Introduction
Congenital heart disease (CHD) is the commonest birth defect worldwide, affecting millions of newborns annually [
1‐
3]. The actual prevalence is difficult to determine because not all patients with CHD are diagnosed early. A recent systematic review integrating 260 studies showed that the birth prevalence of CHD globally continued to rise between 1970 and 2017, increasing by 10% every 5 years [
4]. With the improvement of medical technology, anesthesia, and extracorporeal circulation, the diagnosis and treatment of CHD have become increasingly sophisticated, and the types of diseases treated have gradually become more complex. Surgery is still the most important and effective treatment for children with CHD, which improves the survival rate of children but may also bring a series of postoperative complications [
5]. Delirium is one of the common postoperative complications, with an incidence rate of 9.8%-68% in children undergoing cardiac surgery [
6‐
8]. It is currently receiving increasing attention from the medical community.
Delirium is a manifestation of the acute cerebral dysfunction and is characterized by five features: (1) disturbance in attention and awareness; (2) development over a short period and fluctuating in severity throughout the day; (3) additional disturbances in cognition, such as memory deficit or disorientation; (4) the disturbances in attention, awareness, and cognition not being explained by a known or developing neurocognitive disorder; and (5) history, physical examination, or laboratory findings showing evidence of the disturbances being a direct physiological consequence of one or more etiologies [
9]. Despite its typically transient nature, delirium is strongly associated with adverse outcomes, including prolonged hospitalization, increasing potential mortality, impact on prognosis, causing long-term cognitive dysfunction, and differentially affecting the quality of life of the child after discharge from the hospital [
10‐
13]. From an economic perspective, the diagnosis of delirium in children increases medical and healthcare costs [
14]. Therefore, prevention has emerged as a pivotal focus of current clinical research.
Identifying risk factors for delirium is crucial for its early identification and prevention, which can effectively decrease its incidence in children. However, there is limited research on delirium after cardiac surgery in children, and the independent risk factors for delirium varied in previous studies. The risk factors and prevalence of delirium have yet to be well established. Therefore, this study aimed to determine the potential risk factors and prevalence of delirium after cardiac surgery in children, to provide a reference for the early clinical identification of high-risk groups, and the implementation of effective prevention and management.
Discussion
Our study was the first systematic review of risk factors for delirium after cardiac surgery in children. Based on the inclusion of 12 studies in the current meta-analysis, involving a total of 1976 patients, the pooled prevalence of delirium is 39.0%. By conducting a qualitative synthesis of 39 predictors and a quantitative meta-analysis of 13 factors, we identified two definite factors, four possible factors, and 32 unclear factors related to delirium. The definite factors included age and mechanical ventilation duration, while the possible factors included developmental delay, cyanotic heart disease, CPB time, and pain score. The results of our systematic review present an up-to-date comprehensive summary of the latest evidence, which can provide information for early identification of high-risk delirium after pediatric cardiac surgery and the development of interventions to reduce and prevent delirium.
The pathophysiology of delirium is not fully understood, but several theories have been put forth to explain the neuropsychiatric disturbances. Possible etiologic factors include brain changes revealed by neuroimaging, sepsis-related inflammation, genetics, biomarkers, and neurotransmitters [
28‐
30]. The incidence of delirium in children after cardiac surgery is generally higher than in the group of nonsurgical children in the intensive care unit, which may be attributed to the correlation between the severity of the disease and delirium in children [
31]. In comparison to nonsurgical critically ill children, children who undergo cardiac surgery exhibit more pronounced characteristics of critical illness, including specific risks such as preoperative hypoxemia, neurodevelopmental abnormalities, fluid overload, electrolyte disorders, and hypothermia [
32]. Additionally, the extracorporeal circulation techniques commonly employed in pediatric cardiac surgery may induce extensive endothelial cell activation, systemic inflammatory response, and thromboembolic events [
33], which in turn lead to brain damage and inflammation, hence the higher incidence of delirium in children after cardiac surgery [
10,
22,
34]. Delirium can lead to prolongation of hospitalization, increased healthcare costs, impaired cognitive function, and higher mortality, causing immediate and long-term harm to patients. Hence, early identification of delirium helps healthcare professionals to take preventive and therapeutic measures as early as possible to reduce the adverse effects of delirium.
Our findings align with previous research indicating that age is the most critical risk factor affecting delirium [
6,
7,
10,
19,
20,
22]. The younger the age, the higher the likelihood of delirium. Maldonado proposed a related neuropathological hypothesis known as neuronal aging [
35], whereby changes in intracellular signaling, stress-regulated neurotransmitters, and cerebral blood flow all lead to neuronal loss. The hypothesis may have a counterpart at the other extreme of age, a fragile immaturity hypothesis. Considering the infant brain, continuous central nervous system (CNS) regional development, neurogenesis, migration, synaptogenesis, and myelination reflect the immaturity of the CNS. These developing brains may exhibit heightened vulnerability to delirium due to the impact of stress and disease. Further research is still needed to explore the pathophysiology of delirium in young children and the impact of delirium on their long-term neuropsychiatric health.
Developmental delay was identified as a possible risk factor for delirium. Children with developmental delay in the CNS are more susceptible to the effects of cardiac bypass, anesthesia, and surgery [
22]. Furthermore, due to the challenge faced by evaluators in determining whether the level of consciousness and cognition of children with developmental delays is altered compared to their baseline conditions, more precise tools are needed to assess the interaction between developmental delay and delirium. Lyu et al. [
19]. demonstrated that the risk of delirium in male children was 2.127 times higher than in female children. Similarly, a study by Alvarez et al. [
10] indicated a higher probability of delirium in male children. However, other studies have not found a significant association between gender and the occurrence of delirium [
6,
8,
18,
22,
24]. Moreover, the European Society of Anesthesiology evidence-based and consensus guidelines on postoperative delirium do not recommend gender as a risk factor for delirium [
36]. Therefore, further research is warranted to expand the scope of studies and explore the relationship between gender and delirium.
