Alleviation of cocaine-induced coronary vasoconstriction by nitroglycerin

1ACCYUI .It-Nn

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58 1

AuymL 199C5k1-G

REPORTS ON THERAPY Alleviation of Cocaine-Induced Coronary Vasoconstriction By Nitroglycerin WALTER C- BROGAN III, MD- PHD, RICHARD A . LANGE . MD, FACC . ANATOLE S . KIM, MD . DAVID 1 . MOLITERNO, MD . L . DAVID HILLIS, MD, FACC D.11us,

Texa .u

Cocaine Induces vasoconstriction 0! eotcardlal eomnary arteries

in patients with and wilhoot coroner, asleep disease, and (his vasoconstriction is particularly marked in segments narrowed by atherosclerosis . )o assess the effect of nitru ;;lycerin on cocaineinduced coronary vasoconstriction, computer .uuiisted quantita. five analysis was performed on nondiseased and diseased coronary artery segments In 23 patients 110 men, 5 women, aged 43 to 65 veers) 1) at baxllon, 2) after administration of intranasal saline solution (in 8 patients) or 2 nagJkg of cocaine tin 15 patients), and

then7) after administration of sublingual piaeebo(in 6 patientst or

As cocaine abuse has increased . numerous reports of co. vain-associated myocardial ischemia and infarction hate been published (1--23) . Recent data 1241 suggest that chest pain is a frequent complaint among cocaine abusers seeking medical attention . Since cocaine causes central and peripheral adrenergic stimulation, it often increases heart rate and systemic arterial pressure . thereby augmenting myocardial oxygen demand. Increased myocardial oxygen demand may induce tsehemia in patients with limited coronary reserve . for e xample . i n those with severe coronary artery disease. In addition . cocaine causes coronary artery vasoconstriction in patients with and without coronary artery disease 125,261 . and this vacucunstridiun is particularly marked in arterial

0.4 or 0.8 nag of nitroglycerin (in 9 patients) in the IS patients gieen -inn . In response to m eaine administration, coronary artery cross . sectional area decreased 22 ± 7% (mean a SDI in nondiseased segments Ip a

0 .05) and 45 ± 18% in diseased segments ip

0,02). The magnitude of vasoconstriction was greater

up =

0 .01) In

the diseased segments. Sublingual nitroglycerin abolished the sasrsxllrstrir •einn in both nondiseased and diseased segments . Thus, nitnrgtycedn alleviates cocaine-induced vasoconstriction in patients wish -nary artery disease . (J Am Coil Cardiof 1991 ;18:581-6)

receptors in that it is alleviated by p hentolamine . a n alphaadrenergic blocking agent (25 .28), and potentiated by propranolol . a beta-adrenergic blocking agent (26) . Because the administration of an alpha-adrenergic blocker such as phentolamtne usually causes a profound fall in systemic arterial p ressure. i t has limited clinical utility in the patient with cocainoassuciated chest pain. In such a patient . the administration of an effective, rapidly acting and well tolerated aotianginal agent is desirable . Therefore, the present study was performed la assess the influence of sublingual nitroglycerin on coronary artery dimensions in patients given intranumal cocaine during cardiac catheterization .

. cucai n c segments narrowed by atherosde ro, I s t2?) . I n hurl

may induce myocardial ischemia and, on o ccasion. infarction. b y increasing myocardial oxygen demand or decreasing myocardial oxygen supply, or hoth . Cocaine-induced coronary vasoconstriction appears to he mediated by siintulalion of eurunary artery alpha aduenorgic

From thetxpvrlmcnr JImern,d(btOsom .Czrd "..aavlarl)m.isinn .1St Cnrcarymy or Teas Suulhwalern sled-1 (enter_ )ata,. Teen and ma Cardiac Cathate,m,ntlnn labnmlnn P,rkl,oed yleew,A Hmplml . IX,L1 Thi„IUJy u,unpurtoJ in non hs hchemic Specialixd Cants orNr.tarh Gn.nt1II,1t tr„m1h,N ,,,null llmu„(Held) . eileadu.MeI,tnJ and by a ;ram from the Tesa, afhmec of the A-:m fleet A . mSu, n. Tew star, eripl mo red De-be, III, tsll : n, ,d nuns .aipl ,c,i,,d Febrary a. 1491 . aaepted Fcb our, I ; . 1411 . Addnnfurruponn: L . ofid HiIii,.9o.RminCOT lIlt Lnneral y C Texas Seth+c •lem 71cJical rcnLn . 503II,- Ihre, Ikulnard. 11,11T, xn, 75:11, ~ IY91

hr Lh, Amarlam retrace ul'(ardndap :.

