A review on neurodevelopmental abnormalities in congenital heart disease: focus on minimizing the deleterious effects on patients

Abstract

Due to the surgical procedures, the longevity of congenital heart patients is dramatically increased; however, these patients suffer from concomitant neurodevelopment abnormalities, which include deficits in cognitive, executive and behavioral functions. There are more chances of seizure development and incidences of ischemic stroke in these children. Indeed, there are pathological changes in the brain, which include a reduction in the volume of the brain, metabolic alterations, alterations in the functional connectivity, dysregulation of angiogenesis and changes in the apparent axon density along with orientation dispersion. The management of neural abnormalities depends on the type of symptoms observed in these patients. There have been limited studies that have focused on identifying the interventions that may limit the impact of neurodevelopmental abnormalities. It has been reported that dexmedetomidine, α₂-adrenergic receptor agonist, produces neuroprotection in infants undergoing surgery for congenital heart disease. Moreover, there have been some studies focusing on the impact of mode of feeding, anticoagulation, and effect of other anesthetics on the neurodevelopmental changes in congenital heart disease pediatrics. The present review discusses the neurodevelopment abnormalities in congenital heart disease pediatrics with a focus on different interventions that have been explored by different scientists to limit the deleterious effects on the patients.

KEYWORDS:

• Neurodevelopment
• dexmedetomidine
• cognition
• congenital heart disease
• angiogenesis
• anesthetic

Introduction

Congenital heart diseases are the functional and structural changes in the heart, circulatory system, or large vessels, which develop during cardiac embryogenesis. Congenital heart defects are the most common congenital anomalies, including aortic valve stenosis, coarctation of the aorta, patent ductus arteriosus, pulmonary valve stenosis, septal defects, single ventricle defects, tetralogy of Fallot and transposition of the great arteries (Garcia and Peddy 2018; Tassinari et al. 2018). These defects are significant causes of morbidity and mortality in children worldwide. However, with the advent of surgical procedures, the longevity of these patients is dramatically increased. However, these patients suffer from concomitant neurodevelopment abnormalities, which persist for the whole life (Peyvandi et al. 2019). From the data of 25, 985 Swedish children and young adults with congenital heart disease, it was found that patients with congenital heart disease have about 11 fold greater risk of development of ischemic stroke in comparison to the normal population (Mandalenakis et al. 2016).

Moreover, the deficits in cognitive, executive, communication, and behavioral functions are very common in these patients (Jakab et al. 2019; White et al. 2019). The neurodevelopment abnormalities observed in congenital heart disease patients are due to the impairment in brain maturation (Morton et al. 2017) and pathological alterations in the brain (Mebius et al. 2017). These pathological changes are reduction in the total volume of the brain, white brain and hippocampus (von Rhein et al. 2014; Rollins et al. 2017); metabolic changes (Vedovelli et al. 2019); functional connectivity between different portions of the brain (De Asis-Cruz et al. 2018) and changes in the apparent axon density and orientation dispersion (Easson et al. 2020).

Accordingly, it is suggested that there is a need for follow-up and application of early intervention following surgery to limit the neurodevelopment abnormalities (Butler et al. 2019). The management of these abnormalities is dependent on the type of symptoms observed in these patients. However, there have been few studies that have focused on identifying the interventions that may limit the impact of neurodevelopmental abnormalities. It has been reported that dexmedetomidine, α₂-adrenergic receptor agonist, produces neuroprotective effects in infants undergoing surgery for congenital heart disease (Schwartz et al. 2016). Moreover, there have been few studies focusing on the impact of mode of feeding (Holst et al. 2019), anticoagulation (Leijser et al. 2019) and the effect of other anesthetics (Fleck et al. 2015) on the neurodevelopmental changes in congenital heart disease pediatrics (Table 1). The present review discusses the neurodevelopment abnormalities in congenital heart disease pediatrics with a focus on different interventions that have been explored by different scientists to limit the deleterious effects on the patients.

