Document oemXddnbm9O2M9L2oLKp8Oq8r

MUSC LIBRARY a 34 0 126680c .ii i ms The New Encgp rleactn'vd^ PLAINTIFF'S EXHIBIT Journal of Madf^ie ^JtD SI BfUblUbed In U u The NEW ENGLAND JOURNAL OP xMhOK A&D SUKOXBY VOLUME 321 NOVEMBER 2, J989 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 Oi ellette 1209 The Effect of Parity on the Later Develop ment of Non-Insulin-Dependent Diabetes Mellitus or Impaired Glucose Tolerance ...................................... Donna Kritz-Silvlrstlin. Elizabeth Barrftt-Connor, and Deborah L Wingarij 1214 Asbestos-Associated Diseases in a Cohort of Cigarette-Filter Workers............................ James A. Talcott, Wendy A. Thurber, Arlene F. Kantor, Edward A. Gaensler. Jane F. Danahy, Karen H. Antman, and Frederick P. Li 1220 Mechanisms of Disease Hypercapnia........................................................... Steven E W einberger. Richard M Schwartzstein. andJ. Woodrow Weiss 1223 Medical Intelligence Drug Therapy -- Oral Hypoglycemic Agents John E. Gerk h Reversible Cardiac Dysfunction Associated with Interferon Alfa Therapy in AIDS Patients with Kaposi's Sarcoma............ Lawrenu R. Din ion. Robirt L W.m.kll. Josil'll A Kovals. Bi tm y Hirbiv Margake'i Parker. Hlnka Masie. Anthony S. Fai ci. and H. Clifford Lam 1231 1246 Case Records of the Massachusetts General Hospital A 74-Year-Old Woman with Subxiphoid Pain and Narrowing of the Esophagus.............................................. Mark B. Orkingik and Legist ]. 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?...................... FI. Gilbert Welch 1261 Correspondence Wider Use of Testing for HIV Infection? ............. Mortality among 1862 HIV-Antibody-Positive Civilian Applicants for Military Service: Preliminary Results............................................... Tuberculin Skin Reactivity in HIV-Seropositive Intravenous Drug Addicts................................... Acyclovir to Prevent Cytomegalovirus Infection in Renal-Graft Recipients................................... Permanently Decreased Renal Blood Flow and 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 Rhabdomyolysis 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 the Bedside Presentation.................. Richard J. Simons. Robert G Bails. Roblrt Zeus, and Clifford W. Zwjllich 1273 Book Reviews..................................................... 1275 Notices................................................................... 1278 Information for Authors.............................. 1280 Owned, Published, and ' Copyrighted. 1989. b\ the Massachusetts Medical Societ\ 1 HI. M W KN(;i,ANM Joi'KNM Ol MI.I)ICIM. N..\ >. I ,'<* ASBESTOS-ASSOCIATED DISEASES IN A COHORT OF CIGARETTE-FILTER WORKERS James A. Taj.con, M.D.. Wendy A. Thdrber. R.N., Ari.ene F. Kantor, Dr.P.H., Edward A Gaensi.er, M.D.. Jane F. Danahy, B.A.. Karen H. Antman. M.D., and Frederick P. Li, M.D. 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 a Massachusetts factory that manufactured cigarette fil ters 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 lung 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.) HE inhalation of asbestos may result in pulmo the study (the mortality analysis), or until the diagnosis of a first Tnary fibrosis (asbestosis),1 lung cancer,2 or malig cancer (the morbidity analysis). There were 773 and 766 personyears of follow-up in the mortality and morbidity analyses, respec nant mesothelioma.3 We recently observed three casestively. of malignant mesothelioma among former employees We attempted to contact each worker, or his nexi of kin if the of a Massachusetts company that manufactured ciga rette filters containing crocidolite asbestos from 1951 to 1957.4 We now report a marked excess in mortality and morbidity from asbestos-related diseases in an 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 company employees begun by one of us in 1971. For 29 workers we were able independent cohort of 33 workers who made these 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 all deceased workers. Medical From 1951 to 1957, a subsidiary of a Massachusetts