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'tvrw. I HLTSrC LIBRARY a340 128680c The New Englarj^D A> xlvrni^ini *ctl:w MSxHIBff to- 740 Journal of Mediae BatabUahad la 1SU u* The NSW ENGLAND 40CSNAL O_ _F st SVSGBBT VOLUME 321 NOVEMBER 2, 1989 NUMBER 18 Original Articles Suicidal Ideation and Suicide Attempts in Panic Disorder and Attacks.................. Myrna M. Weissman, Gerald L. Klerman, Jeffrey S. Markowitz. and Robert Ovellftte 1209 The Effect of Parity on the Later Develop* meat of Non-Insulia-Dependent Diabetes Mellitus or Impaired Glucose Tolerance................................. Donna Krttz-Silverstkik, Elizabeth Barrett-Connor, and Deborah L. Wingard 1214 Asbestos-Associated Diseases in a Cohort of Cigarette-Filter Workers........................ Jakes A. Talcott, Wendy A. Thurber, Arlene F. Kaktor, Edward A. Gaeksler, Jane F. Danahy, Karen H. Aktman, and Frederick P. Li 1220 Mechanisms of Disease Hypercapnia..................... Steven E. Weinberger, Richard M. Schwartzstein, and J. Woodrow Weiss 1223 Medical Intelligence Drug Therapy -- Oral Hypoglycemic Agents 1231 John E. Girjch Reversible Cardiac Dysfunction Associated with Interferon Alfa Therapy in AIDS Patients with Kaposi's Sarcoma............. Lawrence R. Dlvton. Roblri . Walker. Josfph A. Kovacs. Bttrev Herpin. Margaret Parker. Henry Masil. Anthony S. Favci. and H. Clifford Lane 1246 Case Records of the Massachusetts General Hospital A 74-Year-Old Woman with Subxiphoid Pain and Narrowing of the Esophagus.............................................. Mark B. Orrinoer and Evgeni J. Mark 1249 Editorial Panic Attacks and the Risk of Suicide........ Peter Reich 1260 Sounding Board Health Care Tickets for the Uninsured: First Class, Coach, or Standby?...................... 126] H. Gilbert Welch Correspondence Wider Use of Testing for HIV Infection? ...... Mortality among 1862 HIV-Antibody-Positive Civilian Applicants for Military Service: Preliminary Results ....................................... Tuberculin Skin Reactivity is HIV-Seropositive Intravenous Drug Addicts ...................... .. Acyclovir to Prevent Cytomegalovirus ^Infection in Renal-Graft Recipients ............................. Permanently Decreased Renal Blood Flo* *td Hypertension after Lithotripsy..................... Cholesterol Embolization after Treatment with Tissue Plasminogen Activator ....................... Treatment of Inadvertent Intrathecal Injection of Vincristine............................................ Increasing Prevalence of Excessive Erythrocytosis with Age among Healthy High-Altitude Miners..................................... More on Rhabdomyolvsis Associated with Cocaine Intoxication..................................................... A Proposal to Help New House Officers............. Our Stubborn Quest for Diagnostic Certainty ... 1265 1267 1268 1268 1269 1270 1270 1271 1271 1271 1272 Occasional Notes The Physiologic and Psychological Effects of tiie Bedside Presentation.................. Richard j. Simons. Robert G. Baily. Robert Zeus, and Clifford W. Zwiluch 1273 Book Reviews............................................. 1275 Notices.....................'................................... 1278 Information for Authors......................... 1280 Owned, Published, and CCopyrighted. 1989, by the Massachutens Medical Society 7> Ni*. I'toiAv: fi MiiWJNJ ,1>n\ tvjf-iTr . tr \rri.h tr,.n. rrtn.-n.il .din - N:..*ns.- t 95^-;R.-:- Subscripiion price: $*4 UO pet \r*r. Srmd-cla*> pnMapr paid at Bo&mn and at additional milinc ofhrcs. POSTMASTER Send addrjrss ebanco to P.O. Box 803. Waltham. MA O.^M-OXoT a * I??*1 THE NEW ENGLAND JOURNAL OF MKDICIKK N\ 2. 