Methods Study patients . We studied 23 patients (18 men . 5 women • aged 43 to 65 years) undergoing cardiac cathelerizalion for the evaluation of chest pain . The protocol was approved by the Human Subjects Review Committee of the University of Texas Southwestern Medical Center, and all patients gave written informed consent . Each was told that cocaine might induce tachycardia, hypertension, arrhyth . mias . aaginu or seizures, and each understood that he or she hod nothing to gain by participating in the study. None adoatled to previous cocaine use . Antianginal drugs (betandrcnerglc blocking agents, calcium channel antagonists and nitrated were discontinued 24 h before the study . All palien, were studied in the fasting state after oral administralion of 5 to 10 mg of diazepam . Experimental protocol- A 9F arterial sheath was inserted percutaneously in the femoral artery • through which an 8F 0731-109791 53.50



582

BROGAN nT AL . COCAINE-INDUCED VASOCONSTRICTION AND

Nil

1ACC vat . It. No . 2

ROGLYCERIN

ME- 1991 :581-6

Table 1 . Hemodynamic and Aneriugraphic Responses to Inlrarasal Saline or Cocaine Hydrochloride Solution Grunt' 11 . - 8)

Group ll In = 151

At Saline Heen we Ibeurvmln} Sysm0earthlalpreanere Imm Hg1 Hcan rate-systols pressure pradocl I x10') Mean arleoel pnsowe Iron Hgl Coronary curry area Imm -1 Left anrenor descondrng Proximal Middle instal Len Itleunetea Prnxiaenl Middle Distal

Baseline 71 e 9 135016

71 t9 127116

Baseline 76-14 141!25

After Cocaine 77!14 150!'25'

8.8

11 .3422'

8 .941 .5

10.6019

91 =_ 10

92 ! 11

99 t 16

.65 5.12 x 0 269 a 0. 12 1 .25 _ 0.40

5 .45-11.88 2.81=a64 1 .89 a 0.51

7'_8'_3 .18 3.79 •_ 2 .18 233 t 1 .20

601_236' 3.03 1 .47 1.97 t 1 .35'

7.70- 4 .13 4.90-273 2'6= I67

7.43

x 498 4.R9 x 2 30 2.42 t 1 .17

5 28 1

2 .99 3 30 - 0.42 290 t 1 .23

4.21 x 1 .762.08 m 0.99 1 .81 • 0.62'

t

1 .5

Soldier

107

16'

t

'p 7 0.05 in camparilon with the corresponding baseline value . All aalxs are mean values t I SD.

of the left cororrary artery . Systemic arterial pressure was measured through the sheath's side-port extension and heart rate was determined by electrocardiographic (ECGI monitoring. Baseline values for heart rate and arterial pressure were recorded, and cincad;iography of the left coronary artery was performed in orthogonal views (right anterior oblique with caudal angulation and right anterior oblique with cranial angulation) . Then patients were randomly assigned to receive either intranasal saline (Group 1, n = 8) or 2 mgikg of 10% cocaine hydrochloride solution (Croup It, n - 15) . Fifteen minutes later, hemodynamic measurements were )udkins catheter was advanced to the ostium

blood sample was obtained to measure serum cocaine concentration (by gas chromatography) and cineaogioaaphy of the left coronary artery was performed in identical obliquities, Later, a sublingual placebo )Group 11A . n = 6) or 0.4 or 0.8 mg of sublingual nitroglycerin (Group 1111, n = 9) wax administered to those given cocaine . The amount of nitroglycerin was chosen to reduce mean serial pressure 10% to 15% (but not to '175 mm Hg) in comparison with the mean arterial pressure observed after cocaine administration. Five minutes after the placebo or nitroglyc erin was administered. hemodynamic measurements and cineangiography were repeated . repealed ; a

Table 2 . Hemodynamic and Arleriographie Responses to Inlraeosal Cocaine Followed by Sublingual Placebo or Nitroglycerin in 15 Patients Group IIA In = 6) After Sardine Near) rate (bealsrminl Systolic arterial pressure Imm fig) Heart rote-syelalk pressure