company records establishing the cause of death independently were availa manufactured cigarette filters according to a patented "dry" and ble for 22 of the 28 deceased workers, including all those whose dusty process in which asbestos, cotton, and acetate fibers were death was possibly related to asbestos. These included the results of mechanically mixed, carded, and deposited on crepe paper.5 The a postmortem examination in 8 workers, other pathology reports for parent company produced other asbestos-containing products be 10, and other medical records for 4. Only death-certificate diagnoses tween 1942 and 197) by the conventional "wet" papermaking proc were obtained for six workers. All 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 amphibole family of long, straight asbestos fibers, was the studies (1 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.3,6 presumably be bodies (in 12 workers) or clinical studies (in 3 workers). In living cause of its unusual resistance to degradation in the lung.7 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 tiona) Labour Office's scheme for the classification of pneumoco air. which was within the then-current Massachusetts standard of nioses.8 175 particles per milliliter. These levels greatly exceed the current Relative risks for morta)it\. or the ratio of the numbers uf death' National Institute for Occupational Safety and Health standard of observed to the numbers expected, were based on death rates spec if- 0.1 asbestos fibers (not particles' per milliliter. ic to age and calendar time, according to cause, among the L .S. A list of all employees directly involved in manufacturing ciga male population.9 The numbers of newly diagnosed (incident) can rette filters at the factorv on September 22. 1953. was obtained from cers observed, other than mahenant mesothelioma, wen comp.-.ri-d th records of the Massachusetts Division of Occupational H\- with those expected on the basis of incidence rate> sprciti. tv ae- git iK. The cohort included none of the factory workers previously and calendar time, according to site, from the Connecticut riese nbed b\ us.' T he median ae< of these 33 w lute men on that dau Registry .H More stable expected values for malignant niesoth?-;i was 34 years (range, 21 to 67). The subjects were studied from that ma, an uncommon tumor, were calculated with data from the Sui- date until their death or until December 3i. 1988. the closing date of veillance. Epidemiology. and End Results program of the Nationa* Cancer Institute, which provided rates in approximated in pen cn: From the Division of Biostatistics and Epidemiology.. Dana-Farher Cancer Institute (J.A 7.. A.F.K , K.H.A . F.P.L the Department of Medicine. Har vard Medical Schtwl (J.A.T.. K.H.A . F.P.L ). the Clinical Studies Section. Clinical Epidemiology Branch. National Cancer Institute (W A T.. A.F.K.. of the l\S popul.ition for the time periods 19"3 to 197b and 1(*" i. 1980! 1 1 ` (and Connelly R: personal communication.'- In the i.ik il lations of significance and confidence intervals, an undcrhmg Pois son distribution was assumed J.F D . F.P.L. ), and the Division of Thoracic Services. Boston University School of Medicine (E.A G ). Boston Address reprint requests to Dr Talcoti a: Results the Dana-Farber Cancer Institute. 44 Bir.nry Si.. Boston. MA 02115 Supported in pan h> a grant (1 F32CAO&242 > from the National Cancer Institute Twenty-eight (85 percent) of the 33 workers had and h\ the Kellogg Foundation Program in Clinical Effectiveness Ms Thurbci is the recipient of an Arm Potter Research Nursing Fellowship, and Dr GuvioLr h^ received a Research Career Award tHLi i 731 iron; the National Heart. Lung. died, and 5 ''re alive. The 28 deaths observed wen 3.4 times the number expected (8.3 deaths: on the cr.d Bh*od Institute basis of mortality rates lur the l\S. white male p . - ' \iii N.. it: AM'I.MO1' ASS( >( :i\] j;|) |)|s| S^ls IN ( l(. Akl III-|| i;| l.K WOKKf -- TAICOI'I 11 Al l-VI 1 able 1 Observed and Expected Numbers of Deaths among 33 Cigarette-Filter Makers. According to Cause ot Death * rfM <*i in *1" Cancers <1C|) I4(V Diseases of resptrafon system ()CI> 519) diseases of circulatory system OCD3<XM58i All other Total No oi Dl ATM'. OHM HV||i Ufinii- 15 1.8 7 05 s 4.1 1 19 28 8.3 kiumi Ks iut'- ti 2 (4 <vi? 4i |4 7 (5 9 TO 31 1.2 (0.4-2.8) 0 5 in.tt-3.lt) 3 4 12.2-4.9) Cl denotes confidence interval, and 1CD International Classification of Diseases lation (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 Jung 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. It) 3 of these patients, the can cers were not diagnosed in communities near the factory, and at the time of diagnosis the medical histories obtained on hospital admission and the discharge summaries did no; mention exposure to as bestos. Asbestosis was diagnosed in 19 workers, in cluding the 5 workers who died from the disease. 10 who were diagnosed incidentally on the basis of pa thology specimens, and 4 of th< 5 men who were still alive For 23 workers whose period of cigarette-filter mak ing could be determined, the median duration ol em ployment was 1.7 scars (range. 0.7 to 4). The median time spent at other jobs in the papet company before 1971. when the use of crocidohte ended, was It) years 'tunge. 0 to 25). The median intervals irom the first * ism r to asbestos to the diagnosis ol cancer were 28 s t ars lor lung cancel irangc. 17 to 40) and 31 s cat s lot malignant mesothelioma (range. 26 to 37). We were unable to find an association between cither duration of filter making or lota: time employed by the compa ny and asbestos-related deaths, which predominated in all exposure groups For example, of six workers with few er 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 years. 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.1419 Since differences in analytic techniques and the composition of study and reference populations may influence rela tive risks,20 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.19,21 Several factors mav 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.' --'- In most industrialized nations other than the United States, crocidolite is now regulated more strictly than other asbestos fibers -' The outcomes in cohorts of Table 2. Observed and Expected Incidence of Czr.ce: among 33 Cigarette-Filter Makers. According to Site * Tf PI OF CaMH. Nr. oi Cancers CeSFk\ED EXPECT: ! OBSfFVH; K\Pt : Tf 1 (ov, no Lung Malignant mesothelioma^ Other malignant canecry Ail 11- 0.7 5 0.01 3 2" >Q 3.5 15.1 (7.5-;4M' i !5(i ll 1 i (0 2- 3 5 5 13 3 - 8 Ci denote^ confidence inters a' ^Includes lour squamou'-cel! turr.~ tv.o adenvtcar,. imm..-. thrc\ smali .Ui rurn largc-cel; tumor, and one unJinerena -.-2 tumor Dr. three. lb-. pr\r,..r\ v;, wc' r . ?*.- : or: i THkNIAV I NGI.AM) JOl KNAl. Of MI DH IM. Nov. 2, ]>" manufacturing workers with a predominant exposure to rroeidolite have been described previously in Brit ain'' and Canada/1' hut not the United States. In ad dition. the nature ol the industrial process may have bad an independent effect on outcome. McDonald and towoikers 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 crocidolite 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.27 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 not 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 possibilitv that is supported by an earlier report of a worker employ ed part-time for nine months as a cigarette-filter maker, in whom sympto matic asbestosis developed 18 years later.28 However, the latencv period observed in our subjects between the first exposuic to asbestos and the diagnosis of canc et was not shortei than that observed previously .2' We could identify no incremental risk of asbestos-re lated disease that was incurred by additional employ ment at die parent company , despite the additional exposure to crocidolite dust. In the manufacturing of other paper products at the company, water was add ed to the asbestos and other fibers to produce a pulp The wet pulp probablv produced a less dusty environ ment during mixing and handling than did the drv process oi making cigarette filters. Cigarette smoking, a known cocarcinogen with as bestos 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.30 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.31 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 are indebted to Dr. Rose Goldman for assistance in locating the records of the Massachusetts Division of Occupational Hygiene and to Drs. Brian MacMahon, Robert J. Mayer, and Colin Begg for helpful comments on the manuscript. References ]. Merewether ERA. The occurrence of pulmonary fibrosis and other pulmo nary affections in asbestos workers J lnd Hyg 1930; 12:198-222, 239-57. 