15510 ASBESTOS-ASSOCIATED DISEASES IN A COHORT OF CIGARETTE-FILTER WORKERS James A. Talco7-i, M.D., Wendy A. Thi'rber, R.N., Arlene F. Kantor, Dr.P.H., B.A., H.Edward A. Gaensi.er, M.D.. Jane F. Danahy, Karen Antman, M.D., and Frederick P. Li, M.I). Abstract To estimate the effects on health of occupa tional exposure to crocidolite, a highly toxic form of asbes tos. we studied a cohort of 33 men who worked in 1953 in e Massachusetts factory that manufactured cigarette fil lers containing crocidolite fibers from 1951 to 1957. Twenty-eight of the men have died, as compared with 8.3 deaths expected. This increased mortality was attribut able to asbestos-associated diseases. Fifteen deaths were caused by cancer, as compared with 1.8 expected (relative risk, 8.2; 95 percent confidence interval, 4.6 to 13.4), including eight from iung cancer, five from malig nant mesothelioma, and two from other types of cancer. There were seven deaths from nonmalignant respiratory disease, as compared with 0.5 expected (relative risk, 14.7; 95 percent confidence interval, 5.9 to 30.3), of which five were due primarily to asbestosis. In contrast, the mortality rates from cardiovascular diseases and all other causes were not increased. Four of the five living workers have pulmonary asbestosis; three of them have recently diagnosed cancers, including two additional lung cancers. We conclude that the extremely high morbidity and mor tality in these workers were caused by intense exposure to crocidolite asbestos fibers. (N Engl J Med; 321:1220-3.) THE inhalation of asbestos may result in pulmo the study (the mortality analysis), or until the diagnosis of a first nary' fibrosis (asbestosis),1 lung cancer,2 or malig cancer (the morbidity analysis). There were 773 and 766 personnant mesothelioma.5 We recently observed three casesytievaerlys.of follow-up in the mortality and morbidity analyses, respec of malignant mesothelioma among former employees We attempted to contact each worker, or his next of kin if the of a Massachusetts company that manufactured ciga rette filters containing crocidolite asbestos from 1951 to I957.4 We now report a marked excess in mortality and morbidity from asbestos-related diseases in an independent cohort of 33 workers who made these worker had died. We requested information about the worker's em ployment and health history' and asked permission to review his medical records. For 18 workers, this information was supplement ed with data gathered in an ongoing health survey of companyemployees begun by one of us in 1971. For 29 workers we were able to determine the total duration of employment by the company; for filters. 23, the length of time spent manufacturing cigarette filters was known. Methods An experienced nosologist determined the underlying cause of death from the death certificates of ml! deceased workers Medical From 1951 to 1957, a subsidiary- of a Massachusetts company records establishing the cause of death independently were availa nanufactured cigarette filters according to a patented "dry" and dusty process in which asbestos, cotton, and acetate fibers were mechanically mixed, carded, and deposited on crepe paper.1 The ble for 22 of the 28 deceased workers, including all those whose death was possibly related to asbestos. These included the results of a postmortem examination in 8 workers, other pathology repons for parent company produced other asbestos-containing products be 10, and other medico] records for 4. Only death-certificate diagnoses tween 1942 and 1971 by the conventional "wet" papermaking proc were obtained for six workers. AH diagnoses of cancer were verified ess, in which asbestos was added to a pulp. Crocidolite, a member by* a pathology report (18 workers) or radiographic and endoscopic of the amphiboie family of long, straight asbestos fibers, was the studies (I worker). Asbestosis was diagnosed in deceased workers primary type of asbestos used, It is strongly associated with asbesto- on the basis of the presence of pulmonary fibrosis and asbestos sis, lung cancer, and malignant mesothelioma,1'1 presumably be bodies (in 12 workers) or clinical studies (in $ workers). In living cause of its unusual resistance to degradation in the lung.1 Measure workers, asbestosis was diagnosed on the basis of a chest radiograph ments at six production locations in the factory on October 27,1952. scored by one of us as 1/0 or more, according to the Interna showed an average of 80 particles of asbestos dust per milliliter of tional Labour Office's scheme for the classification of pneumoco air. which was within the then-current Massachusetts standard of nioses.