Sickle Cell Trait, Rhabdomyolysis, and Mortality among U.S. Army Soldiers

Sapna Charania, Mercer University College of Pharmacy

 

Exertional rhabdomyolysis is characterized by the severe breakdown of skeletal muscle tissue that is precipitated by strenuous physical exertion, leading to systemic manifestations that typically include myoglobinuria. Although anyone who performs strenuous exercise may be at risk for developing exertional rhabdomyolysis, some individuals may be more susceptible than others. [1]

A number of such cases have been attributed to sickle cell trait, a condition in which persons are heterozygous for the sickle cell mutation in the beta-globin gene of hemoglobin. Extreme heat and humidity, high altitude, exercise-induced asthma, and pre-event fatigue due to illness or lack of sleep are considered to be primary risk factors for exertional rhabdomyolysis in persons with sickle-cell trait. Sickle cell trait is most prevalent among persons with African ancestry. [2]

It is not fully understood whether sickle cell trait itself or some other unidentified but associated metabolic defect makes a small subgroup of patients with sickle-cell trait more susceptible to the development of exertional rhabdomyolysis. [3]

According to Sickle Cell Disease Association of America, there is lack of scientific evidence that substantiates a significant correlation between sickle cell trait in athletes and training related sudden death. [4]

  

 

Title: Sickle Cell Trait, Rhabdomyolysis, and Mortality among U.S. Army Soldiers [1]
Design Retrospective, cohort; N = 47,944
Objective To determine if sickle-cell trait is associated with a higher risk of exertional rhabdomyolysis and death
Study Groups Black soldiers in the U.S. Army who had undergone testing for sickle-cell trait (HbAS)

Sickle-cell trait (n = 3564); No sickle-cell trait (n = 44,380)

Methods Cox proportional-hazards models were used to test whether the risks of exertional rhabdomyolysis and death varied according to sickle cell trait status.
Duration January 2011 to December 2014
Primary Outcome Measure Risk of exertional rhabdomyolysis and death

 

Baseline Characteristics
Characteristic Sickle Cell Trait

(n = 3564)

No Sickle Cell Trait (n = 44, 380)
Male sex-no. (%) 2488 (69.8) 31,822 (71.7)
Age-years 30.7 ± 7.8 30.5 ± 7.6
Body-mass index –kg/m2 26.8 ± 3.8 26.8 ± 3.7
Tobacco use in previous six months-no. (%) 788 (22.1) 9,909 (22.3)
Prescription medication in previous two months-no. (%)    
Statin 43 (1.2) 569 (1.3)
Antipsychotic agent 29 (0.8) 442 (1.0)
Stimulant 9 (0.3) 189 (0.4)
Results
Outcome Sickle Cell trait

(n = 3564)

No Sickle Cell Trait

(n = 44,380)

Hazard Ratio (95%Confidence Interval [CI]) p-value
Exertional rhabdomyolysis-no. (%) 42 (1.2) 349 (0.8) 1.54 (1.12 to 2.12) 0.008  
Death-no. (%)        
Any cause 7 (0.2) 89 (0.2) 0.99 (0.46 to 2.13) 0.97
Battle-related 1 (<0.1) 13 (<0.1) 0.96 (0.13 to 7.37) 0.97
Non-battle related 6 (0.2) 76 (0.2) 0.99 (0.43 to 2.27) 0.98
Adverse Events Common Adverse Events: N/A
Serious Adverse Events: N/A
Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions Sickle cell trait was not associated with a higher risk of death than absence of the trait, but it was associated with a significantly higher risk of exertional rhabdomyolysis.

 

The results of this study are significant as two previous population-based studies of sickle cell trait and adverse outcomes showed substantially higher risks (by a factor of 20 to 30) of sudden, unexplained deaths among black military recruits and of exertion-related deaths among black football players participating on National Collegiate Athletic Association (NCAA) Division 1 teams. [2,5]

This study is unique because the hemoglobin type of each participant in the analytic study population was confirmed by laboratory results rather than by self-report or medical history.

Another noteworthy finding is that obesity and tobacco use were each associated with a significantly higher risk of exertional rhabdomyolysis, and the magnitude of the risk was similar to that associated with the presence of sickle-cell trait (tobacco use: hazard ratio, 1.54; 95% CI, 1.23 to 1.94; p<0.001 and obesity: hazard ratio, 1.39; 95% CI, 1.04 to 1.86; p = 0.03). A recent prescription of an antipsychotic or statin medication was associated with an approximate tripling of the risk of exertional rhabdomyolysis in this study population, as compared with no use of the specified medications (antipsychotic use: hazard ratio, 3.02; 95% CI, 1.34 to 6.82; p = 0.008 and statin use: hazard ratio, 2.89; 95% CI, 1.51 to 5.55; p = 0.001). [1]

 

References:

 

  1. Nelson DA, Deuster PA, Carter R, Hill OT, Wolcott VL, Kurina LM. Sickle Cell Trait, Rhabdomyolysis, and Mortality among U.S. Army Soldiers. N Engl J Med. 2016; 375:435-442

 

  1. Kark JA, Posey DM, Schumacher HR, Ruehle CJ. Sickle-cell trait as a risk factor for sudden death in physical training. N Engl J Med. 1987;317:781-7

 

  1. Koppes GM, Daly JJ, Coltman CA, Butkus DE. Exertion-induced rhabdomyolysis with acute renal failure and disseminated intravascular coagulation in sickle cell trait. Am J Med. 1977;63:313-317.

 

  1. Sickle Cell Disease Association of America. http://www.sicklecelldisease.org/about/sickle-cell-101/. Accessed August 15, 2016.

 

  1. Harmon KG, Drezner JA, Klossner D, Asif IM. Sickle cell trait associated with a RR of death of 37 times in National Collegiate Athletic Association football athletes: a database with 2 million athlete- years as the denominator. Br J Sports Med. 2012;46:325-30.
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