Prevention of Exercise-Related Death Unexplained by Preexisting Disease (EDU) Associated with Sickle Cell Trait (SCT) without Hemoglobin (Hb) Screening or Hb Specific Management
Authors: Kark John A , Labotka Richard J. , Gardner John W , Ward Frank T 
Published: October 2019

Abstract
Abstract 945
We previously reported EDU rates 37.5 fold higher among recruits with SCT than without Hb S in military entry basic training for 1977–1981(Kark JA et al. New Engl J Med 1987;317:781-87, revised). The National Collegiate Athletic Association now requires identification of SCT athletes to reduce this risk, based on a single institution opinion untested by controlled observation, that EDU's of college football players with SCT were due to explosive rhabdomyolysis from exertional sickling unrelated to muscle heat production. A mild syndrome of “exertional sickling” was postulated, consisting of myalgia with flaccid leg weakness, usually responding to O2 inhalation within 30 minutes. Their plan is for non-medical personnel to use SCT screening results to assign SCT athletes training runs at reduced intensity and to pull them out of exercise for myalgia more often than non-Hb S athletes, practices chosen for safety but detrimental to their sports career (Gatorade Sports Science Institute Sports Science Exchange 2006;19:1-4). The cited football EDU's with SCT were actually associated with multiple risk factors for exertional heat illness (EHI), e.g. competitive activity with incomplete acclimation to heat, sustained hot weather, high body mass index, poor fitness, and/or heat-retaining clothing. We conducted a prospective controlled trial to reduce EDU rates for all recruits by better prevention of heat retention during exercise. We compared changes in EDU rates from 1977–1981 versus 1982–2001 at test recruit centers providing our intervention to changes at control centers using prior practice (Kark JA et al. Blood 1997; 90: 447a). The intervention included adjustment of observed water intake, exercise intensity, and work-rest cycle based upon the current heat index on site, early clinical assessment with rectal temperature for recruits who failed to keep up or became symptomatic, and early aggressive medical management of EHI. We did not alter training practices, exercise performance standards, or treatment by Hb type. O2 was given only for signs of failure to adequately oxygenate arterial blood. EDU rates at test centers were reduced 22-fold for those with SCT (0 deaths/ 29,500 recruits vs 14/37,300, significant with P=0.0003) and 2-fold for those without Hb S (6 deaths/1.8 million vs 15/2.05 million, not significant with P= 0.1), but were not substantially reduced at control centers for recruits with SCT (4 deaths/13,500 recruits vs 14/37,300, RR= 0.8, P=0.7) or for recruits without Hb S (6 deaths/ 1 million recruits vs 15/2.1 million, RR=0.85, P=0.8). Despite not screening for SCT, recruits at Army test centers had a significant reduction of mortality with SCT (0 deaths/21,000 recruits vs 7/17,100, RR= 0.06, P=0.002) and without Hb S (4/1.1 million recruits vs 15/2.1 million, RR= 0.3, P=.048). Reducing heat retention with exercise may have eliminated excess EDU with SCT. Survival with SCT did not require prevention of ordinary exertional sickling by measures targeted to SCT. Our intervention appeared to reduce EDU's for people without Hb S by nearly 50%. We also studied all cases of recruit EHI at one basic training center using our intervention during 1979–1991. Rates of non-fatal EHI were 32 cases/5010 recruits with SCT versus 1,834 cases/263,000 recruits without Hb S, a relative risk that was not significant (RR=0.92, P=0.7). The incidence of symptomatic muscle injury, ataxia, falls, hypotension, tachycardia, elevated biochemical markers for EHI, and non-focal encephalopathy were not significantly different for SCT vs Non Hb S recruits. We did not identify a specific non-fatal syndrome associated with SCT. The predominant mechanism of EDU with SCT might involve initial severe EHI from heat retention, subsequently exacerbated by complications related to Hb S, rather than initiation of tissue damage by exertional sickling in the absence of EHI. Proof for any form of exercise might require similar descriptions of all EHI and EDU cases among at least 27,000 people with SCT and population controls during at least one hot season of heavy exercise. Prevention of this morbidity and mortality for SCT probably does not require genetic screening in the absence of effective specific remedies. It may be more effective to provide appropriate prevention and management of exertional heat illness, including isolated rhabdomyolysis, to all exercising people regardless of hemoglobin type.

Disclosures:
Labotka: HemaQuest Pharmaceuticals, Inc: Research Funding.