Table 1. Summarized findings of different interventions on neurodevelopmental abnormalities in children undergoing heart surgery.

S. No	Interventions	Type of study	Results	References
Non-Pharmacological Interventions
1.	Feeding Mode	Retrospective cohort study (n = 208)	Lesser neurodevelopment delay in orally fed children in comparison to enteral tube-fed children	Holst et al. (2019)
2.	Feeding Mode	Retrospective cohort study (n = 194)	Infants on oral feedings developed lesser neurodevelopmental impairment in comparison to infants on G-tube feedings	Jadcherla et al. (2017)
Pharmacological Interventions
3.	Dexmedetomidine	Retrospective cohort study (n = 12,142)	Patients had improved outcomes in patients receiving dexmedetomidine	Schwartz et al. (2016)
		Randomized, single-blind study (n = 80)	Decreased levels of neuron-specific enolase and S-100β protein along with improvement in oxygen metabolism suggesting reduced brain injury	Gong et al. (2019)
		Retrospective study (n = 256)	Significant preservation of intelligence quotient and neurodevelopment undergoing surgery	Huang et al. (2020)
4.	Erythropoietin	Prospective phase I/II clinical trial (n = 42)	No neurological protection from erythropoietin	Andropoulos et al. (2013)
5.	Ketamine	Randomized clinical study (n = 24)	No significant differences in the expression of cytokines, chemokines, S100, and neuron-specific enolase between ketamine-treated and placebo	Bhutta et al. (2012)
6.	Dextromethorphan	Randomized, placebo-controlled trial (n = 13)	Treatment with dextromethorphan exhibited fewer brain abnormalities, however, the effects were not significantly different in comparison to placebo	Schmitt et al. (1997)
7.	Allopurinol	Single centered, randomized, placebo-controlled, blinded trial	Ketamine produced neuroprotection in higher-risk HLHS patients without any significant effect in lower risk, non-HLHS infants	Clancy et al. (2001)
8.	Anticoagulants	Two-center, observational cohort study (n = 118)	No benefit of preventing brain injury with the use of anticoagulation	Leijser et al. (2019)

Methodology

The literature to write this review was collected using ‘PUBMED’ ‘EMBASE’ and ‘Google Scholar’ using different keywords including ‘congenital heart disease’ ‘neurodevelopmental abnormalities’, ‘infants’ ‘children’ ‘cardiac surgery’, and ‘neuroprotection’.

Neurodevelopmental abnormalities in congenital heart disease infants

Diverse range of abnormalities related to brain functioning

It is very well reported that infants with congenital heart disease exhibit a wide range of neurodevelopmental abnormalities, including deficits in language, executive function and behavioral abnormalities (Peyvandi et al. 2019; White et al. 2019). Executive function impairments are among the most prevalent neurodevelopmental morbidities in youth with congenital heart disease (Nattel et al. 2017; Calderon et al. 2019). Children and adolescents with congenital heart disease (CHD) are at risk for mild to moderate cognitive impairments. In particular, impaired working memory performance has been found in CHD patients of all ages (Ehrler et al. 2020). The disrupted or delayed maturation of white matter may persist into adolescence and is associated with working memory impairments, particularly if present in the frontal lobe (Ehrler et al. 2020). Furthermore, cerebral injury in the form of arterial ischemic strokes, white matter injury, subdural hemorrhage and intracranial hemorrhage is also common in pediatric children suffering from congenital heart disease (Kelly et al. 2019). Furthermore, children with complex congenital heart disease experience a high incidence of perioperative seizures (Desnous et al. 2019).

