Sudden death in high school athletes: a case series examining the influence of sickle cell trait

Abstract

While exertional related death (ERD) is an uncommon cause of death in the pediatric population, identifying athletes at risk for ERD may be helpful in reducing the occurrence as counseling and urgent medical evaluation may be prioritized in these athletes. The National Center for Catastrophic Sports Injury Research (NCCSIR) reported 17 high school athlete ERD in 2016 due to cardiac, environmental, and other medical conditions.¹ One identified risk factor for non-cardiac ERD is sickle cell trait (SCT), which affects more than 3 million people in the United States.^2,3 Studies have demonstrated that military recruits and college athletes with SCT have up to a 37-fold increased risk of ERD compared to peers without SCT.^4,5 Exertional collapse associated with sickle cell trait (ECAST) has a spectrum of presentation that varies from severe muscle pain to fulminant cardiovascular collapse, leading to ERD.⁶ The term ECAST was adopted by a summit of experts on SCT in wartime fighters and athletes to better describe and distinguish these presentations from those reported in individuals with sickle cell disease.^6,7 Currently, the mechanism for ECAST is not well understood. Exertional sickling is thought to be due to local muscle circulation hypoxemia, local hyperthermia, dehydration of the red blood cells coursing through the working muscles, and profound lactic acidosis, leading to rhabdomyolysis and fatal hyperkalemia.^8,9

Cases of ERD following ECAST have been described in the military and college athletics populations, dire yet non-fatal ECAST cases have been reported in teenage athletes.^5,10–12 We present a case series examining ERD following ECAST in high school athletes. Three cases were identified between 2013–2016; one through direct patient care and two through the National Center for Catastrophic Sports Injury Research (NCCSIR). The case presentations include hospital records (only Case 1), autopsy findings, and case reports.

Case Report:

Case 1:

A 14-yr-old white male American football athlete with known SCT experienced muscle weakness and collapsed on the field during a preseason conditioning session, and was taken immediately to a nearby emergency department. On arrival, he was tachycardic, tachypneic, febrile to 101.5 °F, and drowsy with metabolic acidosis. In the ED, axillary ice packs were placed and he was given 2.8 liters of intravenous fluids over two hours with resolution of his fever (99.6 °F) but little improvement in his metabolic acidosis. He was admitted for exertional heat stroke and dehydration. After admission, he developed worsening metabolic acidosis, hyperkalemia, significant rhabdomyolysis (CK >40,000), and progressed to cardiac arrest within 8 hours of admission. After 40 minutes of cardiopulmonary resuscitation, he had a return of spontaneous circulation. He was then transferred to a tertiary pediatric hospital for further care. Upon arrival to the Pediatric Intensive Care Unit (PICU), he was found to be in disseminated intravascular coagulation (DIC) and acute myoglobinuric renal failure secondary to rhabdomyolysis. Aggressive fluid resuscitation and blood transfusion was undertaken with minimal improvement. Within hours of arrival to the PICU, he developed abdominal compartment syndrome due to the massive resuscitation and underwent a bedside decompressive laparotomy with temporary abdominal wall closure. He was then started on continuous renal replacement therapy (CRRT) for acute anuric renal failure. Despite aggressive resuscitation, dialysis, and attempted correction of his coagulopathy, he progressed to multi-organ system failure and died within 24 hours of collapsing on the football field.

On autopsy, he was found to have extensive sickle cell vaso-occlusion involving his spleen, kidneys (Figure 1), liver, and muscles (Figure 2). There was also evidence of profound DIC, rhabdomyolysis, diffuse cerebral edema and uncal herniation. Final clinical and pathologic diagnosis supported ECAST with fatal exertional rhabdomyolysis.

Figure 1.

Part of the renal cortex with intratubular pigmented granular casts (black arrows); note the presence of sickled red blood cells (white arrow), H&E, 400x.

Figure 2.

Right calf muscle biopsy. Disintegrated myocytes, with muscle cells lysis (white stars) representing rhabdomyolysis. H&E, 400x.

Case 2:

A 16-yr-old black male with known SCT reported cramping during a summer American football conditioning session. He was evaluated on the field by emergency medical services, but no injuries or illnesses were identified. Later that evening, he became unresponsive at home and was taken to a local hospital where he was treated for dehydration, metabolic acidosis, hyperkalemia, hyperglycemia, and rhabdomyolysis. Despite fluid resuscitation, he continued to have a profound metabolic acidosis, and acute myoglobinuric renal failure due to rhabdomyolysis. He continued to deteriorate and died within 24 hours of presentation to the hospital. Autopsy findings showed sickle cell vaso-occlusion of the peripheral vasculature, spleen, liver, and muscles. Cause of death was ECAST with fatal exertional rhabdomyolysis.

Case 3:

A 14-yr-old Hispanic male with unknown sickle cell status reported stomach pain and collapsed at baseball practice. He was taken to a local hospital where he was alert and oriented on arrival. He was found to have metabolic acidosis, rhabdomyolysis, and an acute kidney injury, and was admitted for exertional heat stroke. Despite fluid resuscitation, he continued to have profound rhabdomyolysis, developed DIC, and abdominal compartment syndrome requiring a laparotomy for decompression. He progressed to multi-organ system failure and died within 48 hours of onset of symptoms. Post-mortem, SCT was identified on hemoglobin electrophoresis. Autopsy findings showed sickle cell vaso-occlusion of the spleen, liver, kidneys, and brain. Cause of death was ECAST with fatal exertional rhabdomyolysis.

