DOT/FAA/AM-07/12 Office of Aerospace Medicine Washington, DC 20591 First-Generation H1 Antihistamines Found in Pilot Fatalities of Civil Aviation Accidents, 1990–2005 Ahmet Sen Ahmet Akin Gülhane Military Medical Academy Department of Aerospace Medicine Eskisehir 26020, Turkey Kristi J. Craft Dennis V. Canfield Arvind K. Chaturvedi Civil Aerospace Medical Institute Federal Aviation Administration Oklahoma City, OK 73125 May 2007 Final Report NOTICE This document is disseminated under the sponsorship of the U.S. Department of Transportation in the interest of information exchange. The United States Government assumes no liability for the contents thereof. ___________ This publication and all Office of Aerospace Medicine technical reports are available in full-text from the Civil Aerospace Medical Institute’s publications Web site: www.faa.gov/library/reports/medical/oamtechreports/index.cfm Technical Report Documentation Page 1. Report No. 2. Government Accession No. 3. Recipient's Catalog No. DOT/FAA/AM-07/12 4. Title and Subtitle 5. Report Date First-Generation H1 Antihistamines Found in Pilot Fatalities of May 2007 Civil Aviation Accidents, 1990–2005 6. Performing Organization Code 7. Author(s) 8. Performing Organization Report No. Sen A,1 Akin A,1 Craft KJ,2 Canfield DV,2 Chaturvedi AK2 9. Performing Organization Name and Address 10. Work Unit No. (TRAIS) 1Department of Aerospace Medicine 2FAA Civil Aerospace Medical Institute Gülhane Military Medical Academy P.O. Box 25082 11. Contract or Grant No. Eskisehir 26020, Turkey Oklahoma City, OK 73125 12. Sponsoring Agency name and Address 13. Type of Report and Period Covered Office of Aerospace Medicine Federal Aviation Administration 800 Independence Ave., S.W. Washington, DC 20591 14. Sponsoring Agency Code 15. Supplemental Notes This work was accomplished under the approved task AM-B-07-TOX-202. 16. Abstract First-generation H1-receptor antagonists are popularly used for alleviating allergy and cold symptoms, but these antihistaminics cause drowsiness and sedation. Such side effects could impair performance and, thus, could be the cause or a factor in accidents. Therefore, the prevalence of these antagonists was evaluated in aviation accident pilot fatalities. During civil aircraft accident investigations, postmortem samples from pilots involved in fatal aviation accidents are submitted to the Civil Aerospace Medical Institute (CAMI) for toxicological analyses. These analytical findings are stored in a database. This CAMI Toxicology Database was examined for the presence of the first-generation antihistamines in pilot fatalities of civil aircraft accidents that occurred during a 16-year (1990–2005) period. Of 5383 fatal aviation accidents from which CAMI received specimens, there were 338 accidents wherein pilot fatalities (cases) were found to contain the antihistaminics brompheniramine, chlorpheniramine, diphenhydramine, doxylamine, pheniramine, phenyltoloxamine, promethazine, and triprolidine. Of the 338 accidents, 304 were general aviation accidents; 175 of the 338 pilots held private pilot airman certificates. Antihistamines were detected alone in 103 fatalities (1 antihistamine in 94 fatalities and 2 antihistamines in 9), while other drug(s) and/or ethanol were also present in an additional 235 fatalities. Thirty-five of the 338 fatalities had more than 1 antihistamine. The antihistamines were found in approximately 4 and 11% of the fatalities/accidents in 1990 and in 2004, respectively. Although blood was not available for the analyses in all 338 cases, the blood concentrations (ng·mL•1) were 5–200 (n = 8) for brompheniramine; 4–6114 (n = 67) for chlorpheniramine; 9–3800 (n = 125) for diphenhydramine; 10– 1309 (n = 33) for doxylamine; and 4 (n = 1) for phenyltoloxamine. The use of antihistamine(s), with/without other drug(s) and/or ethanol, was determined by the National Transportation Safety Board to be the cause in 13 and a factor in 50 of the 338 accidents. The majority of the accidents were of the general aviation category. There was an overall increasing trend in the use of antihistamines by aviators during the 16-year span. Blood levels of the antihistaminics were in the sub-therapeutic to toxic range. Findings from this study will be useful in investigating future accidents involving antihistamines. 