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Thoracic Research Scholar ship 1988 : Pulmonary Thromboendarterectomy for Chronic Thromboembolic Pulmonary Hypertension at the University of California, San Diego S tein Iversen
Sum ma ry
At th e University of Californ ia . Sa n Diego pulm onary thromboendarterectomy (PTE) has eme rged as a n effective measure in the trea tme nt of chronic th romboembolic pulmon ary h ypertens ion. Unresolved emboli become organized by incorp oration into the vascula r wa ll a nd may form st rictures. webs. ba nds and /o r membra nous occlusions a nd ca use pu lmon a ry hyperte nsion refra ctory to medic al treatm en t. When pu lmon ary vas cula r resistan ce exceeds 300 dyn -sec -crn'" and the vasc ular wa ll cha nges a re locat ed to begin at or proximal to the lobar a rte ry level. surgery is ind icated. Th e ope ra tion is performed usi ng ca rdiopulmonary byp as s. deep hyp oth ermia and pe riod s of circulatory a rres t. Th e dissection of eac h segmental artery is carried out in the media layer fro m se pa rate incisions in th e right and left pulm on ary a rtery at the level of the perica rd ial flexion. Pulmona ry rep er fusion edema may com plicates the postopera tive course . a nd pulmonary hemorrh age . res pira tory insufficiency necessitating prolong ed ventilatory su p port and secon dary multi orga n failure are main ca use s of hospital mor tality. Between Octob er 1984 and Septe mber 1988 103 patients with a mea n age of 50 ± 16 yea rs und erwent PTE. Conse quen tly. pulm onary vascular resistance could be red uced from 788 ± 370 to 299 ± 150 dyn -sec -cm" a nd ca rd iac index incr ease d from 2.0 ± 0 .6 to 3.2 ± 0.8 t/rntn-m". Hospital mo rtality was 11.7 % (12/10 3 patients). Thu s. pu lmonary th romboend arter ectomy effectively reduces pulmonary hyp ertension at a n acce ptab le low risk . The results indicate that pati ents shou ld be d iag nose and refe rred for surge ry a s early as possib le. Pulmo nale Th rom ben da r te rt e k tnm le a ls chir urg isc hc The raple de r chro nischen throm bembolische n pulmo nalen Hypert cnle a n der Unlve rslty of Ca lifo rnia. San Die go Durch das Th or axchirurgische Reisestipendium der Deutschen Gesellschafi fur Thorax -, Hera - und GefaBchirurgie wu rd e mir von August bis Novem ber 1988 ein Gas tarztaufen thalt in der Division ofCardiotho raci c Surge ry (Leiter: Pat O. Daily M. D.) a n der Universi ty of Californ ia. Sa n Diego. ermo glicht . Ziel des Aufcn tha he s war d ie Dia gnostik und Beh andlun g de r durch chro nische Lungenembolie verursachten pu lmo na len Hyperto-
Thorae. ca rdiovasc. Surgn 38 (1990) 86-90 © Georg Thieme Verlag Stuttgart- New York
nie zu erle rne n. Nur dart ist die Beha nd lung dieser seltene n ab er lebe nsbedrohlichen Spatkomplikat iun sta ttgehabter Lungen embolien dureh pu lm on ale Thrombend arterickt om ie zu ei ne r wirkungsvollen Ma Bnahm e her angereift. Bei fehlender endo gene r Lyse fiihr en a bge la ufene l.un gen embolien du rch Organisation zu narbigen Obst ruktio nen und Vers chHissen der Pulmonalgefa Be mit der allmahlichc n Entwicklun g cines pulmo na len Hochdrucks. der dur ch mcdikamentose The rapie nur we nig zu beei nflussen ist . Durch bilatera le pul mon ale Thrombe ndarteriektom ie la ssen sich die thrombembolisch en Obst ruktionen bes eltlgen und der pulmonale Ilochdruck we itgehe nd se nken . Die Indik at ion ist a b cine m pulm on alen GefaBwiderstand tiber 300 dyn -s -cm "? gegeb en . Varaussetzu ng filr die Dperabilitat ist der Nachweis von narbigen GefaBverandc ru nge n. begin nend in l ldh e oder proxi ma l de r l.oha rarter ien . Die Operat ion wird unt er Anwe nd ung der extrakc rpo rale n Zirkulation in tie fer Gan zkorperhypotherm ie und Per loden von Kreisla ufstillsta nd vorg enom me n. Dcr postope ra tive Verlauf ist du rch das Entste he n ei nes pu lmon alen Reperfusionsodems knmpliziert. das be i schweren Erschein un gsformen akut hamorrhagis ch und todllch verl aufcn kan n. zumi ndest abe r cine respira torisch e Insuffizienz mit La ngzeitbca tmung zur Polge hat. Von Okto bcr 1984 bis Septe mbe r 1988 wurden 103 Patlenten mit einem mittleren Alter von 50 ± 16 Ja hre operi e rt. Der Lungengefallwidersta nd lieB sich von 788 ± 370 a uf im Mittel 299 ± 150 dyn -s -cm ' " sc nken und der Herzind ex stleg dab ei von 2.0 ± 0.6 a uf 3.2 ± 0 .8 L' min/m" Die Ste rblichkeit bctrug 11,7 % (121103 Patien ten], wobci die lIaupttodesursa chen respi ratorisches un d/ od er Multiorga nver sagen sowie akute pu lmonale Ha rmorrhagie n wa re n . Die Erge bnisse zelgen, da Bd ie pulm ona le Thrcmbendarteriektnm ie ein effektives The ra pieverfa hren der th romb embotisch bedlngten chro nische n pulm on alen Hypertonic lst. ver bunden mit ei ne m akzeptabl en Opera tio ns risiko. Urn dleses gering zu halt en. so llten die Pati enten moglichs t Irtlh di ag nostiziert und der Beha ndlu ng zugeflihrt word en . Key wo rds
Chron ic pulmonary embolism - Pulmonary hyper ten sion - Pulmona ry th romboendarter ectomy
Received for Publica tion : February 12. 1990
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Klinik fur Ilcr z-, Tho rax- un d Gcfci.Ochi rurgie am Klinikum der Joh annes Gutenberg -Universitat . Mainz
Thorac. cardioVCISC. Surg1l 38 (1990)
Thoracic Research Scholarship 1988
Introducti on
Th ro mboembolic pulmonary hypertension