Discussion:

We present three cases of high school athletes with fatal ECAST. This condition is likely under recognized and misdiagnosed as exertional heat stroke (EHS). The greatest incidence of EHS is among football participants, occurring at a rate of 4.5 cases per 100,000 athletes.¹³ However, the exact incidence of ECAST is not known. The presenting symptoms of ECAST include muscle weakness and collapse, as well as altered mental status.¹⁴ ECAST can be differentiated from EHS by obtaining a rectal temperature, with a temperature greater than 104°F being seen in EHS. It is important to obtain a rectal temperature in these patients because oral, axillary, aural, and temporal temperatures do not provide accurate core body temperatures.¹⁵ Despite rectal temperature being the most accurate measurement, one study found less than 1% of athletic trainers treating EHS actually used this tool in initial evaluation.¹⁶ We could not obtain in our cases initial rectal temperature from the medical records.

On presentation to the hospital, all three athletes had metabolic acidosis, which did not respond as expected to fluid resuscitation. This is likely due to the exertional sickling that led to profound rhabdomyolysis and kidney failure. Continuous renal replacement therapy (CRRT) has previously been used successfully to treat acute kidney injury due to rhabdomyolysis, and is especially beneficial in patients with refractory hyperkalemia, acidosis, and volume overload.¹⁷ CRRT was used in the first athlete; however, he was unable to recover from his profound DIC and multisystem organ failure.

The exact mechanism of ECAST with exertional rhabdomyolysis is unknown, but one proposed mechanism is exertional sickling in the microcirculation of working muscles caused by four major factors: extreme local hypoxemia in the circulation of muscles, local hyperthermia, dehydration of RBCs coursing through the working muscles, and profound lactic acidosis.^8,9,18 The sickling in the microcirculation then lead to rhabdomyolysis and fatal hyperkalemia.⁹ The exercise intensity is thought to be another major risk factor for the development of ECAST.¹⁹ Maximum intensity events can occur both from all-out sprinting for 2 to 5 minutes, or after hour-long high-intensity practices.¹⁹ Other on field risk factors include sudden increase in training intensity (i.e. first day of physical conditioning), training at high altitudes, suboptimal physical conditioning, and lack of exercise and heat acclimatization.²⁰ ECAST is uncommon for the number of athletes that have SCT and therefore some view this event as being multifactorial with multiple insults being required.¹⁸ The first case had recently been treated for streptococcal pharyngitis. This may have lowered the threshold for him to develop ECAST. Other case reports have discussed consecutive rigorous workouts and physiologic stress leading up to the ECAST.²¹

In 2010, the NCAA required all Division I athletes to know their sickle cell status in hopes that this may prevent exercise related sudden death in SCT athletes.²² This policy was the result of a legal settlement by the NCAA with the family of a football player who collapsed during practice and later died due to ECAST.²² The decision by the NCAA has been controversial with concerns that screening alone may not improve outcomes for the athletes.² However, the NCAA SCT program over 8 years has decreased the ECAST death rate in Division 1 football conditioning.²³ Newborn screening should help identify individuals with SCT in the pediatric population for counseling. However, many individuals are not aware of their sickle cell status or the risks associated with SCT despite newborn screening.

Prevention of ECAST should be the primary goal for athletes with SCT, as well as their parents, coaches and athletic trainers.²⁴ Proposed primary prevention strategies focus on exercise modifications for SCT athletes.²⁵ This includes athletes setting their own pace with exercise, slow increase in the pace of training with longer breaks between exercises, avoiding extreme high-intensity tests, and knowledge of predisposing factors (i.e. heat, altitude, dehydration, asthma, and recent illness), and early symptoms with modification or cessation of training session when these factors are present.^19,25

Almost all of the cases of ECAST with ERD previously reported in the literature are in African-American athletes or military recruits.^{3,5,18,21,26–32} The three athletes in this series were of different reported ethnicities (Case 1 white, Case 2 black, and Case 3 Hispanic). This is important since the prevalence of SCT is known to be 8% for African-Americans, 0.5% of Hispanics, and 0.2% of Caucasians.^2,3 Genetic heterogeneity considerations have lead to expand pan-ethnic carrier and newborn screening practices including sickle cell.³³ For an athlete being evaluated for exertional collapse, it is important to consider that any patient may have SCT regardless of ethnicity and be at risk for ECAST.

Conclusion:

All three of the athletes in our case series died within 48 hours of symptom onset, demonstrating how lethal ECAST can be. Patients should be urgently evaluated at the hospital if a collapsed athlete has known SCT. Rapid differentiation should be made between ECAST and EHS, as treatment differs significantly between them. In EHS, a lack of aggressive cooling may result in DIC and multisystem organ failure³⁴, whereas in ECAST, aggressive cooling is not needed. Athletes with suspected ECAST should undergo aggressive resuscitation with a low threshold for early transfer to a tertiary care facility for further management and potential hemodialysis. Even with aggressive therapies, ECAST with rhabdomyolysis can be fatal, and thus athletes and parents should be counseled about this risk.

Consent:

This case series was reviewed by the institutional review board (IRB) at University of North Carolina and determined to be exempt from oversight (IRB #17–0696). Additionally, guardians gave written informed consent to publish Case 1 in this series.