* 175 particles per milliliter. These levels greatly exceed the current Relative risks for mortality. or the ratio of the numbers of death' National Institute for Occupational Safety and Health standard of observed to the numbers expected, were based on death rates specif 0.1 asbestos fibers (not panicles) per milliliter. ic to age and calendar time, according to cause, among the U.S. A list of all employees directly involved in manufacturing ciga male population.* The numbers of newly diagnosed (incident) can rette filters at the factory on September 22,1955. was obtained from cers observed, other than malignant mesothelioma, were compared th< records of the Massachusetts Division of Occupational Hy with those expected on the basis of incidence rates specific to ac< giene. The cohort included none of the faciory workers previously and calendar time, according to site, from the Connecticut Turk-: described by us.4 The median age of these 33 white men on that date Registry.,r' More stable expected values for malignant mescihrin>- was 34 years (range, 21 to 67). The subjects were studied from that ma, an uncommon tumor, were calculated with data from the Sur date until tbeir death or until December 3), 1988, the closing date of veillance, Epidemiology, and End Results program of the National Cancer Institute, which provided rates in approximately 10 percent Frorr. the Division of Biosutistics and Epidemiology. Dana-Farber Cancer Josriiute (J.A.7,, A.F.K.. K.H.A.. F.PX.t. the Department of Medicine. Har vard Medical School (J.A.T.. K.H.A. F.P.L.). the Clinical Studies Section. Clinic*.' Epidemiology Branch. National Cancer institute (W.A.T.. A.F.K.. of the U.S. population for the time periods 1973 to 197(> and 1577 u> IQgQM.u Connelly R: persona) communication). In the calcu lationsf significance and confidence intervals, on underlying Pois son distribution was assumed.1' J.F.D. F.P.L.), and the Division of Thoracic Services. Boston University School cf Medicine (E.A.G.). Boston. Address reprint requests to Dr TaJconat Results die Daiu-Fvber Cancer Institute. 44 Bmney St.. Boston. MA 02115Supportedin pan by giant (IF32CA0S242) from the Nations) Cancer Institute and by the Kellogg Foundation Program a Choice} Effectiveness. Ms Thurber is the recipient of an Amy Potter Research Nursing Fellowship, and Dr. C*.uk.-r has received a Research Career Award (HU l"3i from the National Mean. Lang, end Blood Institute Twenty-eight (85 percent) of the 33 workers had died, and 5 v*re alive. The 28 deaths ohserved were 3.4 times the number expected (8.3 deaths) on the basis of mortality rates for the U.S. whjty male patvt- V..! S.'l N... IN ASlXrOS ASStK:|ATKI)|)!sr.JNMMN^K*Aki:rn..MI.Tr.R WORMRS- lAI-COTI 1"l Al. |2?| Table 1 Observed and Expected Numbers ot Deaths among 33 Cigarette-Fitter Makers. According to Cause ot Death.* r*i*w < htiH No < Dl AIMS luiAtiM 8r* fV* Hi oouavtj. itnnn> rKvr> <tct> i4(v2.> IS 1.8 DiniV' of respowon mtem 7 0.5 <)CJ> 460-5)W bitcaw. of cimdMofy system fiCD 390-45#) 5 4.1 All ocher 1 1.9 Tout 28 8 3 8 2 <4.6-13 4) 4.7 <5.0-30.3) 1.2 (0.4-2.8) 05 (0.0-3.0) 3.4 <2.2-4.9> *Ct denote? confidence >ml, and KD Fterr--ianil Qnutfictueo H Daenacv lan'on (Table 1). This increased mortality was primar ily attributable to asbestos-associated cancers and other respiratory diseases. Eight deaths were caused by lung cancer (relative risk, 13.1; 95 percent confi dence interval, 5.6 to 27.2), five by malignant meso thelioma, and five by asbestosis. Another worker, whose death certificate listed emphysema as the cause of death, died seven months after the diagnosis of a lung adenocarcinoma. The relative risk of death was higher during pro gressively later periods of follow-up: 2.1 during the first 10 years, 2.4 during the second decade, and 4.8 thereafter (17 deaths observed; 95 percent confidence interval, 2.8 to 7.7). In the most recent follow-up peri od, 1973 to 1988, six deaths were due to lung cancer, five to mesothelioma, three to asbestosis, and one each to rectal cancer, bladder