines have a crucial role in mediating surgery-induced neuroinflammation and postoperative cognitive changes, and dexmedetomidine has been shown to alleviate neurocognitive impairment and reduce the incidence of delirium.^26,27 In a multicentre ICU sedation study, patients treated with dexmedetomidine had fewer delirium events.²⁸ Our study showed that the combined use of del Nido cardioplegia and dexmedetomidine significantly reduced the incidence of delirium within 5 days after surgery. The reduction in delirium occurrences was particularly significant in the subgroup of patients with prolonged CPB time and aortic cross-clamp time. This finding can be attributed to the cumulative effect of repeated administration of del Nido cardioplegia containing lidocaine. Lidocaine in del Nido is a sodium-channel blocker and class Ib antiarrhythmic agent, which has an effect on the membrane stability of neuronal cells and stabilization of cardiac rhythm.^29,30 In our study, significantly higher heart rhythm recovery time and temporary pacemaker utilization rate after aortic opening were observed in the treatgroup than in the control group, possibly indicating the influence of lidocaine and dexmedetomidine on cardiac rhythm.³¹ Lidocaine may induce bradycardia in individuals with sinoatrial or atrioventricular node dysfunction. Dexmedetomidine exerts its effects by activating central α2-adrenergic receptors, thereby suppressing sympathetic nervous system activity and reducing ectopic excitability in atrial myocytes. However, high doses of dexmedetomidine may exacerbate atrioventricular block, particularly in patients with pre-existing first- or second-degree AV block. Therefore, the combination of del Nido and dexmedetomidine may have an effect on the recovery of cardiac rhythm.

Myocardial injury is one of the most common complications after cardiac surgery and is associated with increased mortality rates.^32,33 Although elevated levels of CK-MB have traditionally been used to define myocardial injury after cardiac surgery, the current consensus statements have recommended high-sensitivity cardiac troponin as the preferred biomarker.³⁴ The Academic Research Consortium-2 consensus document states that there is no established evidence-based threshold for post-coronary artery bypass graft myocardial troponin levels, but it supports setting the diagnostic threshold for myocardial infarction at 35 times the upper reference limit, taking into consideration new ischaemic evidence.³⁵ Furthermore, the consensus defines a threshold of 70 times the upper reference limit as an independent standard for clinically significant perioperative myocardial injury. Our study found that the peak value of cardiac troponin T occurred within 24 h postoperatively, with an increase of 100–150 times relative to the baseline level, with no differences observed at all time points. There were no significant differences in the other indicators related to myocardial injury and postoperative recovery, such as the incidence of ventricular fibrillation, proportion of left-ventricular ejection fraction reduction >5%, ICU stay duration, and all-cause mortality. Therefore, there were no significant differences in surgical safety indicators between the combination of dexmedetomidine and del Nido cardioplegia.

This clinical study had certain limitations. Due to significant differences in clinical practices between the two groups, complete double-blind randomization was unattainable, which may have influenced the execution of certain clinical decisions. In addition, our clinical trial was conducted within a healthcare setting in a specific region, potentially limiting the universal applicability of the research outcomes. Furthermore, variations in patients’ analgesic and sedative requirements exerted a potential influence on the outcomes of our study. Therefore, more robust experimental designs are needed to explore the clinical effects of combining del Nido cardioplegia and dexmedetomidine.

Conclusion

This study showed that the combination of del Nido cardioplegia and dexmedetomidine was safely used in cardiac surgery with CPB and reduced the incidence of postoperative AF and delirium. In the future, we intend to conduct multicenter trials or studies with different patient populations to confirm the findings.

Footnotes

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.

ORCID iD

Xiaoyu Zhou

References

Rezaei

Peighambari

Naghshbandi

, et al. Postoperative atrial fibrillation following cardiac surgery: from pathogenesis to potential therapies. Am J Cardiovasc Drugs 2020; 20: 19–49.

Sanson

Khlopenyuk

Milocco

, et al. Delirium after cardiac surgery. Incidence, phenotypes, predisposing and precipitating risk factors, and effects. Heart Lung 2018; 47: 408–417.

Keating

. Dexmedetomidine: a review of its use for sedation in the intensive care setting. Drugs 2015; 75: 1119–1130.

Ueki

Kawasaki

Habe

, et al. The effects of dexmedetomidine on inflammatory mediators after cardiopulmonary bypass. Anaesthesia 2014; 69: 693–700.

Duan

Coburn

Rossaint

, et al. Efficacy of perioperative dexmedetomidine on postoperative delirium: systematic review and meta-analysis with trial sequential analysis of randomised controlled trials. Br J Anaesth 2018; 121: 384–397.

Turan

Duncan

Leung

, et al. Dexmedetomidine for reduction of atrial fibrillation and delirium after cardiac surgery (DECADE): a randomised placebo-controlled trial. Lancet 2020; 396: 177–185.

Rasool Khalid

Ahmad

Mughal

. Del Nido Cardioplegia for patients of adult congenital heart disease. TPMJ 2022; 29: 1620–1624.

Rahman

Tam

, et al. A systematic review and meta-analysis of del Nido versus conventional cardioplegia in adult cardiac surgery. Innovations 2019; 14: 385–393.

Sevuk

Dursun

. Tepid modified del Nido cardioplegia in adults undergoing cardiac surgery: a PropensityMatched analysis. Braz J Cardiovasc Surg 2022; 37: 793–800. DOI: 10.21470/1678-9741-2020-0422.

