Sudden death in a young athlete is always an unexpected and striking event. While these events are rare, they are devastating for the families and communities involved. Multiple definitions of sudden death have been used, the most common of which is death within 1 hour of the onset of symptoms.¹ The National Heart, Lung and Blood Institute has defined sudden cardiac death as a sudden and unexpected event without an obvious non-cardiac cause.² Sudden death in an athlete during exercise is defined as unexpected or instantaneous death that occurs during exercise or within 3 hours of exercise due to any cause other than violence.³ The percentage of sports-related sudden deaths, which by this definition can be classified as related to exercise, is approximately 5%.⁴ While there are no criteria to specifically define the different causes of sudden death in athletes, it has generally been accepted that these events can be divided into two categories, sudden cardiac death, and sudden non-cardiac death.

In the last decade, there has been a focus on defining the true prevalence and causes of sudden cardiac death in athletes. In 2011, a study using the US National Collegiate Athletic Association database demonstrated that out of 80 deaths between 2004 – 2008, only 56% were of cardiac etiology. Heat stroke and sickle cell disease were leading causes of non-cardiac sudden death.⁵ More recently in 2016, Maron et al. published a large study using data from the US National Registry of Sudden Death in Athletes from 1980 to 2011. There were 2,046 total athlete deaths with 802 of those classified as sudden cardiac death by autopsy. The most common non-cardiac and non-trauma related causes of sudden death were illegal drug use and sickle cell disease.⁶ A byproduct of the in-depth analysis on sudden cardiac death has been an estimate of the number of cases of sudden death secondary to non-cardiac causes.

More recently, several additional studies have estimated the prevalence of cardiac versus non-cardiac sudden death, including large population and autopsy studies. The largest of which is a nationwide population-based study from Denmark using death certificates, emergency room visits and autopsy reports to estimate the incidence, risk factors and causes of sudden non-cardiac death.² Although this study is not specific to exercise-related sudden death, the population is significant and provides the most common causes of non-cardiac sudden death over a decade. There were 1,691 cases of sudden death including 1,039 cases where an autopsy was performed. Of these cases, 28% were classified as a sudden non-cardiac death. The authors found that younger age and female sex were associated with sudden non-cardiac death. The most common non-cardiac causes of sudden death were pulmonary disease (40%), infectious disease (20%), cerebrovascular disease (18%) and neurologic disease (8%).

While the most common causes of sudden death in athletes remains cardiac, several non-cardiac causes are important to consider, especially as related to prevention. A classification system outlined by Lang et al. proposes that non-cardiac sudden death can be further classified into four subcategories including neurologic, metabolic/endocrine, respiratory and immunologic (occurring infrequently during athletic participation).¹ The neurologic subcategory includes sudden unexplained death in epilepsy (SUDEP), seizure with bradyarrhythmia, and intracranial hemorrhage. In a large study of primarily pediatric patients, SUDEP was the most common cause of sudden non-cardiac death followed by intracranial hemorrhage.⁷ Maron et al. described a cohort of 1,866 athletes with sudden death over a 27-year period in the United States. In this athlete specific population, there were two deaths related to epilepsy and three strokes.⁸ Additionally, there were nine cases of cerebral aneurysms. Several mechanisms of cardiac arrest secondary to intracranial hemorrhage have been proposed, including profound catecholamine release leading to cardiac stunning or a sudden spike in intracranial pressure leading to brainstem dysfunction and respiratory arrest. This respiratory arrest leads to hypoxia ultimately triggering release of adenosine that leads to decreased atrioventricular conduction and eventually pulseless electrical activity (PEA) or asystole.⁹ In practice, this may appear very similar to a sudden cardiac event and it is important to maintain a high level of suspicion for such an event, as further investigation is performed to define the etiology.

Another important environmental cause of non-cardiac sudden death in athletes is heat stroke. In Maron's series, heat stroke accounted for 2.5% of sudden death in young athletes.⁸ Heat stroke occurs when the body's temperature regulation system is incapable of balancing heat production and heat loss resulting in a profound inflammatory response, tissue injury and multiorgan system dysfunction.¹⁰ Not surprisingly, these events occur more often in warmer climates and often in football players who practice in heavy equipment during the late summer months. Athletes are predisposed to heat stroke if they are deconditioned, not acclimatized or dehydrated.¹⁰ Interestingly, most of the events in a 2018 study of American football players occurred in athletes younger than 18 years old.¹¹ The authors hypothesized that this may be related to sub-optimal heat mitigation strategies below the collegiate level.