carcinoma, and acute myo cardial infarction. Cancer developed in 19 of the 33 workers in the cohort during the period of follow-up, as compared with 3.5 cases of cancer expected (Table 2). Among the 19 were 2 living workers with lung cancer and 1 with multiple myeloma. Eleven had lung cancer and 5 had malignant mesotheliomas. Twenty-five workers (76 percent) were known to have been smokers during their lifetimes, 5 (15 percent) were nonsmokers, and for 3 (9 percent) smoking status was unknown. All 11 workers in whom lung cancers developed had been cigarette smokers. In 3 of these patients, the can cers were not diagnosed in communities near the factor), and at the time of diagnosis the medical histories obtained on hospital admission and the discharge summaries did not mention expusure to as bestos. Asbestosis was diagnosed in 19 workers, in cluding the 5 workers who died front the disease. 10 who were diagnosed incidentally on the basis of pa thology specimens, and 4 of the 5 men who were still alive. For 23 workers whose period of cigarette-filter mak ing could be determined, the median duration of em ployment was 1.7 years (range. 0.7 to 4). The median time spent at otherjobs in the paper company before 1971, when the use of crocidolite ended, was 16 years (range. 0 to 25). The median interval?* from the first e?:.*i.\uu* to asbestos to the diagnosis of cancer were 28 years for lung eanrrt (range. 17 to40j and 34 years foi malignant mesothelioma (range. 26 to 37). We were unable to find an association between either duration of filter making or total time employed by the compa ny and asbeslos-rclaird deaths, whirl) predominated in all exposure groups. For example, of six workers with fewer than 2.5 years of other work at the compa ny, three died of lung cancer, one died of peritoneal mesothelioma, one died of asbestosis, and one is alive. No worker had a recognized exposure to asbestos out side the workplace. Two workers were exposed to oth er types of dust -- one as a cotton weaver for 4 years and one (whose diagnosis at death was asbestosis) as a coal miner for 20 yean. Discussion The 3.4-fold increase in the mortality rate in our cohort of cigarette-filter makers was almost entirely attributable to the effect of 18 deaths from asbestosassociated diseases: lung cancer, malignant mesotheli oma, and asbestosis. Lung cancer probably contribut ed to another death and has been diagnosed recently in two of the five living workers. Asbestosis developed in at least 19 of 33 workers, or 58 percent. The relative risk of death from lung cancer in this cohort, 13.1, is similar to the highest reported rates in other industries, which range'from 1.5 to 7.O.14'19 Since differences in analytic techniques and the composition of study and reference populations may influence rela tive risks,30 these comparisons are only approximate. Malignant mesothelioma and asbestosis are rare causes of death, for which the population rates are less reliable than those for lung cancer. Each accounted for 5 of the 28 observed deaths in our cohort (18 per cent) -- a large proportion even among asbestos workers.,9,3, Several factors may account for such high death rates from asbestos-related diseases in our study. One is the predominant exposure to crocidolite asbestos, which has been associated with a higher risk than oth er asbestos fibers for malignant mesothelioma and possibly other asbestos-associated diseases.*'--2 In most industrialized nations other than the United States, crocidolite is now regulated more strictly than other asbestos fibers.-"* The outcomes in cohort> of Table 2. Observed and Expected Incidence of Cancer among 33 < Cigarette-Fitter Makers, According to Site * Tvh or Cantu Ltttif Malignant mesothelioma! Other malignant cancers All No. or Cantu? OSIVU> xmnp* ir 0.7 $ 0.01 3 2.7 19 3.5 Ossrmp'ExnrTrr <W. Cl'* 15.1 (7.5-23.0* 460 1IS0- J0#o 1.1 <0.2- 3.2* 5.5 i? 3-5 6* * Cl denote, confidence Metva? tinelode? tout tquamrv-cell tuevv mo adewccvtn.xu'. dm. smt*-c*i* tuirv'T* <*h toft-cell nmtx. and one ondifiemsjted tunve */r. fftrec. tfh- foma-v rtf; **- t\ ar r.nezrr. if-/ * i:v: Tin: ni:\v kngi,am>journal oi Mr-niciM. Nov. 2, 19B! manufacturing workers with a predominant exposure to crocidofitr have been described previously in Brit ain*' and Canada.'