Pathological changes in the brains of newborns with congenital heart disease

The neurodevelopment abnormalities in congenital heart disease infants have been attributed to pathological alterations in the brain of these patients (Mebius et al. 2017). Most of the studies have focused on the decrease in the volume of the brain or its different portions. A significant decrease in the hippocampal volumes in congenital heart disease patients has been identified, which is negatively correlated with working memory and other executive functions (Fontes et al. 2019). There have more studies showing a significant decline in the volume of total brain, white matter, and cortical grey matter. The reduction in brain volume ranged from 5.3% (cortical grey matter) to 11% (corpus callosum) (von Rhein et al. 2014). The reduction in the white matter microstructure in congenital heart disease infants has also been reported, which was associated with the decrease in cognitive performance (Rollins et al. 2014). The same group of scientists documented that the decrease in the volume of white matter predicts the development of language abnormalities in congenital heart disease infants. Indeed, a reduction of approximately 54 mL in the total brain volume and about 40 mL in cerebral white matter was reported in infants with congenital heart disease in comparison to normal infants. Moreover, this difference in the white matter volume was correlated to the language development indices (Rollins et al. 2017).

It has been reported that there is a reduced regional functional connectivity involving critical brain regions in newborns with congenital heart disease, which may be responsible for early-life brain dysfunction and neurodevelopmental impairments (De Asis-Cruz et al. 2018). In a very recent study, the changes in the apparent axon density and orientation dispersion in the white matter of newborns with congenital heart disease have been reported. Using brain magnetic resonance imaging, the comparison between the axon density and neurite orientation dispersion within white matter was made between normal and congenital heart disease infants. The average neurite density index was much lower, particularly within long association tracts and in regions of the corpus callosum in congenital heart disease infants. Along with it, smaller white matter tract volumes and clusters of lower fractional anisotropy was also reported, without any significant differences in orientation dispersion index. It suggests that the decrease in the density of axonal packing, but not altered axonal orientation, is the important microstructural change in the white matter in infants born with congenital heart disease (Easson et al. 2020). Apart from well-defined pathological alterations in the brain, there are changes in the metabolic profiles in congenital heart disease patients, including higher levels of accumulation of citric acid cycle intermediates and glucose, which has been suggested due to switching to anaerobic metabolism. The presence of these metabolic changes has been correlated with the adverse neurodevelopment pattern (Vedovelli et al. 2019).

Dysregulation of angiogenesis

It has been proposed that there is an overall dysregulation of angiogenesis i.e. an increase in the expression of antiangiogenic and decrease in the angiogenic factors in the brains of fetuses with congenital heart disease. An experimental study identified the changes in the expression of angiogenesis regulating genes in the cerebral tissues obtained from 15 fetuses with congenital heart disease that had undergone termination of pregnancy. Real-time polymerase chain reaction (RT–PCR) revealed the higher expression of soluble fms-like tyrosine kinase-1 (sFlt-1), a tyrosine kinase protein with antiangiogenic properties, in the frontal cortex and basal ganglia of fetuses. There was also a rise in the levels of angiogenesis promoting proteins including, VEGF-A and hypoxia-inducible factor 2-alpha in the frontal cortex and basal ganglia. However, the net balance was towards the antiangiogenic factors, which suggested that fetuses with congenital heart disease have impaired angiogenesis that may be responsible for impaired brain perfusion and abnormal neurological development (Sánchez et al. 2018).

An earlier study reported a similar pattern of changes including an increase in sFlt-1 and angiogenesis promoting proteins and suggested that the imbalance in angiogenic-antiangiogenic factors is associated with developmental defects of the human heart (Llurba et al. 2014). However, these findings are not in line with a study raising the possibility of an increase in blood perfusion in the white matter of newborns with congenital heart disease. Indeed, the extent of blood perfusion was compared in one newborn with congenital heart disease before surgery and three healthy newborns. The cerebral blood flow was increased in the white matter of a newborn with congenital heart diseases. Moreover, there was the overexpression of vascular endothelial growth factor in the injured white matter of the newborn with congenital heart disease (Wintermark et al. 2015). The studies of Wintermark et al. (2015) and Sánchez et al. (2018) report the opposite results, however, both reported the increase in the expression of vascular endothelial growth factor in the brain of congenital heart disease children. Sánchez et al proposed that an increase in the shift to anti-angiogenesis factors may decrease the cerebral blood flow, which may contribute to neurodevelopmental abnormalities. There have been several studies supporting that decrease in cerebral oxygen supply or utilization is responsible for reduced brain size and neurodevelopmental abnormalities (Sun et al. 2015). On the other hand, Wintermark et al proposed that an increase in angiogenesis may contribute to cerebral injury and this hypothesis was based on the studies showing that an increase in angiogenesis is responsible for macular injury and retinopathy (Hartnett 2014). Accordingly, more detailed studies are required to fully elucidate the role of angiogenesis regulating factors in the neurodevelopmental abnormalities in congenital heart disease.