The thor acic Resea rch Schola rs hip of the German Society of Thoraci c and Cardiovasc ular Surgery enabled me to visit the Univers ity Clinic of the Univers ity of California in San Diego. The purp ose of the sta y was to obtain knowledge of diagnostic measu res , criteria for selection of surgical candidates. ope ra tive tec h niques and postoperative man ageme nt of pati ents sutTering fro m chro nic thromb oembolic pulmona ry hyperten sion . Kenneth Moser of th e Division of Pulmona ry Medi cin e and Pat O. Daily from the Division of Cardio thoraci c Surgery have long bee n engaged in the treatment of th is pa tient group. The du ra tion of the stay was th ree mon ths , from Augus t 18 to Novembe r 16, 1988, and after fulfilling the require ments of the "Board of Medi cal Quality Ass u ra nce" in Sacram ento, I was gra nted the sta tus of "Postdoc toral Sch ola r" at the Division of Cardiotho raci c Su rgery under Dr. Daily. Th is licen se permitted "limited patient contact", an d ena bled surgica l pa rticipat ion . Further insight in the peri operat ive course and problems of management was ga ined through the op portunity to cooperate in a retrospective analysis for risk factors in pati ents un dergoing pulmonary th romboendarterectomy (6 , 7). The complete integration and th e cons tant help fulness mad e my studies all th e mor e easy. Not least, the warm hosp italty shown also outside th e hospit al sets standards to follow, and the overall open ess and friendliness made the time in San Diego most pleasant. Th e knowledge obtaine d ha s enabled the initiation of a simila r program for man agem ent of th ese pati ents in Mainz, ba sed en tirely on the pri nciples developed a nd pr acticed in San Diego. Only in San Diego are patients with chronic thromboembolic pulm onary hypertension tr eated on a la rger scale. Between 1974 and 1980 fou r patien ts we re ope ra te d, but the re has been a stead y increase in nu mb er of pa tient referrals , and from October 1, 1984 to Septem ber 20 ,1 988 a total of 103 pati ents un derw ent pulmonary th rom boenda rterectomy. At pr esen t, approxima tely two operations a re performed per week a nd around 50 patien ts are aw ai ting diagn ostic evaluation and surgery. Patients are referred prima rily from North Ame rica , but also fro m othe r continen ts of th e world . Th e patients are prim arily ad mitted to Dr. Moser and th e Division of Pulmon ary Medi cine, wh ere the exte ns ive diagnostics are performed. In close cooperation between the two divisions , the possibilities and indications for surgery a re discussed a nd de te rmine d. Th e pulm ona ry th ro mboendarterectomies are performed by two su rgeons , Pal. O. Daily an d Walt er P. Dembitsk u. Postoperati vely, th e patients are treated in the cardiothoracic surgical intensive ca re un it, and patients sh uttled through the often d ifficult postoperative course with jo int etTorts from collea gues of bot h divisions. I also expe rience d the close team-work in th e ope ra ting room with the regular pr esen ce of pul monologists. Infor mation of the opera tive situs and exten t and localization of patho logical specime ns were obta ine d. Th ese were thoroughly analyzed and docume nted and compa red with th e preopera tive interpretation of pulmonary angiography and an gioscopy. Th is feedb ack and contro l of diagnosti c findin gs were considere d of utmost importan ce to imp rove one's experience an d allow th e correct determinati on of operability in bord er line cas es.
Only infreque ntly does pulmo nary embolism ca use chron ic elevation of pulmonary resistance. Resoluti on of th e thromboembolic mat erial with recovery of norm al pulm ona ry blood now is the natu ral cours e (8). In a sma ll percentage of patients , howeve r, the restoration of the pulmonary vascular bed is incompl et e and pu lmonary hyperten sion persists. Measurable increase in pulmonary pressure occurs only afte r a mor e th an 65 % obstruction of the pulmon ary arteries, and, therefore, with normal pulmonaryvessels and parenchyma prior to embolization there is extens ive bilatera l, incomp letely resolved embo li wh en chro nic pulmonary hyperten sion occu rs. Th romboem holic pulmona ry hypertension is refractory to medical th erapy and the patients hav e, asso ciated with the deg ree of hypertension , s horten ed life expec ta ncy (17).
87
A successful pul monary thromboen darterectomy was first rep orted by S ny der et ai. (16) already 1963 , but th e initial results were poor and mortality high. In an extensive review of the wo rld litera ture Chitwood et ai. (2) counted 85 operated patients worldwide with a mortality rat e of 22 percent. From Europe, experience with pulmona ry t hro mboe nda rterectomy have been publi sh ed by Dor (9) and Cabral (I) in France who advoca te the un ilatera l thora cotomy witho ut utilizin g ca rdiopulmonary bypass. Fro m Germa ny, S alte r (14) has reported on two pati ents with ce ntra l pu lmona ry artery occlusion which were operated upon via sternotomy and und er extra corporeal circulation. Daily (:l) first described his operative tech niques 1980 usi ng sterno tom y, cardiopulmonary bypass and bilat eral pulmonary thr om boendarterectomy in repeated periods of circulatory arrest. Furt he r modificati ons of techniques were pu blish ed 1987 (4) .