80 x 13 140 7 21 11 .0 = L9

Cocaine

8n 147 12.1

0 t 4

l.rtuup Iln le

Af rn Placebo

Baseline

13 25 2 .7

812 II 142 a 22 11 .8x1 .6

72±14 142 t 27

13

101 m 11

101 t I6'

m .1=1 .9

= 9) Mien Cacine

72x13 150 t 27 10.701 .8

Aner Niaaglycenn 87*-15' 120 -_ 21' 10402.3

Product(x10'I

Heart arterial pressure (mm Hg) Coronary artery area Imm') Left a,teri,r descendinc Prnatma1 Middle DotA Left circumflex Prwimd Middle Dual

97 m 15

104 t

108

t

17'

93 t IN-

8917 x 3.88' 3 .15'-0.76' 1 .74 t 0.69'

7 .44 x 2.80 2 .66--0.92 1 75 t 0.56

7 .28 '_'_7_ 2 .61*_0.79 1 .21 0 0.55

62_8'_240 4.19-271 2.71 *- 1.45

5,12-165' 3.26!1 .68' 2 .36 0 1 .57'

648-2.65 4.96 158 3.73 = 0.02

5 .21 = 1 .57' 3.21-1 .01 1 .96 x 0 .74

4.14 4 1.80 225-0 .92 1 .53 t 0 .26

4.10 0 1.54 2.54 x 1.09 1.48 . 0 .77

5.34 t 2.52 .36 x 0 .78 5 3.61 ± 1 .05

4 .26 x 1 .87' 3 25 ± 0,89 2 .13 0 0.72'

5.86 a 244 5.15 x 1 .524.96 a 1 .27

'p 10.05 in compadmn with the other values in the same patients . A N valnes are mean values x I SD .



(ACC . No . 2 AuemrVol1.1. Ix501-h

BROGAN ET AL. COCAINE.INUUCLa vASOCONsrRICTioN AND NITROGLYCERIN

5 83

placebo or nitroglycerin were compared with a repeated measures analysis of variance . Measurements of stenotic and adjacent disease-free (reference) coronary artery segments were compared with a paired t test (30) . For all analyses . a p value < 0 .05 was considered significant .

Figure 1. Cross-sectional area values for nondiseased coronary, artery segments ofadjacent each stenosis at baseline tfeRt after . administration cocainem [center) and ninogbycerin INTGI and(right) Each line represents the data from one patient . 't he mean values a ItheSDvertical at baseline andCoronary after cocaine indicatedandby artery and areanitroglycerin reduced are by cocaine. this decreaselines.in area was alleviated bywasnitroglycerin 'p 0 .05 in comparison with baseline and nitroglycerin . . The cineangiograms coronary wereQuantitative obtained with an L-Uangiography cineangiographic system (General Electric) with an image resolution of 3 .8 line pairs/mm . Computer-assisted quantitative coronary analysis (Cardiovascular Angiography Analysis System . Rotterdam . The Netherlands) was performed on orthogonal projections . according to methods described previously 129) . In each patient, segments of the proximal middle and distal portions of the left anterior descending and circumflex coronary arteries that appeared free of atherosclerotic disease were identified and analyzed . In addition to the analysis of nondiseased segments, quantitative measurements were performed on all segments with coronary stenosis (0500% reduction in Iuminal diameter) and on the nondiseased segments adjacent tit each stenosis (reference segments) . Cane frames were selected at comparable points in the cardiac cycle The luminal diameter of each nondiseased and diseased arterial segment was determined, from which the cross-sectional area was calculated . Thus . for each patient . we calculated the crosssectional area of nondiseased segments of the proximal . middle and distal portions of the left anterior descending and circumflex coronary arteries . diseased segments of each coronary artery and nondiseased segments of the artery immediately adjacent to each stenosis . The variability of this analysis in our laboratory is similar to that previously reported (29) . Statistical methodology . All results are reported as mean values ± I SD . All analyses were performed without knowledge of which pharmacologic agent (intranasal saline or cocaine . sublingual placebo or nitroglycerin) was administered . For each group. measurements at baseline . after intranasal saline or cocaine solution and after sublingual