*' but not the United States. In ad dition. the nature of the industrial process may have had an independent effect on outcome. McDonald and rnworkers found a higher incidence of lung cancer (at comparable estimated levels of exposure to asbestos) among asbestos textile workers than among asbestos millers and miners and manufacturers of friction products. They hypothesized that the unrecognized exposure of textile workers to croddolite or the gen eration of a higher proportion of respirable sizes of asbestos fiber in textile manufacturing may explain the difference.18 The dry, dusty mechanical mixing and carding of asbestos in cigarette-filter making may also have exposed our cohort to a highly respira ble dust. Difficulties in the retrospective estimation of the in tensity and duration of occupational exposure to as bestos are common and were encountered in the cur rent analysis. Other published reports suggest a dose-response relation between exposure to asbestos and asbestosis, lung cancer, and perhaps malignant mesothelioma.6,22 The measured levels of asbestos dust at the cigarette-filter factory we studied were much higher than the current standard, but industrial exposures of this magnitude were often permitted in industrialized nations at the time.37 Moreover, the dust measurements obtained at this workplace on a single day may not be representative. Asbestos-associ ated diseases developed in nearly all the 33 workers in this cohort, making it difficult to identify additional factors in the work environment that modify risk. Al though the duration of exposure was oot known in the case of all workers, very brief exposures were associat ed with the subsequent development of asbestos-relat ed disease; one man who died of asbestosis 27 years later made cigarette filters for less than nine months and had no other exposure to asbestos. Thus, even a brief exposure to this dry process apparently resulted in a high risk, a possibility that is supported by an earlier report of a worker employed part-time for nine months as a cigarette-filter maker, in whom sympto matic asbestosis developed 18 years later.28 However, the latency period observed in our subjects between the first exposure to asbestos and the diagnosis of can cel was not shorter than that observed previously.** We could identify no incremental risk of asbestos-re lated disease that was incurred by additional employ ment t the parent company, despite the additional exposure to crocidolite dust. In the manufacturing of other paper products at die company, water was add ed to the asbestos and other fibers to produce a pulp. The wet pulp probably produced a less dusty environ ment during mixing and handling than did the dry process of making cigarette filters. Cigarette smoking, a known cocarcinogen with asliestos for lung cancer, probably contributed to the high incidence of this disease in our cohort. However, the proportion of men in our study who smoked at any time (76 percent) was within the reported range (67 to 94 percent) for industrial cohorts exposed to asbestos in Western nations.50 In three workers with lung cancer, exposure to as bestos appears to have been overlooked at first as a potential cause. These omissions may reflect the fact that asbestos has a much less common contributory role than cigarette smoking in causing lung cancer. However, documenting occupational exposure to asbestos has medical and legal importance for the patient with lung cancer, which is a more common asbestos-related cause of death than malignant' meso thelioma or asbestosis.51 These results emphasize that intense, localized oc cupational exposures to asbestos may have effects dec ades after the exposures cease and that such effects may remain unrecognized and unreported. Physicians must be alert to the appearance of asbestos-related diseases from novel sources of industrial exposure. The risk of such diseases in persons who smoked ciga rettes containing this filter material is unknown. We art indebted to Dr. Rose Goldman for assistance in locating the records of the Massachusetts Division of Occupational Hygiene and to Drs. Brian MacMahon, RobertJ. Mayer, and Colin Begg for helpful comments on the m*nusaipi. Rznaixas 1. Maewcibcj ERA. The ouiunntt f pulmonary fibrosis and other pulmo nary affections ta asbestos woken. J lad Hyg 1930; 12:198*222.239-57. 