2. Doll R. Mortality from lung cancer in asbestos workers. Br J lnd Med 1955; 12:81-6. 3. Wagner JC, Sleggs CA, Marchaad P. Diffuse pleural mesothelioma and asbestos exposure in the North Weacrn Cape Province. Br J lnd Med I960; 17:260-71. 4. Talcott J, Thurber W, Gaensler E, Amman K, Li FP. Mesothelioma in manufacturers of asbestos-containing cigarette filters. Lancet 1987; 1: 392 5. Knudson HW. Method of making a filter for tobacco smoke. Patent 2,765,515. Washington, D.C.: United States Patent Office, October 9, 1956 6 Mossman BT, Gee JBL Asbestos-related diseases N Engl J Med 1989, 320 1721-30. 7. Wagner JC. Beny G. Skidmore JW . Timbrell V. The effects of the inhala tion of asbestos in rats Br J Cancer 1974; 29.252-69. 8 Internationa! Labour Office. Guidelines for the use of ILO Internationa! Classification of Radiographs of Pneumoconioses. Rev. ed. Occupational safety and health series no. 22. Geneva: International Labour Office, 1980 9 Monson RR. Analysis of relative srvival and proportional mortality Compu: Biomcd Res 197-4: 7:325-32 10 Heston JF. Kelly JAB. Meigs JW . Flannery JT. Forty-five years of cancer incidence in Connecticut 1935-7* Cusano MM. Young JL Jr, eds Nation al Cancer Institute monograph 70 W ashington. D.C.: Government Printing Office. 1986 (NIH publication nc 86-2652.) 11 Spirtas R. Beebe GW , Connelly RR. et al. Recent trends in mesothelioma incidence in the United States Arr J Med 1986; 9:397-407. 12 Connelly RR, Spirtas R. Myers MH. Percy CL. Fraumeni JF Jr. Demo graphic patterns for mesothelioma tr. the United States J Natl Cancer Inst 1987. 78:1053-60 13. Rothman KJ. Boice JD Jr. Epidertiologic analysis with a programmable calculator. Washington. DC: Go\rmment Printing Office. 1979. (DHEW publication no. fNIH 79-1649.* 14. Selikoff IJ. Hammond EC. Seidmir H Mortaliu experience of insulation workers in the United Stales and Car-oud. 1943-76 Ann N Y Acad Sci 1979. 330:91-116 15 Seidman H. Selikoff U, Gelb SK Mortality experience of amosite asbestos factory workers: dose-rcspv-m.M. rtiationships 5 to 40 years after onset of short-term work experience. Am J Lnd Med 1986. 10.479-514. iivi'i K'M`M \ - wj;jnbi:k(;j,k i.i ai. |(> >i ( Ixnii'i! R. VA ;i;vni i )k Min.!ir\ r\,iu nr. 1U4i 1975 amr.^ worker- nnpl.weJ in an a^besio-. tcxiik fru h i, ^nj packing prudubb mam Ijchmng Jr. Irnun k. IXiiktt! JM. uB J>um- arui diwa-w. Park fun-! ill Patl.a'o' BublMurv W^pl.43 P Ann'iroiir BK. ik K)cr>. NJJ. Mu4 AW. MoM- M.S Monthly n< miner' ami milLi- *>: cnx ijolnc in \k cMcrrt AimmIi,: Bi J InJ Mi J 1988. 4V5-1 3 18 Melkirui!.' AP. Fry JS. \5<x>!k' AJ. MJaumM J( pus! exposure ami mortality m at! Ameru an chry sonic a'>bi xt<s {nclion priKlueb plan! B? J Inc Med PS-i. 41.151-' IV FinkcBicin MM Mortality amone cmnl"y\A ol an Ontario aM*csios-ccmcn: factory Am Rc\ Kespir Dw 1984. 129754-61 20 Frumkin H. Berlin J Asbestos exposurt and gastrointestinal malignanc> review and meta-analysis Am J Ind Med 1988. 14.79-95 21 Nicholson WJ, Sclikoff 1J. Scidman H. Lilis R. Formby P Long-term mortality experience of chrysotilc miners and millers in Thetford Mines. Quebec Ann N Y Acad Sci 1979. 330.11-21 22 Bccklakc MR Asbestos-related diseases of the lung and other organs: their epidcmioloes and implications for clinical practice. Am Rc\ Respir Di> 1976. 114:187-227. 23 McDonald JC. McDonald AD Epidemiology of mesothelioma from esti mated incidence Prev Med 1977; 6:426-42 24 Weill H. Hughes JM Asbestos as a public health risk disease and Annu Res Public Health 1986. 