Studies focusing on the impact of different interventions on neurodevelopment abnormalities

Non-Pharmacological

Impact of the feeding mode on the neurodevelopment changes

A significant impact of the mode of feeding has been identified on the outcome of neurodevelopment in congenital heart disease infants. A retrospective cohort study performed by Holst et al on 208 children with congenital heart disease reported that the children on enteral feeding tubes had significantly lower developmental quotient scores in cognition, communication, and motor function in comparison to orally fed children. The developmental delay was much more significant in enteral tube-fed children with the same-aged infants, kept on oral feed (Holst et al. 2019). Another study involving retrospective cohorts of 194 neonates reported the impact of the mode of feeding on the neurodevelopment outcomes. It was reported that infants (60%, n = 117) discharged on oral feedings remained on an oral diet and presented with lesser long-term neurodevelopmental impairment. On the other hand, the remaining infants (40%, n = 77) discharged on G-tube feedings had lower cognitive, communication, and motor composite scores. It further emphasizes the importance of oral feeding in reducing neurodevelopment alterations in congenital heart disease patients (Jadcherla et al. 2017).

Pharmacological Interventions

Dexmedetomidine as an anesthetic in congenital heart disease infants

Safety and efficacy of dexmedetomidine as an anesthetic in infants with heart diseases

Dexmedetomidine is an α₂-adrenergic receptor agonist, which is FDA approved for sedation and analgesia in the intensive care unit (ICU) (Phan and Nahata 2008; Afonso and Reis 2012). As a pre-anesthetic medication, dexmedetomidine produces arousable sedation and anxiolysis, while as an intraoperative adjunctive agent, it provides balanced anesthesia and reduces the neuro-humoral stress response. Moreover, its clinical use has been found to spare the use of opioids and prevent the risk of postoperative delirium or agitation (Kiski et al. 2019). There have been several studies showing the efficacy and safety of dexmedetomidine in infants with cardiac diseases (Chrysostomou et al. 2009). Moreover, its safety persists beyond 24 h, without the emergence of rebound effects after its discontinuation (Guinter and Kristeller 2010). A retrospective observational study conducted in the cardiovascular intensive care unit has reported that critically ill neonates and infants with heart disease remain hemodynamically stable in response to dexmedetomidine infusion during surgery. Moreover, it was shown to reduce the concomitant dose of opioid and benzodiazepine agents (Lam et al. 2012). There has been another retrospective study showing the efficacy and safety of dexmedetomidine in critically ill infants and children with congenital or acquired heart disease who received dexmedetomidine for more than 96 h. It was shown that the duration and amount of midazolam and morphine infusions were significantly lower in the dexmedetomidine-administered infants (Gupta et al. 2012). The retrospective observational study conducted by Lam et al also reported the safety and efficacy of dexmedetomidine in children with heart failure. Dexmedetomidine was administered in 21 patients, and it was reported that there was no significant effect on the heart rate, blood pressure, or inotropic score at the termination of infusion. It also led to a reduction in the dose of midazolam. Moreover, the numbers of sedation and analgesic rescue were significantly lower in the dexmedetomidine group, suggesting that the administration of dexmedetomidine in children with heart failure appears to be safe (Lam et al. 2012). Moreover, dexmedetomidine is effective in reducing the length of stay and time to extubation in critically ill ICU patients. However, a relative risk of bradycardia has been identified among patients treated with dexmedetomidine (Cruickshank et al. 2016).

