Congenital heart disease (CHD) is the leading cause of congenital abnormality at birth, with an estimated worldwide incidence ranging from 4 to 8 per 1000 live births [1]. CHD poses great challenges and is a growing health burden on the quality of life and development of children, their families and society. In recent decades, the incidence of CHD has increased due to environmental pollution and to the increasing number of elderly puerperal [2]. The notable progress in cardiac surgery technology has led to a significant increase in CHD surgery in China to about 40,000 cases per year. The primary therapy to correct CHD is surgical operation performed under general anesthesia. However, infants have poor tolerance to anesthesia due to their light weight, immature development of organs, and imperfect compensatory functions [3]. These factors can lead to serious cardiovascular morbidity and mortality in infancy. The long-term effects of intraoperative anesthesia on important organs and on systemic development are still being hotly debated by clinicians.

Although dexmedetomidine is not approved by the Food and Drug Administration (FDA) for children, it has found a role as an attractive anesthetic adjuvant during CHD surgery in pediatric patients because of its sedative effects and cardiopulmonary profile [4]. Numerous studies have described the clinical effectiveness of dexmedetomidine therapy during congenital heart surgery and in the cardiac intensive care unit (ICU) [5]. Dexmedetomidine has been widely used to simultaneously provide effective sedation, anxiolysis, and to relieve the adverse effects of mechanical ventilation [6]. Moreover, prophylactic and postoperative medication with dexmedetomidine can be used to maintain hemodynamic stability [7] and reduce the intraoperative stress hormone response [8].

There are however potential adverse events from the use of dexmedetomidine for cardiovascular and respiratory effects. The most common clinical presentations of adverse hemodynamic events are bradycardia and hypotension, which occur during the initial loading dose with conduction abnormalities [9, 10]. Nevertheless, these are generally considered to be self-limiting and typically have no clinical significance [11].

A previous study suggested that intraoperative dexmedetomidine could improve survival in adult patients undergoing cardiac surgery [12]. However, adults are physiologically very different to infants, meaning this outcome cannot be extended to infants. So far, no studies have to our knowledge reported the impact of dexmedetomidine on long-term outcomes in pediatric cardiac patients.

In the present study we have retrospectively evaluated the effect of intraoperative dexmedetomidine infusion on outcomes in pediatric cardiac patients.

This single-center, retrospective study examined 1480 consecutive children who underwent pediatric cardiac surgery from January 1st, 2014 to December 31st, 2015.

Children who underwent open-heart surgery for CHD were included in the study. To be eligible, they were required to be younger than 12 months, weigh $\ge$2.5 kg, and be scheduled for elective cardiac surgery with cardiopulmonary bypass. The exclusion criteria were emergency surgery, significant neurological disorders that prevented accurate titration of sedative and analgesic agents, history of preoperative serious arrhythmia (ventricular fibrillation, third-degree atrioventricular block), or underwent several staging surgeries in one admission. A total of 1384 children were finally included in the study, of which 889 received dexmedetomidine during the intraoperative period and 495 did not. Data was collected for patient characteristics, medical history, preoperative medications, procedural characteristics, and clinical outcomes.

To our knowledge, this is the first study to evaluate the long-term safety and efficacy of dexmedetomidine for children undergoing pediatric cardiac surgery. We found that intraoperative dexmedetomidine infusion was associated with lower 30-day (1.57% vs. 4.24%) and 1-year (2.36% vs. 6.67%) postoperative mortality in consecutive cases of children undergoing pediatric cardiac surgery. Our results also suggest that intraoperative dexmedetomidine infusion can reduce the incidence of cardiac arrest after surgery, and significantly improve intraoperative urine output.

Approximately 30–50% of infant mortality is due to CHD, despite significant improvements in surgery, anesthesia and ICU management [13]. Many more patients also suffer complications such as arrhythmia, neurologic dysfunction, renal injury, prolonged mechanical ventilation, and reoperation.