Preoperative diagn osti c Preoperative diagnostic measures serve to rule out primary or non -th rom boembolic form s of secondary pulmonary hypertension, to exclude or verify concomitant cardiac and! or pulm onary disease a nd to det ermine the degr ee oft hro mboemb olic pulmonary hypertension and assess tec hnical operab ility (1 1, 13). In pulmona ry hypertens ion secondary to th romboembolism perfusion lung scintiography will nea rly always reveal multiple bilate ral seg me ntal perfusion defec ts with typical mismat ch to a normal ventilation sca n. Right heart catheterization determin es the deg ree of pulmonary hypertens ion . The mean pulmona ry pressure is gene ra lly well above 30 mm Hg, but as cardiac output is compro mised in most of th ese patients , the calculation of pulmonary vascular resistance more accurately reflects the degr ee of pulm onary vascu lar obstruction. When pulmonary wedge pressure is normal and when echocardiography reveals norm al left heart function a nd dimen sions , pulmonary hypertension seconda ry to left heart dysfunction or mitral disease is unlik ely. Left heart catheteriz ation with corona ry a ngiogra phy is routinely performed in all pati ents over 35 years of age or in patients with clinical signs of coronary heart disease.
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Pulmon ary thromboendarter ectomy
71lOrac. cardiovasc. Surgn 38 (1990)
Pulmonaru ollgiography will estab lish the definite diagnos is of chronic pulmona ry embolism. Exact visualization of the pulmona ry arteries is essential for the correct localization of thrombo embo lic vascular changes a nd the refore conventional angi ograp hy remains the golden standard. Separate unilateral injections of contrast solution and sequence films a re preferred to digital subtraction angiog raphic techniques . Pulmonanj ollgioscopy (15) has in many instan ces proven valua ble in helping determin ing extent a nd location of vascular obstru ction , beller defining proxima l land thus oper able) disease. Pulmonarq function studies, althou gh frequentl y normal, a re important to exclude parenchymal diseas es Ii.e. emphysema, chronic obst ructive lung disease, fibrosis etc.) as the cause of pulmonary hypert ension. Indication s for surge ry
Thr ee criteria must be met for su rgery to be ind icated (3,4,5): 1. The presence of severe functional disab ility, primarily dyspn ea at rest or upon exertion acco rding to the NYHA functiona l class III or IV. 2. An increase of pulmonary vascular resistan ce abo ve 300 dyn -see 'em - 5 at rest as a minimum level of pulmonary vascular obstruction, although some patients have been accepted with lower levels when res istan ce significantly increased during exercise. :l . The major determinant of operabili ty is the demonstration by angiography of pulmon ary arterial lesion s beginning at or proximal to the origin of the loba r level. Periph erally at the segmenta l bronc hopulmonary segmental arteries thromboendarterectomy can be performed, but at risk of suboptima l resu lts due to incomplete relief of pulmona ry vascular obst ruction.
Most patients accepted for pulmonary thromboendarterectomy had a caval filter device inserted prior to or du ring surgery. Pathology
The path ological asp ects of chro nic thromboembolic pulmo nary obstruction diITer tota lly from those of acute pulmonar y embolism a nd the refore the surgical implications diverge. A non-resolved thromboembolus becomes or ganized: i. c. after adherence to the vascualr wall there is an ingrowth of granulo cytes and lat er fibroblasts. With time the thrombus is repla ced by fibrous and elastic tissue a nd incorporated in the wa ll (18). In the larger vessels there is complete or incomplete cent ral recan alization which then later appea rs as intraluminar webs an d bands. The lumen may then again be parti ally or totally occluded by seconda ry thrombus formation or thromboemboli superimposed on the fibrotic obstruction. Upon inspectio n of the vessel after pulmonary arteriotomy, therefore, there may be lillie appa rent obstruc tion beside a thickening of the intima, and the recognit ion of obstruction may be diffi cult. The obstructive lesions can only be removed by refined arterial enda rte recto my tech niques.
Stein Iversen
Oper ati ve techniques
The opera tive procedures have been sta nda rdized since 1984 (4, 5). Following sternotomy and esta blishi ng total ca rdiopulmonary bypass, the core temp erature is lowered to 20 ' C. The pericardial flexion is mobilized bilaterally over the pulmonary arteries . and separa te arteriotomies - two on the right and one on the left side - performed within the hilar st ructures but extra pleural. After identification of the correct plane of dissection, this is ca rried out circumferentially starting pro ximal at the hilar arteriotomi es going distally into each segmenta l a rtery. Due to the increased br onchial artery collateral flow in thes e patients. accurate visualization is impossible during peripheral dissection and repeated period s of total circulat ory arrest are inevitable. Concomita nt card iac lesions a re corrected during the same procedure if necessary. The interatrial septum is always ins pected for the presence of an open forame n ovale which is closed . Tricuspid regurgitation is only corrected if severe and accom pan ied by low ca rdiac output, as a mild to moderate regurgitation tends to dimin ish postoperatively with the decrease in right ventricular stra in. Pos toperativ e course With adequate amount of obstructive material removed there is an immediate decrease in pulmonary resistance, but this reflects more the improvement of ca rdiac output rather than the lowering of pulmona ry arter y pressure. Insuffi cient removal of chronic thromboembolic obstru ctions, especially at risk when these are located distally in the segmental a rteries, may lead to acute right hea rt failure a nd death or, if survived, be associated with poor improvement of symptoms due to persistent pulmonary hypertension. The postoperative period may be complicated by pulmonary reperfusion edema (6, 10, 12). This edema occurs to some degree in all patients and is localized to a reas of pulmonary parenchyma distal to vess els which have been desoblitcrated . The path ogenesis remains unclear, most possibly it is a form of focal lung inju ry caused by oxida nts and proteo lytic enzyme release, with additional contributory eITects of cardiopulmonary bypass, anticoagulation, and increased perfusion pressur e in a previously underperfused area. The spectrum of severity is wide, ranging from an acute hemorrhagic form with lethal exit to mild degr ees of edema revealed as infiltrates on chest radiographs with no influence on gas excha nge. Nevertheless, the reperfusion edema contributes to postoperative respiratory insufficiency in many of thes e alr eady pr eoperatively compromised patients, necess itating prolonged intub ation an d ventilatory support and predisposing secondary pulmonaty infection.
