Aetiology

There can be multiple causes associated with sudden cardiac death in the paediatric population (Fig 1) ^{Reference Meyer, Stubbs and Fahrenbruch4} and even more underlying causes for the development of CHDs. The asymptomatic nature of many CHDs can contribute to children not being screened appropriately or having relevant cardiac examinations, and often this results in late discovery of the underlying pathology at autopsy.

Figure 1. Aetiology of SCD by age group. ^{Reference Meyer, Stubbs and Fahrenbruch4}

Classification

Congenital abnormalities which lead to sudden cardiac death in children can be classified into congenital structural heart defects, congenital coronary artery anomalies, and congenital cardiac arrhythmias, otherwise known as primary electrical disturbances. ^{Reference Wren27} Table 1 lists the conditions which fall into each category with congenital structural heart defects further subdivided into simple and complex defects. ^{Reference Serinelli, Arunkumar and White28}

Table 1. A summary of the congenital cardiovascular defects affecting the paediatric population

It is important to differentiate between simple and complex structural heart defects as sudden cardiac death in children aged <1 year is more frequently associated with the latter. ^{Reference Serinelli, Arunkumar and White28} One retrospective study identified 64 cases of children with CHDs presenting with sudden death with half of these cases undiagnosed preceding autopsy. 81% of this cohort was infants and the commonest malformation was found to be atrioventricular septal defects, a complex defect. ^{Reference Serinelli, Arunkumar and White28} Complex cardiac congenital defects progressing to sudden cardiac death is further supported in a review by Liberthson which identified literature in which patients with Tetralogy of Fallot had a 6% risk of sudden cardiac death, between 3 months and 20 years of age, after reparative surgery and individuals following an atrial switch operation for transposition of the great arteries were associated with a 2–8% risk of sudden cardiac death. ^{Reference Serinelli, Arunkumar and White28,Reference Liberthson29} Although these findings do not identify the risks associated exclusively with children <18 years, it is still noteworthy as the combination of these findings highlight that the fatal consequences of CHD still linger even after corrective interventions. This places emphasis on the importance of continued perusal in this area of study.

Complex CHDs also tend to coexist with congenital coronary artery anomalies. ^{Reference Lowry, Olabiyi, Adachi, Moodie and Knudson30} Although most cases of congenital coronary artery anomalies tend to be benign, in isolation, congenital coronary artery anomalies can be associated with myocardial ischaemia, ventricular arrhythmias, and sudden death. ^{Reference Frommelt31} Anomalous aortic origin of the left coronary artery from the right sinus of Valsalva accounts for roughly 40% of all major coronary anomalies, however, is deemed to have little clinical significance. Anomalous aortic origin of the right coronary artery from the left sinus of Valsalva is estimated to account for 35% of major coronary anomalies and is important in that it can lead to myocardial ischaemia and sudden cardiac death. Another variant is when there is a single coronary artery and half of the cases are usually encountered alongside other forms of CHD. ^{Reference Flores, Moore and Statile32} Variants with coronary arteries which follow an interarterial course between the aorta and pulmonary artery are thought to have the highest risks of sudden cardiac death, especially when the young individual is engaging with strenuous physical exertion. ^{Reference Brothers33} One study analysed clinical and pathological reports in 242 patients with isolated congenital coronary artery anomalies to identify the frequency and mechanisms pinned with sudden cardiac death. ^{Reference Taylor, Rogan and Virmani34} A key finding was that the younger patients (<30 years old) were at a greater risk of sudden cardiac death, especially following exercise or significant exertion. Although this included patients beyond the paediatric population, it warrants further probing to determine which age groups are most at risk.