2. DoOR. Mortality from tog cases asbestos worfcen. BrJ tad Med 1955; 12:81-6. 3. Wagner JC, Sieggs CA, Martian? P. Diffuse plan} mrsothetioma and Mbetios exposure in tbe North Worere Cape Province. BrJ lad Med 1960; 17:260-71. 4. Takoe J, Umber W, Pannier E. Ananas K, Li FP. Meao&ebooa in manufacturers of usbcstos-cuuamung cigarette fibers. Lancet 1987; 1: 392. 5. Knodsoo HW. Method of making a fiber for labacco rake. Patent 2,765.515. Washington. D.C.: IMaed States Patent Office. October 9. 1956. 6. Mosanan BT. Gee JBL. Asbestos-related diseases. N Engl J Med 1989. 320:1721-30. 7. W agner K. Bern C. Skidmore JW". Timbrel] V. Tbe effects of tbe inhala tion of asbestos in rats. Sr J Cancer 1974; 29.252-69. 8. international Labour Office. Gudebaes for die me of 1L0 International GassiiScation of Radiographs of Pneumoconioses. Rev. cd. Occupation*] mfety and health series no. 22. Gaeva international Labour Office. 1980. 9. McnsonRR. Analysis of relative m-vival and proportional mortality. Coenput Biomed Res 1974: 7:325-32 10. Heston IF. Kell) JAB. Meigs JW.Flannel) JT. Forty-five years of cancer incidence in Connecticut 1935-79 CusanoMM. YoungJLJr.eds. Nation al Cancer Institute monograph 70 W ashington. D.C.: Government Printing Office. 1986. (NIH publication nr. 86-2652.) 11. Spinas R. Beebe GW, Conaelty RR. ct ai. Recent trends in mesothelioma incidence in the United States. As J Med 1986; 9:397407. 12 Connell) RR. Spinas R. Myers MH. ftrey CL. Ftaumeni JF Jr. Demo graphic patterns for mesothelioma c the United States. J Natl Cancer Inst 1987,78:1053-60. 13. Rothman KJ, Boice JD Jr. EpidnMogic analysis with a programmable calculator. Washington. D.C.: Gommenl Printing Office, 1979. (DHEW publication no. (N1H> 79-1649.) 14. SeHkoffll. Hammond EC. Scidsan H Mortality experience of insulation workers the Untied Stales wdGmada. 1943-76. Arm NY Acad Sci 197V. 330*1-116. 15. SeidmanH.SelikoffU.GelbSK Mortality experience of tmosite asbestos factor) workers: dose-renamac ictatMMiships 5 to 40 years after onset of ahon-senn work experience. Am J lad Med 1986: 10:479-514. \..i v-i v. ir. HYI'FW-ArSH - WEINBEKtll.R ET Al. 1223 Ik Koktnwnf\ Lfmrn R. Wapiw Jk Miwfelrn jvnrni'. !940- 1V75 mf workm nnpt.ncJ m an avHrMO' textile ln> ii.HI *nj pfelinF mam< lat'iuimr (a.-ilm In Lrmrn K. Dement JM. tJv itgsi and disease Pari hwoi V-.nl" III Patliat-** IuMi4x-tv IVW 17 Amivuonr HK. k Kkr*. Mi. Mu4 AW. KuN MS Mnrulii) n> miner' and milici>(mwKfiiiite in Hestem AumuIm Bi J fnd MeJ IVbf.45.5-13 lb MeDmuk! Al). Fn JS. Wooilr> AJ. MiDonjl) JC Dust exposure and mnrtaliH in an Amerkan chrx sntile fnctHwi pnrfurt' piani Bi J Ifld Med I9M.4J.151-7. IV. Finki-ktcm MM Mwtalin amnnp rtnpl'V'x;' oJ an Oaurto asleMW^emen: .laei.vx. Am Re* Respir Di I9W. )2V.754-61. 20. Frutnkin H. Beilin J Asheyo exposun and fiMrotmntmal aalipnancx review and meta-analyxis. Am J ind Med 198k. 14:79-95. 21. Nicholson WJ. Selikoff U. Seidman H. Lilis R. Fornh) P. Loop-tenr monalit) experience of etuysotik minets and millm in Tbetford Mines. Quebec. Ann N Y Acad Sci 1979. 330.11-21. 22. Becklakc MR Asbestos-related diseases o( the limp and other orpins: terr cpidemMopv and knpficaikjfts for clinical practice. Am Rev Resptr Ob 1976. 114: (7-227. 23. McDonald JC. McDonald AD. Epidemiology of metotbetiomi from tab- maied incidence. Prev Med 1977; 6:426-42. 2* WH H. Hughe* JM Arieio *> a puMie heahh rid. dneasc and nolicv. Aitnu Rex Public Health 1986. 7:171-92. 25. AchewetED.Gardner MJ.PippardEC.Crime U* Mortality of twogwuij*. of women who manufactured pv- masks from ctirvunik and crrcidoliu asbestos, a 40-year follow-up B> J Ind Med 1982. 39.344.8. 