Current results From October 1984 to Sept embe r 1988 a total of 103 patients unde rwe nt pulmonary thro mboendarterectomy. The mea n age of patient s was 50 ± 16 yea rs , ranging from 20 to 82 yea rs and pr eoperatively 43.8 % and 48.5 % of the pa tients were in NYHA functional class III and IV, respectively.
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88
• -,
Fig. 1 Pre-operative pulmonaryangiogram of apatientundergoingpulmonary thromboendarterectomyforthromboembolicpulmonary hypertension. Extensive perfusion defectsarefound inallthree rightlobesand inthe left lower lobe
Pulmonaryvascular resistance could be reduced from a mean of 788 ± 370 to 299 ± 150 dyn -sec-em." postoperatively. Cardiac index increased from mean 2.03 ± 0.56 U mln-m/ to 3.22 ± 0.75 L'min-m", Hospital mortality was 11. 7% (n ~ 12/1 03), an d the main caus es of death were respiratory and multiorgan failure an d acute pulmonary hemorrhage. Univariate and multivari ate analyses of risk factors for hospital morbidity (i. e. reperfusion edema, respiratory insufficiency and ventilator dependency) an d mortality in these patients (7) could identify failur e to lower pulmonary res istance by more than 50%, the numb er of blood products required postoperatively, prolonged cardiopulmonary bypass times , presence of as cites, and decreased arterial pOz while breathing room air as predictors of perioperative complications . Only ascites as a sign of chronic right hear t failur e was proved as an independant predictor of ventilator depend en cy. The preoperative level of pulmona ry vascular resistan ce approached significance for hopspit al mortality. Older age, assoc iated disease, and severe symptomatology (NYHA IV) were tr end s th at did not reach sta tistical significance. Moser (12) has reported a long term follow-up (mean 28 month s, range 7 months to 16 years) of35 patients. Only one of the pati ents remain ed in NYHA functional group III! IV. In 17 of these 35 patients a repeat right heart catheterization 4 to 12 months postoperatively revealed further decrease of pulmonary vascular resistance. In no instance was there a deteriorati on of the primary postoperative result. but maximum clinical improvement was often delayed for up to one yea r after surge ry. The dat a of followup although not complete, suggest a three year survival of 85.3% (6). Conclusion
Fig.2 Theoperativespecimenfromthesamepatientreflectstheanatomy of thepulmonary arterytree.The intimawith thethromboembolicobstructions havebeen dissectedfromallsegmentalarteriesoftheright lungand the left lower lobe, secondary thrombus formation issuperimposed inthe lumen
Thus, pulmonary thromboend arterectomy has emerged as an effective measure in the tr eatment of chro nic th romboemb olic pulmonary hypertension at an acceptab ly low operative risk. The results also indicate that all patients suffering from pulmon ary hypertension should be screened for a thromboembolic etiology and evaluated for surgical tr eatm ent as ea rly as possible. Literature
2
Cabro l. Ch., A. Cabral. J. Acar, I. Gandj bakhch, G. Guiraudan. L. Laughlin. M.-F. Matt ei. and P. Gadea u: Surgical correction of chronic postembolic obstructions of the pulmonary arteries. J. Thora c. Cardiovasc. Surg. 76 (197 8) 620 - 628 Chitwood . ltV, R., D. C. Sobtston. and A. S. Wechs ler: Surgical treat-
3
5 (1984) 507 -53 6 Daily, P.O.. G. G. Johnsto n. C. J. Simmons. and K. M. Moser:
I
ment of chronic unresolved pulmonaryembolism. C1in. Chest. Med. Surgical management of chronic pulmonary embolism. Surgical management and late results. J. Throac. Cardiovasc. Surg. 79 (1980) 523 - 531 .. Daily. P.O., W, P. Dembitsky, K. L. Peterson. and K. M. Mos er:
S
6
Fig. 3 Thepostoperativepulmonary angiogramreveals complete restoration ofpulmonaryblood flow
Modifications of techniques and early results of pulmonary thromboendarterectomy for chronic pulmonary embolism. J. Thcrac. Cardiova sc. Surg. 93 (1987) 22 1-2 33 Daily , P. O., ltV, P. Dembit sky. and S. Ivers en: Technique of pulmonary thromboendarterectomy for chronic pulmonary embolism. J. Cardiac. Surg. 4 (1989) 10- 24 Daily. P. O.. ltV, P. Dembits ky . S. lvers en. K. M. Mos er. and ltV, Auge r: Current early results of pulmonary thromboendarterectomy for chronic pulmonaryembolism. Eur. J. Cardiothorac. Sorgo(1990) in press
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Thom e. cardiovasc. Surgn 38 (1990)
Thoracic Res earch Scholarship 1988
Thome. eardiovase. Surg n38 (19901 7
/I
'I
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II