Neonates and infants

Congenital malformations are the chief cause of neonatal death, occurring in 2–3% of live births. Structural heart disease is diagnosed in the first year of life in 4–8/1000 infants and 10% of these cases have fatal consequences. The predominant diagnoses made in neonates include hypoplastic left heart syndrome, pulmonary atresia and transposition of the great arteries, all of which are severe and can lead to cyanosis, congestive heart failure, cardiovascular collapse, and shock. ^{Reference Pinar35} In addition, aortic valve stenosis, coarctation of the aorta, and Tetralogy of Fallot are also severe diagnoses, which may be recognised in the first year of life. Sudden unexpected neonatal death and sudden infant death syndrome are both phenomena, which share certain features and have also been shown to have underlying cardiac causes. ^{Reference Weber, Ashworth, Risdon, Brooke, Malone and Sebire36,Reference Adams, Good and Defranco37} A retrospective analysis by Weber et al found that out of 32 explained sudden unexpected neonatal death associated with undiagnosed congenital abnormalities, 12 (38%) were attributable to clinically undetected structural CHD including transposition of the great arteries, coarctation of the aorta, hypoplastic left heart syndrome, and pulmonary atresia. Thus, CHD was the commonest single group of congenital malformations associated with sudden unexpected neonatal death. ^{Reference Weber, Ashworth, Risdon, Brooke, Malone and Sebire36} Although this is a significant value when discussed alongside the sample size and should be included when assessing the burden of sudden cardiac death in paediatric CHD patients, it is believed that sudden cardiac death is more likely to occur in patients beyond the neonatal period and a third of CHD deaths occur during infancy.

Sudden infant death syndrome is most commonly related to environmental factors such as sleeping positions, sleeping environment, and smoking during pregnancy. However, cardiac disorders and especially congenital arrhythmias are responsible for a small number of cases. ^{Reference Adams, Good and Defranco37} Congenital arrhythmias encompass a spectrum of different electrical disturbances including Brugada syndrome, long QT syndrome, and catecholaminergic polymorphic ventricular tachycardia, amongst others. In particular, the long QT syndrome has been suggested to have strong associations with sudden cardiac death in early childhood. ^{Reference Saul, Schwartz, Ackerman and Triedman38} It is commonly known to progress towards torsades de pointes, ventricular tachycardia and fibrillation manifesting as seizures and syncope in seemingly healthy individuals, and so it is understandable as to why this link has been speculated in the past. One genetic study by Arnestad et al demonstrated that 9.5% of patients who suffered from sudden infant death syndrome were found to carry functionally significant variants of long QT syndrome genes, which may have contributed to this premature death. However, without electrocardiogram evidence prior to death, it is difficult to conclude a definite relation between long QT syndrome and sudden infant death syndrome. ^{Reference Arnestad, Crotti and Rognum39} Another genetic analysis in Korea also identified a number of sudden infant death syndrome victims (7.5%) who carried gene variants associated with long QT syndrome, but then found that this variation may also be a common polymorphism in Asians and hence failed to demonstrate a favourable link between long QT syndrome and sudden infant death syndrome. ^{Reference Son, Kim, Yang, Choi, Lee and Yoo40} A key limitation of both of these studies is that DNA investigations use anonymised data to draw conclusions, and hence, this prevents identification and provision of prophylactic therapy to relatives of the deceased individuals who may also be mutation carriers and at increased risk of sudden cardiac death. However, if the overall results fail to show any meaningful relation between long QT syndrome and sudden infant death syndrome then prophylaxis, in any case, may not be beneficial. The results from both of these studies show that whilst some genetic links have been identified, further objective assessments and studies are needed in order to support previous claims of sudden death during childhood in patients with long QT syndrome. ^{Reference Saul, Schwartz, Ackerman and Triedman38}

Screening and prevention

A crucial element in improving mortality rates from sudden cardiac death is prevention. In such cases, earlier the patient is diagnosed and treated, the better survival chances. However, apart from primary prevention, secondary prevention strategies have been implemented with the aim of deterring further cardiac damage. Screening is the first step forward. With sudden cardiac death occurring in young individuals in seemingly good health, screening for potential risk factors is essential, particularly when these individuals lead an athletic lifestyle. ^{Reference Maron, Doerer, Haas, Tierney and Mueller41} Exercise exacerbates the effects of CHD, however, 73% of sudden cardiac arrest has been reported to occur when the patient is sedentary. ^{Reference Allan, Morrison, Pinter, Tu and Dorian42} In a study by Mahoney et al 1996, 13% of individuals with sudden cardiac arrest between 2 and 24 years were found to have at least one cardiovascular risk factor. ^{Reference Mahoney, Burns and Stanford43} For this reason, dietary and safe exercise has been publicly recommended. Genetic analysis of sudden cardiac arrest in patients can still be beneficial for relatives. Cascade testing is an important screening mechanism to identify causative mutations, considering a likelihood of 25–50% of first-degree relatives experiencing sudden cardiac arrest in their lifetime. In a retrospective study at a tertiary paediatric referral centre, following evaluation of paediatric patients with a family history of sudden death, 9.3% were diagnosed with a hereditary cardiac disease with Q T syndrome being the most common diagnosis. In 5.5% of all patients, non-hereditary cardiac disease diagnosis had been made and in another 12.4%, findings of uncertain significance resulted. ^{Reference Webster, Olson and Schoppen44}