26. McDonald AD. McDonald JC Mesothelioma afin cncidohie exposure during pas mask manufacture Environ Res 197k. 17.34(^6. 27. Nowinski PA. Chronology f asbestos refutation in the Uniied States work places. In: Amman K. Atsner J. eds. Asbcstos-reiated malipnarwy. Orlando. Fla: Gnmc A Stratton. 198799134. 28. Goff AM. Gaenskr EA. Asbestcwh following brief exposure in ciparettc Biter manufacture. Respiration 1972.29:83-93. 29. Selikoff U, Hammond EC. Seidman H. Latency of asbestos disease among insolation workers in the United States and Cauda. Cancer 1980.46:2736- 40. 30. Department of Health ad Human Services. The health consequences of smoking: cancer and chronic lung disease in die workplace: a report of the Surgeon General. Washington. D C.: Government Printing Office. 1985: 206-8. (Publication no. DHHS (PHS) 85-30207.J 31. TaJcoti JA, Amman KH. Asbestosrelaied malignancy. Cun Probt Cancer 1988:12:135-78. /\ MECHANISMS OF DISEASE Frakkun H. Epstein, M.D., Editor \_________________ _____ __________________ ) HYPERCAPNIA Sjxven E. Weinberger, M.D., P-'CHARD M. SCHWARTZSTEIN, M.D., and J. Woodrow Weiss, M.D. exchanger (the lungs), the mechanical system (chest wall and respiratory' muscles), and the control system (respiratory centers of the central nervous system) contribute to the production of hypercapnia in dis ease states. PaCOjFundamental Factors Determining According to the standard equation, PaC03 is pro portional to carbon dioxide production (VC02) and inversely proportional to alveolar ventilation (Va): HYPERCAPNIA is a well-recognized consequence The constant K has the value of 0.863 mm Hg when of a variety of diseases, not only those involving carbon dioxide production is expressed in milliliters the lungs but also those affecting the neural, muscularp, er minute under standard conditions (dry gas at chest-wall. and circulatory components of the respira standard temperature and pressure) and alveolar ven tor)' system. In the past 20 years, we have developed a tilation is expressed in liters per minute under body- greater appreciation of the way these components in conditions (saturated gas at body temperature and teract in the genesis of hypercapnia. The impaired pressure). Alveolar ventilation represents the compo elimination of carbon dioxide that results in hyper nent of total ventilation per minute (expired minute capnia reflects noi merely abnormal lung function, but ventilation) that reaches perfused alveoli and is there rather a complex interaction of abnormalities in respi fore effective in the elimination of carbon dioxide. The reion- drive, muscle function, and lung function. portion of expired minute ventilation normally re In this papej. wc will first consider the fundamental maining in airways is "wasted** in terms of gas ex factors controlling the elimination of carbon dioxide change and is frequently referred to as dead-space and thus determining the partial pressure of arteri ventilation. al carbon dioxide (PaCO;) We will then discuss ` Because dead-space ventilation does not contribute the mechanisms and clinical implications of hyper to the elimination of carbon dioxide whereas alveolar capnia to establish the clinical context in which it ventilation does, any change in the relative amount of commonly occurs. We will stress the ways that the gas dead space to alveolar ventilation will alter the volume of carbon dioxide eliminated, assuming expired min From the CWk- A litr~ Rocaroh Ireuiiuic and th.* Harvard-Tnonidike Lab ors!.; hi-::.!?-:; Def-anmcn: -f Mcdictiu. Bflb laf! Hosprta! 4i.dHHrvxJN:.c;.c Si-nooI.biVior.. Addio-tcpim: requestsuD: Weinberger ti the I'ulmonsr. I n:t. Beth1me! Hospiist. ?3v Br,*>kiu>r Avc.. Bostoc. MA 02215. ' Surr.-vu.-i p-. i Pulmor.arv SprculucJ Cv..:.-r oi Research gr*n- (HL-19: -0 fr.^rr jh. V.*Hc..i. Lt"-:.anJ B'<v4Natpr!In-uiutoof Haa?r ute ventilation is constant. The partitioning of each breath into a dead space and an alveolar component is commonly expressed as the ratio between the volume of dead space and the total volume per breath -- i.e.. the tidal volume. This ratio, normally U.3U. can be altered by varying the tidal volume, since theanaiomi- . -* t '