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Daily . P. O.. W P. Dembitsky, S . /ve rsen. K. M . Moser, and W. Auger: Hisk factors for pu lmona ry thromboen darterectomy. J. Thorac . Cardiovasc . Surg. ( 990 ) in press Dalen. J. Ii.. and J. S. Alpe rt: Natural history of pulmon ary embo lism . Prog. Cardiovasc. Dis. XVII (1975) 259 - 270 Dar. v. . J. Jourdan . H. Sc hmitt. M. Saba tier . J. J. Amuif. and P. Kreitmann: Delayed pulm onary thro mbectomy via a periphe ra l a pproac h in the treatment of pulmonary embo lism and sequa lae. Thora c. Cardiovasc . Surgeo n 29 (1981) 227 -232 Leoinso n, H. M.. D. Shure, and K. M. Moser: Heper fusion pulmonary ede ma after pulmonary thromboenda rte recto my. Am. Rev. Respi r. Dis. 134119861124 1-1242 Mose r. K. M. . H. G. Spragg, J. Utley. and P. O. Daily : Chronic thrombotic obst ruction of major pulmon ary ar teries. Ann. Intern . Med. 99119831 299- 305 Moser, K. M., P. O. Daily, K. L. Pete rson, W. P. lJembilsk y, 1. M. Vap nek, D. S hure, J. Utley . and C. A rchibald: Throm boend arter ectomy for ch ronic, major vessel thro mboe mbo lic pulmonary hypertens ion in 42 patie nts: Immediate an d long-term results. Ann . Intern . Med . 10711987) 560-565 Ntcod. P., K. M. Peterson, M. S. Lev ine, Ii. Dittrich. M. Buchbinder. F. Chappuis, and K. M. Mose r: Pulmonary angiogra phy in severe chro nic pulmonary hypertension. Ann. Intern . Med . 107 (1987 )
565-568
S tein Iversen H
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If>
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Satter. P.: Pulmonary em bolecto my with the aid of ext raco rporea l circulation. Thor ac. Cardiovasc . Surgeo n 30 (1982 ) 31-35 Shure. D.. G. Gregorates. and K. M. Moser: Fibero ptic angiosco py: Role in the diagnosis of chron ic pulmona ry arterial obstruction. Ann. Intern . Med. 103 (1985) 84 4-850 Snyder, 1\.. D. C. Ken t. and B. F. Bais ch: Successful endarterecto my of chron ically occlusive pulmon ary artery. J. Thora c. Card iovasc . Surg. 45 11 9631482 Riedel. M. . V. Stanek, J. W idims ky. and I. Prerovs ky : Long term follow-u p of patie nts wit h pulmona ry embolism. Late prognos is and evolution of hemodynam ic and respiratory data. Chest 81 ( 98 2) 15 1-158 Wage fwoort . C. 1\.. and N. Wagefwoort : Pathology of pulmonary hypertension . John Wiley & Sons Medical Pub lication , New Yor k, 1977
Dr. med. S tein loers en
Klinik fur lIerz -, Tho rax- und GefaBchir urgic am Klinikum de r Joha nnes Gute nberg-Unlversitat Langen beckstr. 1 D-650 0 Mainz lIFHG Downloaded by: Universite Laval. Copyrighted material.
90
Thoracic Research Scholar ship 1988 : Pulmonary Thromboendarterectomy for Chronic Thromboembolic Pulmonary Hypertension at the University of California, San Diego S tein Iversen
Sum ma ry
At th e University of Californ ia . Sa n Diego pulm onary thromboendarterectomy (PTE) has eme rged as a n effective measure in the trea tme nt of chronic th romboembolic pulmon ary h ypertens ion. Unresolved emboli become organized by incorp oration into the vascula r wa ll a nd may form st rictures. webs. ba nds and /o r membra nous occlusions a nd ca use pu lmon a ry hyperte nsion refra ctory to medic al treatm en t. When pu lmon ary vas cula r resistan ce exceeds 300 dyn -sec -crn'" and the vasc ular wa ll cha nges a re locat ed to begin at or proximal to the lobar a rte ry level. surgery is ind icated. Th e ope ra tion is performed usi ng ca rdiopulmonary byp as s. deep hyp oth ermia and pe riod s of circulatory a rres t. Th e dissection of eac h segmental artery is carried out in the media layer fro m se pa rate incisions in th e right and left pulm on ary a rtery at the level of the perica rd ial flexion. Pulmona ry rep er fusion edema may com plicates the postopera tive course . a nd pulmonary hemorrh age . res pira tory insufficiency necessitating prolong ed ventilatory su p port and secon dary multi orga n failure are main ca use s of hospital mor tality. Between Octob er 1984 and Septe mber 1988 103 patients with a mea n age of 50 ± 16 yea rs und erwent PTE. Conse quen tly. pulm onary vascular resistance could be red uced from 788 ± 370 to 299 ± 150 dyn -sec -cm" a nd ca rd iac index incr ease d from 2.0 ± 0 .6 to 3.2 ± 0.8 t/rntn-m". Hospital mo rtality was 11.7 % (12/10 3 patients). Thu s. pu lmonary th romboend arter ectomy effectively reduces pulmonary hyp ertension at a n acce ptab le low risk . The results indicate that pati ents shou ld be d iag nose and refe rred for surge ry a s early as possib le. Pulmo nale Th rom ben da r te rt e k tnm le a ls chir urg isc hc The raple de r chro nischen throm bembolische n pulmo nalen Hypert cnle a n der Unlve rslty of Ca lifo rnia. San Die go Durch das Th or axchirurgische Reisestipendium der Deutschen Gesellschafi fur Thorax -, Hera - und GefaBchirurgie wu rd e mir von August bis Novem ber 1988 ein Gas tarztaufen thalt in der Division ofCardiotho raci c Surge ry (Leiter: Pat O. Daily M. D.) a n der Universi ty of Californ ia. Sa n Diego. ermo glicht . Ziel des Aufcn tha he s war d ie Dia gnostik und Beh andlun g de r durch chro nische Lungenembolie verursachten pu lmo na len Hyperto-