Results Of the 23 patients, 4 had angiographically normal coronary arteries'70th, . 10 had one-vessel coronary artery disease (defined as •- narrowing of luminal diameter of a large epicardial coronary aneryl . 5 had two-vessel disease and 4 had three-vessel disease . Group I (eight control patients) . In these patients, heart rate . arterial pressure, heart rate-systolic pressure product and epicardial coronary artery areas were similar before and 15 min after administration of intranasal saline solution (Table II Croup 11 (15 study patients) . These patients were given 2 mglkg of intranasal cocaine (total dose 100 to 250 mgt . The scrum. cocaine concentration at the time of angiography was 0.11 0 .05 mg/liter (range 0.04 to 0 .22) . With the administration of cocaine, systemic arterial pressure and heart rate-systolic pressure product increased and coronary artery cross-sectional area decreased (Table I) . No patient had chest pain or ECG evidence of ischemia . In the six patients who were given sublingual placebo after cocaine (Group IIA). the hemodynamic and arteriographic values2).measured in response to cocaine were not altered (table In contrast, cocaine-induced vasoconstricnon was abolished in the nine patients who were given Figure 2. Cross-sectional area values for diseased coronary artery segments at baseline IIeO1 and after administration of cocaine (center) and nitroglycerin (NTGI (right) . Each line represents (he data patient. Thearemeanindicated values *-by ItheSD vertical at baseline cocainefromandonenitroglycerin linesand. after Coronary alleviated artery areabywasnitroglycen reduced by .cocaine . and this decrease area sp =: 11.05 in comparisonin with hascllne and mtrog(ycerin .

f Baseline

After Cocaine

After PITS



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1ACC vat . Ia. No, I Aunusl t'NLSst-5

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rate J. Efacl of Nitroglycerin on Cocaine-induced Vusoconerricuon in Sionmic and No ndisrased Segments of Coronary Arteries Nine Patients D"ea"d Area Pe¢em Area Percent Scram Cw:uiat Inrunary Area A Mini Chase After Change C'maine Anne Coaine 5Th ,. Duo ('un unrr,~tinn 11-fix S,mLy6mq Ielm~l Rm3ilec !mm'I C-PAllenl

21M!

09

3

100

lo7

4

13o

0114

7

208

ILII

150

0.09

'_91

0.10

1x5

0 .08

-LAD maim,d . kderoroc SICnolic LAD, pruvmal Reference Slenotie LAD .proslnul kelerence Serene LAD . nadir Reference smnauc LC. . proeimal Reference Slenotic LC, middle Reference Stenalic LAD. middle Neieruece Stenmic LCc.praxlmal Reference sacred,

Mean

113

It.Llx

LCc.omaimel Rercrencc stcmi'.le Reference

Sri

45

(1.115

horatie

9

D .IN

in Percent ('hnngo H . ..

3 .55 1175

2 v1 050

-17 -35

4 .54 0 .92

87) 243

6.55 0.75

-25 -69

167 2 .72

17 263

-I1 12

I V1

5 .96 1,23

-31

7.36 L56

26 51

4

1.71 IAs

273 I .17

-32 -29

4 .1X1 269

58 130

9 63

2.82 1 .4'

2.24 1 .08

-21

4 .12 2 .66

84 146

46 81

2.94 1.69

Isn

-13 -36

6.63

1_11

260

249 115

134 38

2.13 1.13

175 0.66

- 17 -42

3 .76 1 .37

114 Hit

77 21

5.67 2.52

472 1 .19

-1, -59

7.08 _._

so 91

23 -10

3.91 0 .50 4 .54• 2p 1,62 0 R4

3,43 0 .19 355' „76 0.89' 0.58

-12 -77 17 -45t _18

5.76 0.57 5S6' 1 .58 1 .96 0 .83

68 200 90 x70 132 265

47 -31 39 n45 21 x35

--2

28 -5

'p < 11 .05 m mmfama with the nurespnedmg values In reference or stenu;ic segrnenio in < 0.02 in conlpuricon with the percent change in the reference mondiseasedl segments . LAI3 - lea anledor dcsaeeding. LCv It", circumflex, N1G - nitreelytedn, sublingual nitroglycerin (Croup IIRI . Furlhermore, in these nine patients, cocaine caused a greater reduction (p - 0 .01) in the cross-sectional area of diseased, stenodc segments than of nondiseased )reference) segments (Fig . I and 2, Table 31 . a phenomenon previously noted (271 . In both diseased and nondiseased segments, nitroglycerin alleviated the cocaine-induced vasoconstriction and the magnitude of nitroglycerin-induced vasodilation was similar in stenolic and reference segments (Fig . I and 2 : Table 3) . Discussion Cocaine induces central and peripheral adrenergic stimulation by blocking the presynaptic reuptake of norepinephrine and dopamine 131) . In addition to its use as a local anesthetic during rhinolaryngologic surgery (32-34) .itsrecreational abuse is widespread . Numerous reports (1-23) have described various cocaine-induced cardiovascular complications, including myocardial ischemia and infarc-