Related to this is the phenomenon of rhabdomyolysis due to abnormal muscle breakdown following exercise, which can lead to acute kidney injury, compartment syndrome and, in severe cases, death.¹⁰ Fortunately, in a large series, death related to rhabdomyolysis occurs in less than 1% of sudden death in athletes.⁸ Athletes taking substances which speed muscle breakdown, those with preexisting myopathy, and especially patients with sickle cell trait may have a worse course. In fact, athletes with sickle cell trait are at 40 times greater risk of exercise- or sports-related sudden death than those without.¹⁰ In these athletes, exercise-associated sickle cell collapse often mimics heat stroke but occurs earlier in exercise or while indoors. Knowledge of athletes' medical conditions is paramount for the coaching/athletic team to enable most accurate first response upon collapse.

The metabolic/endocrine subcategory includes inborn errors of metabolism (IEM), electrolyte derangement, and adrenal insufficiency.¹ While more than 30 causes of IEM have been linked to sudden death, defects in the fatty acid oxidation cycle and mitochondrial disorders are most prevalent.¹² More relevant for athletes is exercise-associated hyponatremia secondary to fluid overload. Most cases are reported during long distance running races with up to 30% of endurance athletes demonstrating hyponatremia after their event.¹³ In the most severe cases, this may lead to pulmonary edema, brain edema and death. Adrenal insufficiency, type I diabetes mellitus, and anorexia leading to hypoglycemia are other important considerations, occurring less often.

Respiratory causes of sudden death include pulmonary embolism, hypoventilation syndrome, airway obstruction, asthma, pulmonary hypertension, and respiratory infection.¹ Pulmonary embolism is the most common cause of respiratory mediated sudden non-cardiac death. In cases of pulmonary hypertension, sudden death may be the presenting symptom and can be related to respiratory failure, right ventricular failure, or arrhythmia.¹⁴ In athletes, cases of sudden death related to a pulmonary cause are infrequent, accounting for only 2% of cases.⁸

In conclusion, in addition to common cardiac causes of sudden death in athletes, there are many non-cardiac causes which are important to recognize. The varied etiologies, which are outlined above should serve as a rubric by which to form a differential diagnosis for each patient. Table 1 demonstrates key history and physical exam findings in each category as well as testing to be performed. A thorough history of the patient and the family is essential to narrow the wide differential diagnosis and guide a targeted clinical examination and advanced testing. It has become standard of care to screen family members of patients with sudden death, especially when a cardiac etiology is suspected. Many of the non-cardiac causes are also heritable and therefore screening for these should be included, especially in patients less than 50 years old.

Table 1: Non-cardiac Causes of Sudden Death in Athletes

	History/Predisposing Factors	Physical Exam	Next steps
Neurologic •Epilepsy •Stroke or Cerebrovascular accident (CVA)	Seizures Weakness	Tonic-clonic activity Pupillary abnormalities, loss of reflexes	Electroencephalogram (EEG), neurology consultation, Head CT
Environmental •Heat stroke •Rhabdomyolysis	Previous heat related events, summer Dehydration, summer, sickle cell	Hyperthermia, confusion Severe pain, extremity swelling	Reduce body temperature Serum CK levels, hydration
Exercise associated sickle cell collapse	Sickle cell trait	Pain, weakness especially in legs, normothermia	Hydration, pain control
Metabolic •Hyponatremia •Hypoglycemia	Excessive hydration Poor oral intake prior to event, dieting	Confusion, altered mentation Bradycardia, altered mentation	Heat CT, Electrolyte levels, glucose
Respiratory •Asthma •Pulmonary embolism (PE)	Previous asthma exacerbations Hypercoagulable state, obesity	Poor air entry, wheezing Chest pain, shortness of breath	Bronchodilators Chest CT with PE protocol