Thorae. ca rdiovasc. Surgn 38 (1990) 86-90 © Georg Thieme Verlag Stuttgart- New York
nie zu erle rne n. Nur dart ist die Beha nd lung dieser seltene n ab er lebe nsbedrohlichen Spatkomplikat iun sta ttgehabter Lungen embolien dureh pu lm on ale Thrombend arterickt om ie zu ei ne r wirkungsvollen Ma Bnahm e her angereift. Bei fehlender endo gene r Lyse fiihr en a bge la ufene l.un gen embolien du rch Organisation zu narbigen Obst ruktio nen und Vers chHissen der Pulmonalgefa Be mit der allmahlichc n Entwicklun g cines pulmo na len Hochdrucks. der dur ch mcdikamentose The rapie nur we nig zu beei nflussen ist . Durch bilatera le pul mon ale Thrombe ndarteriektom ie la ssen sich die thrombembolisch en Obst ruktionen bes eltlgen und der pulmonale Ilochdruck we itgehe nd se nken . Die Indik at ion ist a b cine m pulm on alen GefaBwiderstand tiber 300 dyn -s -cm "? gegeb en . Varaussetzu ng filr die Dperabilitat ist der Nachweis von narbigen GefaBverandc ru nge n. begin nend in l ldh e oder proxi ma l de r l.oha rarter ien . Die Operat ion wird unt er Anwe nd ung der extrakc rpo rale n Zirkulation in tie fer Gan zkorperhypotherm ie und Per loden von Kreisla ufstillsta nd vorg enom me n. Dcr postope ra tive Verlauf ist du rch das Entste he n ei nes pu lmon alen Reperfusionsodems knmpliziert. das be i schweren Erschein un gsformen akut hamorrhagis ch und todllch verl aufcn kan n. zumi ndest abe r cine respira torisch e Insuffizienz mit La ngzeitbca tmung zur Polge hat. Von Okto bcr 1984 bis Septe mbe r 1988 wurden 103 Patlenten mit einem mittleren Alter von 50 ± 16 Ja hre operi e rt. Der Lungengefallwidersta nd lieB sich von 788 ± 370 a uf im Mittel 299 ± 150 dyn -s -cm ' " sc nken und der Herzind ex stleg dab ei von 2.0 ± 0.6 a uf 3.2 ± 0 .8 L' min/m" Die Ste rblichkeit bctrug 11,7 % (121103 Patien ten], wobci die lIaupttodesursa chen respi ratorisches un d/ od er Multiorga nver sagen sowie akute pu lmonale Ha rmorrhagie n wa re n . Die Erge bnisse zelgen, da Bd ie pulm ona le Thrcmbendarteriektnm ie ein effektives The ra pieverfa hren der th romb embotisch bedlngten chro nische n pulm on alen Hypertonic lst. ver bunden mit ei ne m akzeptabl en Opera tio ns risiko. Urn dleses gering zu halt en. so llten die Pati enten moglichs t Irtlh di ag nostiziert und der Beha ndlu ng zugeflihrt word en . Key wo rds
Chron ic pulmonary embolism - Pulmonary hyper ten sion - Pulmona ry th romboendarter ectomy
Received for Publica tion : February 12. 1990
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Klinik fur Ilcr z-, Tho rax- un d Gcfci.Ochi rurgie am Klinikum der Joh annes Gutenberg -Universitat . Mainz
Thorac. cardioVCISC. Surg1l 38 (1990)
Thoracic Research Scholarship 1988
Introducti on
Th ro mboembolic pulmonary hypertension
The thor acic Resea rch Schola rs hip of the German Society of Thoraci c and Cardiovasc ular Surgery enabled me to visit the Univers ity Clinic of the Univers ity of California in San Diego. The purp ose of the sta y was to obtain knowledge of diagnostic measu res , criteria for selection of surgical candidates. ope ra tive tec h niques and postoperative man ageme nt of pati ents sutTering fro m chro nic thromb oembolic pulmona ry hyperten sion . Kenneth Moser of th e Division of Pulmona ry Medi cin e and Pat O. Daily from the Division of Cardio thoraci c Surgery have long bee n engaged in the treatment of th is pa tient group. The du ra tion of the stay was th ree mon ths , from Augus t 18 to Novembe r 16, 1988, and after fulfilling the require ments of the "Board of Medi cal Quality Ass u ra nce" in Sacram ento, I was gra nted the sta tus of "Postdoc toral Sch ola r" at the Division of Cardiotho raci c Su rgery under Dr. Daily. Th is licen se permitted "limited patient contact", an d ena bled surgica l pa rticipat ion . Further insight in the peri operat ive course and problems of management was ga ined through the op portunity to cooperate in a retrospective analysis for risk factors in pati ents un dergoing pulmonary th romboendarterectomy (6 , 7). The complete integration and th e cons tant help fulness mad e my studies all th e mor e easy. Not least, the warm hosp italty shown also outside th e hospit al sets standards to follow, and the overall open ess and friendliness made the time in San Diego most pleasant. Th e knowledge obtaine d ha s enabled the initiation of a simila r program for man agem ent of th ese pati ents in Mainz, ba sed en tirely on the pri nciples developed a nd pr acticed in San Diego. Only in San Diego are patients with chronic thromboembolic pulm onary hypertension tr eated on a la rger scale. Between 1974 and 1980 fou r patien ts we re ope ra te