lion .and recently published data 1241 suggest that chest pain is a frequent complaint among cocaine abusers seeking medical attention . We have previously shown that cocaine causes coronary artery vasoconstriction (25.26). which is especially marked in coronary artery segments narrowed by atherosclerosis (27) . This cocaine-induced coronary vasoconstriction appears to be caused by stimulation of coronary artery alpha-adrenergic receptors . because it is abolished by phentolamine . an alpha-adrenergic blocker (25,28) . However, the administration of an alpha-adrenergic blocking agent to a patient with cocaine-associated angina or impending infarction may be hazardous, because its effects usually include marked systemic arterial hypotension . In this setting, the administration of a rapidly acting, well tolerated antianginal agent that, is effective in alleviating cocaineinduced coronary vasoconstriction is desirable . Iplluenee of nitroglycerin on cocaine-induced coronary vasoconstriction. Our d-la . obtained in 23 patients at the time of cardiac cathetenzation, demonstrate that cocaine



JACC Vol . I9. No. v. Aegu,l W1i81_a

BROGAN E'I' AL. CDCAINEINOCCEDv5S000NSTRICTIONANDNITROGLYCERIN

585

induces vasownstriction of both nondiseased and diseased coronary artery segments (Fig . I and 2. Tables I and 3) and that the magnitude of ibis vasoconstriction is particularly marked in the latter . These findings are consistent with previous observations from our laboratory 125-271 . Sublingual nitroglycerin, given in a dose sumcicnt to reduce mean

flashed coronary vasoconstriction in response to even a modest amount of cocaine . we hypothesize that the ingestion of a large dose leads to intense and unabated coronary vasoconstriction that, in turn, causes myocardial ischemia, infarction or sudden death .

systemic arterial pressure 1000 to 1590, effectively mile Autes

We acknowledge the skilled technical nasvlanec of Randy Christian . Nancy S,nldt. Moats Solu . Sheds Brady. Jacyui Jones and Kelly St .-

cocaine-induced vawcunstriclion (Table 21. Furthermore . its vasaldilativc 'Rest is of similar magnitude in nondiseased and diseased coronary artery segments (Fil: . I and 2 : 'fable 3) . Inappropriate coronary vasocouslrichon in patients with atherfwclerdle coronary artery disease . The anginal threshold in patients with coronary artery disease may he lowered by a variety of maneuvers that induce coronary vasxunstriction- thereby limiting or even abolishing metabolically mediated vasodilation, Thus . exposure to cold 051, cigarette smoking (36), isometric 1371 and isotonic 1381 exercise and cocaine use (25) cause an increase in myocardial oxygen demand and a concomitant decrease in oxygen supply . Antlanginal agert : that prevent this inappropriate increase in coronary tone -nay improve the myocardial oxygen supply% demand ratio. thus preventing the development of ischcmia . Calcium channel antagonists have been shown to prevent the coronary vasoconstriction induced by exposure to cold (391 and cigarette smoking (40). and nitroglycerin abolishes the

coronary vasoconstrictor response to smoking (40i and exercise (37,38) . The data presented here demonstrate that nitroglycerin exerts a similar beneficial effect in pall rots with cocaine-induced coronary vasoconstriction IFi_e . i and 2 . Tables 2 and 3). limitalsons of the study . Our study has certain limitalions . First, we assessed the effects of inlranasal cocaine on the coronary vasculature but did not evaluate its effects when given by other mutes (i .e . . intravenously or by inhalation) . However, host of the reported episodes of cocaincinduced myocardial ischemia or infarction have occurred after its inlranasal administration Ill . Its delivery by other routes is likely to exert a similar effect on the coronary vasculature . Second, we studied the effect of short-term administration of sublingual nitroglycerin in pnticnts with cocaine-induced coronary vusocoD6LDCnOn : we are uncertain if long-term administration of transdermat or oral furors of nitroglycerin would exert a similar beneficial effect. Palfephysiology of myocardial ischemiatlnlarction and sudden death in cocaine abusers . Our patients received only 2 mkrkg of intranasal cocaine (total dose 10S to 250 mgtl achieving a serum concentrttati of 0 .11 - 005 mgrliter (range 0 .04Ia 0.221 . At this relatively modest serum concenlrntinn,the cross-sectional area of the nine coronary stvnoset decreased 45 . IBk . and decreased by >W, in three patients (Table 3). Patients with cocaine-associated myocatdial ischemia . infarction or sudden death . alone or in combination . often have used a much larger amount of the drug ,sometimes it gl, achieving a serum concentration as high as 20 mg/liter (8.12 .A1-44) . in the individual .,ho develops