Although dexmedetomidine does not have FDA approval for use in pediatric patients, it is used with increasing frequency as an anesthetic adjuvant in children undergoing surgery for CHD [8]. Dexmedetomidine has sedative effects without causing significant respiratory depression, thus alleviating the use of opioids and benzodiazepines. This pharmacological profile can lead to better patient-ventilator interaction and less delirium [6, 14]. In addition, experimental studies have shown that dexmedetomidine has organ protective effects [15]. The clinical benefits of dexmedetomidine in adults are widely recognized. Previous studies in adult patients undergoing cardiac surgery have shown that intraoperative dexmedetomidine infusion was associated with improved 1-year postoperative survival and less overall postoperative complications [12]. Our earlier study found that intraoperative dexmedetomidine administration could reduce postoperative atrial fibrillation in adults [16]. However, adults are physiologically different to children with CHD, and hence these findings cannot be extrapolated to children. So far, no studies have to our knowledge reported the impact of intraoperative dexmedetomidine infusion on long-term outcomes following pediatric cardiac surgery, especially in infants.

In the largest study to date, analysis of a CHD database by the congenital cardiac anesthesia society-society of thoracic surgeons (CCAS-STS) found that dexmedetomidine was preferentially used in older or larger infants undergoing less complex CHD surgery [17]. However, the conclusion that dexmedetomidine improved outcomes in children with CHD could not be drawn, since no adjustment was made for confounding variables. In the present study, patients who underwent CHD surgery were younger than 12 months. Our results showed that intraoperative dexmedetomidine was associated with reduced short- (30 days) and long-term (1-year) mortality rates in infants undergoing CHD surgery.

This study also found that dexmedetomidine provided significant benefits against cardiac arrest. In animal studies, post-conditioning with dexmedetomidine improved post-resuscitation cardiac and neurological outcomes in a dose-dependent manner by inhibiting tissue inflammation, oxidative stress, cell apoptosis and necroptosis [18]. Studies have also shown that dexmedetomidine has a protective effect on the myocardium. $\alpha$${}_2$-adrenergic agonists are known to have a protective effect on myocardial ischemia by increasing cAMP levels and enhancing adenosine-induced coronary vasodilatation. Preconditioning with dexmedetomidine has been shown to attenuate myocardial ischemia/reperfusion injury by activating pro-survival kinases [19, 20]. Both preconditioning and postconditioning with dexmedetomidine can therefore effectively protect the heart and brain from ischemia-reperfusion injury [21, 22].

In agreement with a previous report [23], the current study found that intraoperative urine output was higher during dexmedetomidine infusion. Experimental animal studies have shown that dexmedetomidine may induce free-water diuresis and micturition by inhibiting neuronal signaling in large cells of the paraventricular nucleus in the hypothalamus [24]. Dexmedetomidine can also decrease the level of a kidney injury marker [25]. These actions may protect the kidneys during ischemic events.

Several statistical methods were used to adjust for patient characteristics and clinical risk factors. Multiple logistic-regression analysis and Cox regression analysis were used to provide comprehensive comparisons of the treatment groups. In addition, the PSM approach was used to estimate the two derived groups, and all baseline covariates between the two groups were balanced.

This study has some limitations. First, it was a retrospective and non-randomized study performed at a single center. Second, many dates were abandoned in PSM analysis because the two groups were unmatched. Third, although PSM analyses were carried out to reduce selection bias between two groups, potential flaws may still exist in this nonrandomised study. Every patient did receive dexmedetomidine in the post-operative period, we just analysis intraoperative dexmedetomidine to the outcomes. Further high-quality, multicenter randomized controlled trial (RCT) are required to confirm the beneficial effects of dexmedetomidine in pediatric patients undergoing heart surgery for CHD.

Intraoperative administration of dexmedetomidine reduces short- and long-term mortality in children undergoing pediatric cardiac surgery.

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

JM designs the work. HA interprets the data of the work. FX, LL, YY and WL made substantial contributions to the conception and design, acquisition of data, analysis and interpretation of data. FX and LL draft the manuscript; YY and WL revise it critically for important intellectual content. JM and HA were involved in drafting the manuscript and revising it critically for important intellectual content. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The Beijing Anzhen Hospital ethics committee approved this study (Approval No. 2022122X). Exemption from informed consent for retrospective study.

Not applicable.

This work was supported by a grant from the National Natural Science Foundation of China (No. 81871592).

The authors declare no conflict of interest. Hushan Ao is serving as Guest Editor of this journal. We declare that Hushan Ao had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Vincenzo Lionetti.