d, but the re has been a stead y increase in nu mb er of pa tient referrals , and from October 1, 1984 to Septem ber 20 ,1 988 a total of 103 pati ents un derw ent pulmonary th rom boenda rterectomy. At pr esen t, approxima tely two operations a re performed per week a nd around 50 patien ts are aw ai ting diagn ostic evaluation and surgery. Patients are referred prima rily from North Ame rica , but also fro m othe r continen ts of th e world . Th e patients are prim arily ad mitted to Dr. Moser and th e Division of Pulmon ary Medi cine, wh ere the exte ns ive diagnostics are performed. In close cooperation between the two divisions , the possibilities and indications for surgery a re discussed a nd de te rmine d. Th e pulm ona ry th ro mboendarterectomies are performed by two su rgeons , Pal. O. Daily an d Walt er P. Dembitsk u. Postoperati vely, th e patients are treated in the cardiothoracic surgical intensive ca re un it, and patients sh uttled through the often d ifficult postoperative course with jo int etTorts from collea gues of bot h divisions. I also expe rience d the close team-work in th e ope ra ting room with the regular pr esen ce of pul monologists. Infor mation of the opera tive situs and exten t and localization of patho logical specime ns were obta ine d. Th ese were thoroughly analyzed and docume nted and compa red with th e preopera tive interpretation of pulmonary angiography and an gioscopy. Th is feedb ack and contro l of diagnosti c findin gs were considere d of utmost importan ce to imp rove one's experience an d allow th e correct determinati on of operability in bord er line cas es.
Only infreque ntly does pulmo nary embolism ca use chron ic elevation of pulmonary resistance. Resoluti on of th e thromboembolic mat erial with recovery of norm al pulm ona ry blood now is the natu ral cours e (8). In a sma ll percentage of patients , howeve r, the restoration of the pulmonary vascular bed is incompl et e and pu lmonary hyperten sion persists. Measurable increase in pulmonary pressure occurs only afte r a mor e th an 65 % obstruction of the pulmon ary arteries, and, therefore, with normal pulmonaryvessels and parenchyma prior to embolization there is extens ive bilatera l, incomp letely resolved embo li wh en chro nic pulmonary hyperten sion occu rs. Th romboem holic pulmona ry hypertension is refractory to medical th erapy and the patients hav e, asso ciated with the deg ree of hypertension , s horten ed life expec ta ncy (17).
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A successful pul monary thromboen darterectomy was first rep orted by S ny der et ai. (16) already 1963 , but th e initial results were poor and mortality high. In an extensive review of the wo rld litera ture Chitwood et ai. (2) counted 85 operated patients worldwide with a mortality rat e of 22 percent. From Europe, experience with pulmona ry t hro mboe nda rterectomy have been publi sh ed by Dor (9) and Cabral (I) in France who advoca te the un ilatera l thora cotomy witho ut utilizin g ca rdiopulmonary bypass. Fro m Germa ny, S alte r (14) has reported on two pati ents with ce ntra l pu lmona ry artery occlusion which were operated upon via sternotomy and und er extra corporeal circulation. Daily (:l) first described his operative tech niques 1980 usi ng sterno tom y, cardiopulmonary bypass and bilat eral pulmonary thr om boendarterectomy in repeated periods of circulatory arrest. Furt he r modificati ons of techniques were pu blish ed 1987 (4) .
Preoperative diagn osti c Preoperative diagnostic measures serve to rule out primary or non -th rom boembolic form s of secondary pulmonary hypertension, to exclude or verify concomitant cardiac and! or pulm onary disease a nd to det ermine the degr ee oft hro mboemb olic pulmonary hypertension and assess tec hnical operab ility (1 1, 13). In pulmona ry hypertens ion secondary to th romboembolism perfusion lung scintiography will nea rly always reveal multiple bilate ral seg me ntal perfusion defec ts with typical mismat ch to a normal ventilation sca n. Right heart catheterization determin es the deg ree of pulmonary hypertens ion . The mean pulmona ry pressure is gene ra lly well above 30 mm Hg, but as cardiac output is compro mised in most of th ese patients , the calculation of pulmonary vascular resistance more accurately reflects the degr ee of pulm onary vascu lar obstruction. When pulmonary wedge pressure is normal and when echocardiography reveals norm al left heart function a nd dimen sions , pulmonary hypertension seconda ry to left heart dysfunction or mitral disease is unlik ely. Left heart catheteriz ation with corona ry a ngiogra phy is routinely performed in all pati ents over 35 years of age or in patients with clinical signs of coronary heart disease.