17. Key Words 18. Distribution Statement Forensic Sciences, Toxicology, Pilot Fatalities, First- Document is available to the public through the Generation Antihistamines, Antihistaminics, Aviation Defense Technical Information Center, Ft. Belvior, Accident Investigation VA 22060; and the National Technical Information Service, Springfield, VA 22161 19. Security Classif. (of this report) 20. Security Classif. (of this page) 21. No. of Pages 22. Price Unclassified Unclassified 17 Form DOT F 1700.7 (8-72) Reproduction of completed page authorized i ACKNOWLEDGMENTS The Government of Turkey is acknowledged for allowing the participation of Dr. Ahmet Akin and Dr. Ahmet Sen in the Federal Aviation Administration (FAA) International Exchange Visitor Program at the FAA Civil Aerospace Medical Insti- tute, Oklahoma City, Oklahoma. The authors are grateful to Dr. Selim Kilic, Department of Epidemiology, Gülhane Military Medical Academy, Ankara, Turkey, for performing statistical analyses. iii IRST ENERATION NTIHISTAMINES OUND IN ILOT ATALITIES F -G H1 A F P F OF CIVIL AVIATION AccIDENTS, 1990–2005 INTRODUCTION postmortem forensic toxicology undertaking, findings on the prevalence of FGH1AIs in civil aviation accident pilot Although many drugs are pharmacologically classi- fatalities, along with their concentrations in the associ- fied under the category of first-generation H1-receptor ated postmortem blood samples, would be useful in the antagonists (FGH1AIs), all of them are not used for al- investigations of FGH1AI-involved aviation accidents. leviating allergy and common cold symptoms (24). The Therefore, relevant databases were searched to retrieve most commonly used FGH1AIs for treating these medical the applicable necessary information. The findings from conditions are azatadine, bromazine, brompheniramine, the database searches are presented herein. carbinoxamine, chlorpheniramine, clemastine, diphen- hydramine, doxylamine, pheniramine, phenyltoloxamine, METHODS promethazine, pyrilamine, and triprolidine (27). These 13 antihistaminics are primarily marketed as nonpre- Postmortem Samples scription medications; however, depending upon their During the investigation of civil aviation accidents pharmaceutical formulations and preparations, they are occurring within U.S. jurisdiction, autopsied biologi- also marketed as prescription drugs. These FGH1AIs are cal samples—blood, urine, vitreous fluid, spinal fluid, available in various tablet, capsule, caplet, elixir, oint- brain, lung, heart, liver, kidney, and/or other sample ment, and/or injection forms with or without analgesics, types—collected from pilot fatalities are submitted to decongestants, antitussives, expectorants, and/or other the Civil Aerospace Medical Institute (CAMI) for toxi- H1 antagonists (19,20). cological evaluation (3). The submission of specimens is FGH1AIs depress the Central Nervous System (CNS), coordinated through the Federal Aviation Administration’s causing diminished alertness, slowed reaction times, dizzi- (FAA’s) Office of Accident Investigation by the National ness, and sedation (24). Therefore, patients are cautioned Transportation Safety Board (NTSB), which is responsible against operating a vehicle or machinery while using the for investigating all U.S. civilian aircraft accidents. The medications (20,27). FGH1AI-induced sedation does collected samples are shipped in the FAA’s TOX-BOX not only comprise subjective symptoms, like sleepiness, evidence containers (8). The aviation accidents include lethargy, or subtle confusion, but also reflects the objec- accidents associated with registered, as well as unregis- tive impairment of superior cognitive functions (15). tered, aircraft. The first-generation antihistamines have been reported to be associated with significant sleepiness and impaired Toxicology performance on flight tasks, resulting in slowed reac- The submitted biological samples are routinely ana- tion times, memory difficulties, and impaired vigilance lyzed for the presence of carbon monoxide and hydrogen (6,12,16–18,22,28,29). Consequently, this group of cyanide, ethanol and other volatiles, and drugs (7,8). The medications is known to impair superior cognitive func- drugs include a wide range of prescription, nonprescrip- tions and, thus, these drugs have the potential for impair- tion, and illicit drugs. The analyses of all of these foreign ing in-flight performance. Because of the adverse effects, substances (analytes) are conducted according to estab- the first-generation antihistamines are not approved for lished standard laboratory procedures, including initial use by civilian aviators (10,13,23). and confirmatory/quantitative analyses (8). Such analyses The presence of pheniramine in aviation accident are dependent upon the nature of analytes, the sensitivity fatalities has been documented as early as the 1960s (5). and specificity of analytical methods used, and the avail- Brompheniramine, diphenhydramine, and pheniramine ability of specimen types and their amounts. FGH1AIs have been reported to be present in the ground transporta- in the biological samples were screened (initial analysis) tion fatalities in 1978–1979 (9) and chlorpheniramine in by high-performance