For selecting patients with likely sudden cardiac arrest, algorithms should be developed pivoting around symptoms and their manifestation in clinical events. The risk of sudden cardiac arrest in individuals with a history of aborted or resuscitated sudden cardiac arrest is high, other symptoms that may aim in diagnosis include palpitations, chest pain, syncope, and seizures all generally linked to non-sustained arrhythmia. Between 25 and 50% of children with sudden cardiac arrest have experienced previous symptoms, normally syncope and seizure. ^{Reference Winkel, Risgaard, Sadjadieh, Bundgaard, Haunso and Tfelt-Hansen45} Notwithstanding, apart from syncope, such antecedent symptoms are very common in children and adolescents introducing imprecision in prediction. Additionally, screening strategies have been suggested by the National Heart Lung and Blood Institute. Due to cost–benefit reasons, cardiovascular screening should focus on high-risk groups, such as athletes since asymptomatic screening of young individuals has proved to be ineffective. A multitude of assessment methods have been suggested with ECG, physical examination, and history taking as the best contenders. ^{Reference Bagnall, Singer and Tfelt-Hansen46} Whilst algorithms may enhance the efficiency of ECG delivery, the precision and accuracy of these tests are dependent on population prevalence, age, and medication in use. Risk stratification for paediatric patients may also be limited to specific disease criteria, for example, diagnosis of hypertrophic cardiomyopathy and channelopathies. However, being based on adult guidelines, their validity for paediatric population may be contested. ^{Reference Priori, Wilde and Horie47}

Following identification of high-risk individuals, suitable precautionary measures should be taken. An example of this is implantable cardioverter-defibrillator implantation. Findings on the application for implantable cardioverter-defibrillator in paediatric patients are conflicting. Evidence on their use for primary prophylaxis in children is less substantial than in adult counterparts. The risk in implantation of implantable cardioverter-defibrillator is, however, higher in paediatric patients due to lead malfunctions, shock frequency, and difficulty experienced in implantation resulting from the small size of patients and intracranial structures. ^{Reference DeWitt, Triedman and Cecchin48}

Another key feature of secondary prevention is cardiopulmonary resuscitation and automated external defibrillators. In an American study, emergency medical service staff were trained to make a preliminary assessment of the cause of sudden cardiac arrest before initiating a cause-specific cardiopulmonary resuscitation. This resulted in better outcomes than in cases when the sudden cardiac arrest cause was not identified to be cardiac or non-cardiac. However, due to time limitations, the extent of pre-cardiopulmonary resuscitation assessment may be restricted. ⁴⁹ Cardiopulmonary resuscitation training programmes for family members and teachers of paediatric patients with CHD ^{Reference Blewer, Putt and Becker50} together with the provision of self-instruction kits is another facet of secondary prevention aimed at increasing the survival rate from sudden cardiac arrest. ^{Reference Pierick, Van Waning, Patel and Atkins51} Nonetheless, results from a multicentre study suggest that cardiopulmonary resuscitation alone is not as effective as cardiopulmonary resuscitation in conjunction with automated external defibrillators availability. With out-of-hospital cardiac arrest outcomes being low and survival rate being reduced by 10% for each minute cardiopulmonary resuscitation is delayed, ^{Reference Cummins, Ornato, Thics and Pepe52} cardiopulmonary resuscitation-automated external defibrillators programmes have become increasingly popular in community settings. This stems from the fact that some individuals may have not been identified via screening and cardiac arrest is the first presentation of their underlying heart disease. ^{Reference Maron53} Such programmes have been recommended through guidelines by the American Heart Association, indicating that schools with high-risk individuals for sudden cardiac arrest such as patients of cardiomyopathies, channelopathies, congenital, or known cardiovascular disease would require the onsite presence of automated external defibrillators machines. ⁵⁴ With automated external defibrillators still being inaccessible to some areas, wearable off-brand automated external defibrillators might also provide a solution. ^{Reference Everitt and Saarel55}