References

1. Lang JE, Pflaumer A, Davis AM. Causes of sudden death in the young - cardiac and non-cardiac. Prog Pediatr Cardiol 2017;45:2–13.
2. Risgaard B, Lynge TH, Wissenberg M, et al. Risk factors and causes of sudden noncardiac death: a nationwide cohort study in Denmark. Heart Rhythm 2015;12:968–974.
3. Lippi G, Favaloro EJ, Sanchis-Gomar F. Sudden cardiac and noncardiac death in sports: epidemiology, causes, pathogenesis, and prevention. Sem Thromb Hemost 2018;44:780–86.
4. Narayanan K, Bougouin W, Sharifzadehgan A, et al. Sudden cardiac death during sports activities in the general population. Card Electrophysiol Clin 2017;9:559–67.
5. Harmon KG, Asif IM, Klossner D, Drezner JA. Incidence of sudden cardiac death in National Collegiate Athletic Association Athletes. Circulation 2011;123:1594–1600.
6. Maron BJ, Haas TS, Ahluwalia A, Murphy CJ, Garberich RF. Demographics and epidemiology of sudden deaths in young competitive athletes: from the United States National Registry. Am J Med 2016;129:1170–77.
7. Puranik R, Chow CK, Duflou JA, Kilborn MJ, McGuire MA. Sudden death in the young. Heart Rhythm 2005;2:1277–82.
8. Maron BJ, Doerer JJ, Haas TS, Tierney DM, Mueller FO. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980-2006. Circulation 2009;119:1085-92.
9. Zachariah J, Stanich JA, Braksick SA, et al. Indicators of subarachnoid hemorrhage as a cause of sudden cardiac arrest. Clin Pract Cases Emerg Med 2016;1:132–135.
10. Asplund CA, O'Connor FG. Challenging Return to play decisions: heat stroke, exertional rhabdomyolysis and exertional collapse associated with sickle cell trait. Sports Heath 2016;8:117-25.
11. Grundstein AJ, Hosokawa Y, Casa DJ. Fatal exertional heat stroke and American football players: the need for regional heat-safety guidelines. J Athl Train 2018;53:43-50.
12. van Rijt WJ, Koolhaas GD, Bekhof J, et al. Inborn errors of metabolism that cause sudden infant death: a systematic review with implications for population neonatal screening programs. Neonatology 2016;109:297–302.
13. Knechtle B, Chlibkova D, Papadopoulou S, Mantzorou M, Rosemann T, Nikolaidis PT. Exercise-associated hyponatremia in endurance and ultra-endurance performance—aspects of sex, race location, ambient temperature, sports discipline, and length of performance: a narrative review. Medicina 2019;55:537.
14. Durante A, Laforgia PL, Aurelio A, et al. Sudden cardiac death in the young: the bogeyman. Cardiol Young 2015;25:408–23.

Clinical Topics: Arrhythmias and Clinical EP, Congenital Heart Disease and Pediatric Cardiology, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Sports and Exercise Cardiology, Vascular Medicine, Implantable Devices, SCD/Ventricular Arrhythmias, CHD and Pediatrics and Arrhythmias, CHD and Pediatrics and Prevention, CHD and Pediatrics and Quality Improvement, Acute Heart Failure, Pulmonary Hypertension, Hypertension, Sleep Apnea, Sports and Exercise and Congenital Heart Disease and Pediatric Cardiology

Keywords: Sports, Athletes, Death, Sudden, Cardiac, Death, Sudden, Adolescent, Bradycardia, Football, Sickle Cell Trait, Hypertension, Pulmonary, Autopsy, Pulmonary Edema, Brain Edema, Hyponatremia, Adenosine, Intracranial Pressure, Diagnosis, Differential, Anorexia, Catecholamines, Intracranial Aneurysm, Hypoventilation, Standard of Care, Thermogenesis, Heart Arrest, Physical Examination, Risk Factors, Body Temperature Regulation, Rhabdomyolysis, Stroke, Heat Stroke, Seizures, Pulmonary Embolism, Muscular Diseases, Intracranial Hemorrhages, Hypoglycemia, Mitochondrial Diseases, Asthma, Registries, Adrenal Insufficiency, Airway Obstruction, Acute Kidney Injury, Diabetes Mellitus, Emergency Service, Hospital

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