4.2.1.2. Neuroprotective effects of dexmedetomidine

Apart from a simple anesthetic agent, the employment of dexmedetomidine has produced favorable effects on the brain in congenital heart disease infants undergoing surgery. Schwartz et al analyzed the data from the Congenital Cardiac Anesthesia Society-Society of Thoracic Surgeons Congenital Heart Disease Database to study the role of perioperative use of dexmedetomidine in pediatric patients with congenital heart disease. The data of 12,142 patients, in which 3600 received perioperative dexmedetomidine and 8542 did not receive the drug, was collected from 2010 to 2013. The results revealed that children receiving dexmedetomidine had improved outcomes as compared to patients who did not receive dexmedetomidine (Schwartz et al. 2016). A randomized, single-blind controlled study involving pediatric patients (n = 80) with congenital heart disease explored the neuroprotective potential of dexmedetomidine during surgery. The study revealed that the administration of dexmedetomidine significantly attenuated brain injury as assessed by decreased levels of neuron-specific enolase (NES) and S-100β protein. Moreover, dexmedetomidine treatment during surgery improved the oxygen metabolism in brain tissues suggesting the neuroprotective actions of dexmedetomidine during surgery of congenital heart disease pediatric patients (Gong et al. 2019). Another retrospective study on pediatric patients (n = 256) with heart disease undergoing thoracic surgery revealed the significance of dexmedetomidine. The results showed that there was a significant preservation of intelligence quotient scores and neurodevelopment evaluation scores in infants receiving dexmedetomidine in comparison to patients not receiving dexmedetomidine. However, there was no significant difference in overall mortality, duration of mechanical ventilation, or length of stay. Therefore, it may be suggested that the administration of dexmedetomidine may improve neural development in infants with congenital heart disease undergoing surgery (Huang et al. 2020).

Erythropoietin as neuroprotective drug

Erythropoietin has been shown to exert neuroprotective effects due to its anti-apoptotic, anti-inflammatory, and antiexcitatory effects (Fischer et al. 2017). Therefore scientists have employed the use of erythropoietin as a neuroprotectant in patients undergoing heart surgery. There have been mixed reports regarding the use of erythropoietin as neuroprotective agents in older patients undergoing cardiac injury (Lakič et al. 2010, 2016). However, in a prospective phase, I/II clinical trial involving 22 neonates undergoing cardiac surgery did not get neurological protection from erythropoietin administration and results were not statistically different from the placebo group (n = 20) (Andropoulos et al. 2013).

N-methyl-D-aspartate receptor antagonists as neuroprotective drugs

Ketamine

Ketamine is an NMDA receptor antagonist and serves as a dissociative anesthetic. There have been preclinical (Wang et al. 2019) as well as clinical studies (Nagels et al. 2004) showing the neuroprotective effects of ketamine. The employment of ketamine has been shown to attenuate post-operative cognitive dysfunction after cardiac surgery (Hudetz et al. 2009). Based on these reported beneficial effects of ketamine, a randomized clinical trial explored the neuroprotective potential of ketamine in infants (n = 13) undergoing cardiopulmonary bypass surgery for repair of ventricular septal defects in comparison to placebo (n = 11). The results found no significant differences in the expression of cytokines, chemokines, S100, and neuron-specific enolase between ketamine-treated and placebo. It suggested that ketamine failed to exhibit neuroprotective effects in infants with congenital heart disease (Bhutta et al. 2012).

4.2.3.2. Dextromethorphan

Dextromethorphan is a non-competitive antagonist and it has also been shown to exhibit neuroprotection (Pu et al. 2015). In a clinical study involving thirteen children (age 3–36 months) undergoing cardiac surgery with cardiopulmonary bypass, the efficacy of dextromethorphan in attenuating brain injury was explored. The results found that children with dextromethorphan exhibited fewer abnormalities in electroencephalography and MRI, however, the effects were not significantly different in comparison to placebo (Schmitt et al. 1997).