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6 . Chic YC . Brecht K. Daatupta DS . Mhooe F . Myocardial infarction with topical v crier ane,thesiu far nusul surgery. Arch Olularyngol Head Nark Sara 19% :I121998-9a. Nanh AA . Rlipenko ID. Asyctole and ventricular fibrillation associated ails cosmos inmxamican. Chest 1984 :85132-3. R S,erv o RA . Ed-d, WD. Pathogenesis of cocaine-induced Ischemic h•an d,ee,e : autopsy findings in a 21 year-old man. Arch Pallid Lab Med 19x6:110:479-94. 9. Boal F . Havant Cwi . Cardiac ardry,hmta and myocardial tschemia rdcrd I,, cure and alcohol consumption . Postgrad Mid 1 1985 :61 : 10,

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"wozz

SRI. '..

AND SITROGLY(TRIN

VASOCONS I RN I WN

• 24, Itrndy 51 . . Wrens KI) (ocaio-,-Lod medical !13 Am I !,fed 21 . L..V, KA A flownw- if nnaine la adri,neigic hlnckldI Ann

-o..,

27, H

FD.

,nnzi,

1-1 . Ggnma RG . 11111, ii) ""cc of CIC I on 11,41, Coronary artery Jisea+e : in c cite, of An, Coil

ZTTI

. Gilln RA . V- MS . Lull . lth,,oo SIN

•

Schar (it

Ltf,,f of

29, Re,,, R-11i, I- of

12,

11)41)011 In CafOnbfy vascular II. nall'9h x'llh'ncRemit Mart d-.-N Engi I Mid 1974 : 291N'TJT 1131-7 3h W,. .,f.,d MD . Whell,io KR . Kle-1, MS, il al i,nok,nu ..J-d wish Co .,." -, Joeu,e: evidence for 1111Y modelled Ale-u ., n. -rv artery lone. CmLlkio 106.71 . 71 . :W 7 )7 . Brown BG, La Afl . Poison EL . Dodge Ill ki,fli . cunsneistiun .1

. .Lo. .. ..... .. . • .... 11-24, .. . 11, Gage .~ crn SE . He„ CM . M,1,1,ml . ... .. T. i_, Killer M . Grimm J . KrayenNuchl HP. v nlnam of" ., arteries during In u,"Odily by urngly,"In,ngly,"In, C111" eulalian 190P:7):065-7h . 39. (;u mber S . Muller IF . MuJge GH 11 . Grw,man W. y of coronary • =C Am C

cinrnnn-XIgram,. Circulation 19X9 .11'

40. Win.dud MD. hn- DE. Reynolds GA . Apprill P. Black WH, HUh,

W-, E,poi.mmld lk,m . 2nd oJ . York. S1Graw-1151. 1971 :1X5!51. Q3I . Nitchie 151 . -"M L" Wk- In : Gilman .AC . Goodman I .S. KAI TA . Aurk F ads -the Phlo-111IFiL HIII, V h-NUjils,

roric coronary artery air n~n and prevenrion by calcium anlapun .nl, and niu .gLy...in. AO Cadd I 41 . NImL-min RE . Werli CV. Death caused by rear rional Cocaine use' . an

4100-209'

,pdalc . ]A 11A IW .!5l 18*

",l IF;f 12 1 c

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Ann Pl- Siog

,111471-7, 31- 1 4-111 A . Hen l c-bee ace by the mina .} ngaloeiu : n survey . Tram, Aced (1,ML,IImnl 11 Dlaluryngol 1'977794 919-7i . 34 . Vcrl :mn&r JNI J,ih, %IF . Ttc clinical we of C%ojre. Olohry ngol Cl in • Am 19X1,14 :,21-11

12

l

Dl kCld jll,,"I,,

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1988 .115 :106N-

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ra :. Nail )f cm,_

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