7.171-92 25 Acheson ED, Gardner MJ. Pippard EC. Grime LP Mortality of Iwi of women who manufactured fo masks from chry sunk and ere asbestos a 40-year follow-up Bt J Ind Med 1982. 39.344-8. 26 McDonald AD. McDonald JC Mesothelioma after crocidoluc e dunng gas mask manufacture Environ Res 1978. 17.340-6. 27 Nowmski PA Chronology of asbestos regulation in the United Slat places. Jn Amman K. Aisner J. eds Asbestos-related malignancy . ( Fla : Grunc & Stratton. 1987:99 134 28 Goff AM. Gacnsler EA Asbestosis following brief exposure in < filter manufacture Respiration 1972. 29:83-93 29 Selikoff IJ. Hammond EC. Seidman H. Latency of asbestos discasi insulation workers in the United States and Canada Cancer 1980. < 40 30 Department of Health and Human Services. The health consequi smoking cancer and chronic lung disease in the workplace a repc Surgeon General Washington, D.C.: Government Printing Offici 206-8. (Publication no. DHHS (PHS) 85-50207.) 31. TaJeott JA, Antman KH. Asbestos-related malignancy. Cun Prob 1988; 12:135-78. MECHANISMS OF DISEASE Franklin H. Epstein. M.D., Editor \______________________/ exchanger (the lungs), the mechanical system wall and respiratory muscles), and the control s (respiratory centers of the central nervous sy contribute to the production of hypercapnia i ease states. Fundamental Factors Determining PaC HYPERCAPNIA Steven E. Weinberger, M.D., Richard M. Schwartzstein, M.D., and J. Woodrow Weiss, M.D. According to the standard equation, PaC02 i portional to carbon dioxide production (VCOj inversely proportional to alveolar ventilation (X PaC02 = K-- Va YPERCAPNIA is a well-recognized consequence The constant K has the value of 0.863 mm Hg H of a variety of diseases, not only those involving carbon dioxide production is expressed in mill the lungs but also those affecting the neural, muscular,per minute under standard conditions (dry j chest-wall, and circulatory components of the respira standard temperature and pressure) and alveola tory system. In the past 20 years, we have developed a tilation is expressed in liters per minute under greater appreciation of the wav ihese components in conditions (saturated gas at body lemperatur teract in the genesis of hvpcicapnia. The impaired pressure). Alveolar ventilation represents the a elimination ot carbon dioxide that results in hyper nem of total ventilation per minute (expired r capnia reflects not merely abnormal lung function, but ventilation) that reaches perfused alveoli and is rather a complex interaction of abnormalities in respi fore effective in the elimination of carbon dioxid rators driv e, muscle function, and lung function. portion of expired minute ventilation norma! In tin.- p..p'.:. wt wii! first tonoricr the fundamental maining in airways is `'wasted" in terms of g lartnrs comr- 'liing tin- elimination ol carbon dioxide change and is frequently referred to as dead and thus determining the partial pressure- of arteri ventilation. al carbon dioxide (PaCOp We will then discuss Because dead-space ventilation does not cont the mechanisms and clinical implications of hyper to the elimination of carbon dioxide whereas al capnia to establish the- clinical context in which it ventilation does, any change in the relative ante common!' o-. <_ u;s. W e "ill stress the ways that the gas dead space to alveolar ventilation will alter the v of carbon dioxide eliminated, assuming expire! Ft.": ?:>. i. ^ Li.tb. Research lnstnuti anc! the Harvard-Tnomdike La~- ora'o >1 B_:' '--a. H V'pui. Deranrmv Midicim. Bv'v I^-:` abd H j * * ufo V., c . Ns ;. vd. bo-; Adiiib" rejoin' k j j-." !' !* D: V c :r.Ne-ce' a: the PuiroTib' l re;. Bvih Israel Hospital. ?y- B'xK'knn-. A\e . Bo>tor. VA ('221c Sapp 'rtc r r ,, .or.ar* Six v i. o: ki search grac tHL -1 ^ > w.'- :l \ - : - 1 o- . bbdBhwvM-''-'-. . Na.io:;.! lm::*._:c> o.' He.':' utc ventilation is constant. The partitioning o breath into a dead space and an alveolar compo commonly expressed as the ratio between the \ of dead space and the total volume per bre ath the tidal volume. This ratio, normalh =Sb..-iu. . altered bv varvine the tidal volume, since the an