Allopurinol as a neuroprotective drug

Allopurinol is a xanthine oxidase inhibitor and apart from its typical anti-hyperuricemic actions, it has been shown to produce neuroprotective effects in animal studies as well in neonates (Annink et al. 2017). The neuroprotective effects of allopurinol may be due to inhibition of superoxide formation and directly scavenging free radicals (Yıldız et al. 2017). A single-center, randomized, placebo-controlled, blinded trial explored the neuroprotective potential of allopurinol in infants undergoing heart surgery. The authors divided the patients into two categories i.e. hypoplastic left heart syndrome (HLHS) and all other forms of congenital heart disease (non-HLHS). It was found that treatment with ketamine led to significant neuroprotection in higher-risk HLHS patients without any significant effect in lower-risk, non-HLHS infants (Clancy et al. 2001).

Anticoagulants

The use of anticoagulants is recommended for the prevention of the development of stroke in patients with atrial fibrillation and valvular defects. A two-center, observational cohort study of 118 term-born neonates with congenital heart diseases (TGA, n = 83 and SVP, n = 35) studied the effectiveness of anticoagulation therapy on brain injury in neonates undergoing cardiopulmonary bypass surgery. The results revealed the more significant postoperative parenchymal brain injury (stroke) in SVP neonates with the use of anticoagulants as compared to without anticoagulation (31% vs 5%). In neonates with the incidence of preoperative stroke, there was more frequent development of new subdural hemorrhage as compared to without anticoagulation (36% vs 0%). Accordingly, it was stated that there was no anticipated benefit of preventing brain injury with the use of anticoagulation during cardiopulmonary bypass surgery (Leijser et al. 2019).

Impact of propofol

Propofol is widely used in procedural sedation in children during surgeries. Indeed, intravenous propofol is used for the induction of anesthesia, and thereafter, anesthesia is maintained with propofol-remifentanil. Propofol is well known to decrease systemic vascular resistance and arterial blood pressure. Therefore, it has been speculated that due to a decrease in systemic perfusion, the employment of propofol may potentially result in a reduction in cerebral blood flow and oxygenation. A study was performed to measure the changes in the cerebral blood in congenital heart disease children (n = 32, median age = 49 months) undergoing heart surgery using propofol as an anesthetic agent. Propofol was shown to decrease the mean arterial pressure (79 ± 16 vs. 67 ± 12 mmHg) and cardiac index (3.2 ± 0.8 vs. 2.9 ± 0.6 ml/min/m²). However, the cerebral tissue oxygenation index was increased (57 ± 11 to 59  ± 10%) despite a decrease in cardiac index and arterial blood pressure, which may be possibly due to decreased oxygen consumption by the sedated brain with an intact cerebral auto-regulation. Accordingly, it was suggested that the use of propofol as an anesthetic agent does not reduce cerebral blood flow and oxygenation during surgery (Fleck et al. 2015).

Future directions

At present, there are limited options to attenuate brain injury during cardiac surgery for the repair of congenital heart disease. There has been extensive research on the use of stem cells for the repair of congenital heart disease and success has been achieved in many experimental studies. However, the impact of stem cells in preventing brain may need further research.

Conclusion

There have been very few studies that have focused on the reduction in neuronal damage in congenital heart disease patients. Amongst the pharmacological interventions, dexmedetomidine, α₂-adrenergic receptor agonist, has been reported to impart neuroprotection and limit the impact of surgery on neurodevelopment. However, the employment of anticoagulants has not been reported to produce beneficial effects in these patients. The non-pharmacological intervention i.e. oral mode of feeding, has also been found to produce beneficial effects. Nevertheless, there is a need for more studies to identify the interventions that may attenuate the deleterious impact of congenital heart disease on the brain.

Data availability statement

The data will be available on request.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by Appropriate Health Techniques For Poverty Alleviation Program of Health Commission of Jilin Province: [Grant Number 2018FP044].