Diseases and adverse conditions are not only the major cause of prolonged hospitalization and even death in children but may also be important risk factors for delirium. The increased risk of delirium in children with cyanotic heart disease may be due to the effects of prolonged chronic hypoxia, oxidative stress, blood transfusions, and poor nutritional status, all of which may independently act as predisposing factors for delirium [
37,
38]. The majority of patients admitted to the pediatric cardiac intensive care unit (PCICU) after cardiac surgery are under 3 years of age [
39], an age when neurocognitive development is rapid and healthy sleep is critical. Sleep disturbances are recognized as a potential risk factor for the development of delirium, and children with delirium frequently exhibit disrupted sleep patterns. Data from a study by Gregory et al. suggested that the majority of children in the PCICU had severe sleep disturbances [
18]. It is necessary to further explore the importance of improving postoperative sleep status in children undergoing cardiac surgery, as well as the feasibility of continuous dynamic monitoring of sleep in the ICU environment. In addition, one study showed that preoperative lung infections and postoperative complications were risk factors for delirium [
7], with the possible explanation of these exacerbating the severity of the disease. The more severe the patient's condition, the higher the risk of postoperative delirium [
40]. Therefore, it is important to promptly treat preoperative infections and minimize the risk of complications, as this may help prevent delirium.
CPB is a form of assisted circulation specific to cardiac surgery, but this process is non-physiological. Non-pulsatile blood flow affects cerebrovascular autoregulation and interferes with matching cerebral blood flow to metabolism. Hypothermia during CPB is unfavorable for oxygen release. During the warming period, the metabolism of the brain accelerates and the demand for oxygen in the brain increases [
41,
42]. Alvarez's study found that children with delirium had longer CPB durations [
10], which aligns with the findings of Yang et al. [
7]. In addition, pediatric cardiac surgery patients often require postoperative mechanical ventilation, prolonged analgesia, and sedation to improve the safety of tracheal intubation. However, prolonged and continuous mechanical ventilation increases the risk of low cardiac output syndrome, respiratory failure, and severe insufficiency of cerebral blood supply in children [
43], resulting in a greater susceptibility to delirium. This suggests that we should make adequate preoperative preparations for children undergoing CPB to minimize the CPB time, the duration of mechanical ventilation, and the occurrence of various complications.
Accurate selection and evaluation of the appropriate dosage of sedative and analgesic medications are particularly crucial in children at high risk for delirium [
42]. A planned sedation and analgesia regimen can reduce the likelihood of delirium to some extent. In recent years, dexmedetomidine (Dex) has been increasingly used in children [
23,
44,
45]. Dex, a selective alpha-2-adrenergic receptor agonist with sedative, anxiolytic, and analgesic effects without causing significant respiratory depression, has been recommended by the Society of Critical Care Medicine as the primary sedative for critically ill pediatric postoperative cardiac surgical patients [
46]. A growing body of research supports that Dex is less likely to induce delirium compared to benzodiazepines [
23,
47‐
49]. However, intravenous infusion of Dex may lead to dose-dependent hypotension and bradycardia due to its potential sympathetic activity [
50]. In addition, given the limited high-quality evidence available, there is an urgent need for more high-quality randomized controlled trials (RCTs) to further define the short- and long-term safety and feasibility of Dex for pediatric cardiac surgery.
Pain score is recognized as a possible risk factor. Lyu et al.’s study demonstrated that the risk of delirium in children with moderate to severe postoperative pain was 5.856 times higher than that of children with no pain and mild pain [
19]. Previous studies have also indicated that relieving postoperative pain can effectively prevent and treat delirium during postoperative awakening in pediatric patients [
51,
52]. The mechanism remains unclear and may be related to the fact that the pain-induced stress response produces persistently high levels of cortisol, which impairs the function of the central nervous system and thus causes delirium [
53]. Disease severity also directly affects the incidence of delirium and serves as an independent risk factor [
12,
54‐
56]. There are many measures of disease severity in children, and commonly used ones include the Risk Adjustment in Congenital Heart Surgery-1 (RACHS-1) score, the Society of Thoracic Surgeons and the European Association for Cardiothoracic Surgery Congenital Heart Surgery Mortality (STS-EACTS) Score and Pediatric Risk of Mortality (PRISM) III. In the study by Patal et al., children with a RACHS-1 score of 2 accounted for 40% of the total number of children with delirium and were usually associated with multiorgan dysfunction [
22]. Similarly, Mao et al. utilized (PRISM) III to assess the severity of a child's condition and observed a positive correlation between higher scores and an increased likelihood of developing delirium [
20].
The strengths of this systematic review include the systematic approach to identifying all publications containing risk factors for delirium after pediatric cardiac surgery and the division of risk factors into four major categories to provide a logical progression of possible factors of delirium. Nevertheless, the results of this systematic review and meta-analysis must take into account several limitations. First, the vast majority of studies were single-center studies, and most were conducted in the United States and China, which may limit their generalizability. Second, there is a lack of standardization in screening for delirium, and the CAPD is usually done by day shift nurses. Consequently, children with nighttime-only delirium may go undetected, which may lead to an underestimate of the true incidence and duration of delirium. Furthermore, despite the comprehensive and rigorous search strategy employed, it is possible that some studies may have been inadvertently overlooked. Lastly, and most importantly, our pooled analyses describe associations between specific factors and the odds of developing delirium, but these observations do not establish causality.
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