10.

Astrup

Sørensen

. Inhibition of cerebral metabolism by lidocaine. Eur Neurol 1981; 20: 221–224.

11.

Nashef

SAM

Roques

Sharples

, et al. EuroSCORE II. Eur J Cardio Thorac Surg 2012; 41: 734–744.

12.

Sessler

Gosnell

Grap

, et al. The Richmond agitation–sedation scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med 2002; 166: 1338–1344.

13.

Kron

Tan

. Preventing postoperative atrial fibrillation: a stimulating new approach. Circ Arrhythm Electrophysiol 2019; 12: e007865.

14.

Rho

. The management of atrial fibrillation after cardiac surgery. Heart 2008; 95: 422–429.

15.

Comentale

Parisi

Fontana

, et al. The role of Del Nido cardioplegia in reducing postoperative atrial fibrillation after cardiac surgery in patients with impaired cardiac function. Heart Lung 2023; 60: 108–115.

16.

Liang

Dai

, et al. Perioperative dexmedetomidine reduces delirium after cardiac surgery: a meta-analysis of randomized controlled trials. J Clin Anesth 2018; 50: 33–42.

17.

Deiner

Luo

Lin

H-M

, et al. Intraoperative infusion of dexmedetomidine for prevention of postoperative delirium and cognitive dysfunction in elderly patients undergoing major elective noncardiac surgery: a randomized clinical trial. JAMA Surg 2017; 152: e171505.

18.

Nguyen

Huyghens

Parra

, et al. Hypotension and a positive fluid balance are associated with delirium in patients with shock. PLoS One 2018; 13: e0200495.

19.

Wesselink

Kappen

Van Klei

, et al. Intraoperative hypotension and delirium after on-pump cardiac surgery. Br J Anaesth 2015; 115: 427–433.

20.

Lancaster

Schill

Greenberg

, et al. Potassium and magnesium supplementation do not protect against atrial fibrillation after cardiac operation: a time-matched analysis. Ann Thorac Surg 2016; 102: 1181–1188.

21.

Diao

Dai

Wurm

, et al. Del Nido cardioplegia or potassium induces Nrf2 and protects cardiomyocytes against oxidative stress. Am J Physiol Cell Physiol 2023; 325: C1401–C1414.

22.

Osawa

Biesenbach

Cutuli

, et al. Magnesium sulfate therapy after cardiac surgery: a before-and-after study comparing strategies involving bolus and continuous infusion. Crit Care Resusc 2018; 20: 209–216.

23.

Dambrova

Zuurbier

Borutaite

, et al. Energy substrate metabolism and mitochondrial oxidative stress in cardiac ischemia/reperfusion injury. Free Radic Biol Med 2021; 165: 24–37.

24.

Bertero

Maack

. Calcium signaling and reactive oxygen species in mitochondria. Circ Res 2018; 122: 1460–1478.

25.

Wang

, et al. Targeting calcium homeostasis in myocardial ischemia/reperfusion injury: an overview of regulatory mechanisms and therapeutic reagents. Front Pharmacol 2020; 11: 872.

26.

Zhai

Kang

Han

, et al. The effect of dexmedetomidine on renal function in patients undergoing cardiac valve replacement under cardiopulmonary bypass: a double-blind randomized controlled trial. J Clin Anesth 2017; 40: 33–38.

27.

Peng

Applegate

, et al. Effect of dexmedetomidine on cardiac surgery-associated acute kidney injury: a meta-analysis with trial sequential analysis of randomized controlled trials. J Cardiothorac Vasc Anesth 2020; 34: 603–613.

28.

Guimarães-Pereira

Reis

Abelha

, et al. Persistent postoperative pain after cardiac surgery: a systematic review with meta-analysis regarding incidence and pain intensity. Pain 2017; 158: 1869–1885.

29.

Aronowitz

Bocchieri

Hartman

, et al. Serum lidocaine levels in adult patients undergoing cardiac surgery with del Nido cardioplegia. Ann Thorac Surg Short Rep 2024; 2: 302–305.

30.

Zhang

Foo

. Is intravenous lidocaine protective against myocardial ischaemia and reperfusion injury after cardiac surgery? Ann Med Surg 2020; 59: 72–75.

31.

Franko

Parsons

, et al. Adenosine, lidocaine, and magnesium for attenuating ischemia reperfusion injury from resuscitative endovascular balloon occlusion of the aorta in a porcine model. J Trauma Acute Care Surg 2022; 92: 631–639.

32.

Paparella

Guida

Caparrotti

, et al. Myocardial damage influences short- and mid-term survival after valve surgery: a prospective multicenter study. J Thorac Cardiovasc Surg 2014; 148: 2373–2379.

33.

Alpert

. The fourth edition of the universal definition of myocardial infarction. Am J Med 2018; 131: 1265–1266.

34.

Thygesen

Alpert

Jaffe

, et al. Fourth universal definition of myocardial infarction (2018). Circulation 2018; 138: e618–e651. DOI: 10.1161/CIR.0000000000000617.

35.

Garcia-Garcia

McFadden

Farb

, et al. Standardized end point definitions for coronary intervention trials: the academic research consortium-2 consensus document. Circulation 2018; 137: 2635–2650.