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Pulmon ary thromboendarter ectomy
71lOrac. cardiovasc. Surgn 38 (1990)
Pulmonaru ollgiography will estab lish the definite diagnos is of chronic pulmona ry embolism. Exact visualization of the pulmona ry arteries is essential for the correct localization of thrombo embo lic vascular changes a nd the refore conventional angi ograp hy remains the golden standard. Separate unilateral injections of contrast solution and sequence films a re preferred to digital subtraction angiog raphic techniques . Pulmonanj ollgioscopy (15) has in many instan ces proven valua ble in helping determin ing extent a nd location of vascular obstru ction , beller defining proxima l land thus oper able) disease. Pulmonarq function studies, althou gh frequentl y normal, a re important to exclude parenchymal diseas es Ii.e. emphysema, chronic obst ructive lung disease, fibrosis etc.) as the cause of pulmonary hypert ension. Indication s for surge ry
Thr ee criteria must be met for su rgery to be ind icated (3,4,5): 1. The presence of severe functional disab ility, primarily dyspn ea at rest or upon exertion acco rding to the NYHA functiona l class III or IV. 2. An increase of pulmonary vascular resistan ce abo ve 300 dyn -see 'em - 5 at rest as a minimum level of pulmonary vascular obstruction, although some patients have been accepted with lower levels when res istan ce significantly increased during exercise. :l . The major determinant of operabili ty is the demonstration by angiography of pulmon ary arterial lesion s beginning at or proximal to the origin of the loba r level. Periph erally at the segmenta l bronc hopulmonary segmental arteries thromboendarterectomy can be performed, but at risk of suboptima l resu lts due to incomplete relief of pulmona ry vascular obst ruction.
Most patients accepted for pulmonary thromboendarterectomy had a caval filter device inserted prior to or du ring surgery. Pathology
The path ological asp ects of chro nic thromboembolic pulmo nary obstruction diITer tota lly from those of acute pulmonar y embolism a nd the refore the surgical implications diverge. A non-resolved thromboembolus becomes or ganized: i. c. after adherence to the vascualr wall there is an ingrowth of granulo cytes and lat er fibroblasts. With time the thrombus is repla ced by fibrous and elastic tissue a nd incorporated in the wa ll (18). In the larger vessels there is complete or incomplete cent ral recan alization which then later appea rs as intraluminar webs an d bands. The lumen may then again be parti ally or totally occluded by seconda ry thrombus formation or thromboemboli superimposed on the fibrotic obstruction. Upon inspectio n of the vessel after pulmonary arteriotomy, therefore, there may be lillie appa rent obstruc tion beside a thickening of the intima, and the recognit ion of obstruction may be diffi cult. The obstructive lesions can only be removed by refined arterial enda rte recto my tech niques.
Stein Iversen
Oper ati ve techniques
The opera tive procedures have been sta nda rdized since 1984 (4, 5). Following sternotomy and esta blishi ng total ca rdiopulmonary bypass, the core temp erature is lowered to 20 ' C. The pericardial flexion is mobilized bilaterally over the pulmonary arteries . and separa te arteriotomies - two on the right and one on the left side - performed within the hilar st ructures but extra pleural. After identification of the correct plane of dissection, this is ca rried out circumferentially starting pro ximal at the hilar arteriotomi es going distally into each segmenta l a rtery. Due to the increased br onchial artery collateral flow in thes e patients. accurate visualization is impossible during peripheral dissection and repeated period s of total circulat ory arrest are inevitable. Concomita nt card iac lesions a re corrected during the same procedure if necessary. The interatrial septum is always ins pected for the presence of an open forame n ovale which is closed . Tricuspid regurgitation is only corrected if severe and accom pan ied by low ca rdiac output, as a mild to moderate regurgitation tends to dimin ish postoperatively with the decrease in right ventricular stra in. Pos toperativ e course With adequate amount of obstructive material removed there is an immediate decrease in pulmonary resistance, but this reflects more the improvement of ca rdiac output rather than the lowering of pulmona ry arter y pressure. Insuffi cient removal of chronic thromboembolic obstru ctions, especially at risk when these are located distally in the segmental a rteries, may lead to acute right hea rt failure a nd death or, if survived, be associated with poor improvement of symptoms due to persistent pulmonary hypertension. The postoperative period may be complicated by pulmonary reperfusion edema (6, 10, 12). This edema occurs to some degree in all patients and is localized to a reas of pulmonary parenchyma distal to vess els which have been desoblitcrated . The path ogenesis remains unclear, most possibly it is a form of focal lung inju ry caused by oxida nts and proteo lytic enzyme release, with additional contributory eITects of cardiopulmonary bypass, anticoagulation, and increased perfusion pressur e in a previously underperfused area. The spectrum of severity is wide, ranging from an acute hemorrhagic form with lethal exit to mild degr ees of edema revealed as infiltrates on chest radiographs with no influence on gas excha nge. Nevertheless, the reperfusion edema contributes to postoperative respiratory insufficiency in many of thes e alr eady pr eoperatively compromised patients, necess itating prolonged intub ation an d ventilatory support and predisposing secondary pulmonaty infection.
Current results From October 1984 to Sept embe r 1988 a total of 103 patients unde rwe nt pulmonary thro mboendarterectomy. The mea n age of patient s was 50 ± 16 yea rs , ranging from 20 to 82 yea rs and pr eoperatively 43.8 % and 48.5 % of the pa tients were in NYHA functional class III and IV, respectively.
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• -,
Fig. 1 Pre-operative pulmonaryangiogram of apatientundergoingpulmonary thromboendarterectomyforthromboembolicpulmonary hypertension. Extensive perfusion defectsarefound inallthree rightlobesand inthe left lower lobe
Pulmonaryvascular resistance could be reduced from a mean of 788 ± 370 to 299 ± 150 dyn -sec-em." postoperatively. Cardiac index increased from mean 2.03 ± 0.56 U mln-m/ to 3.22 ± 0.75 L'min-m", Hospital mortality was 11. 7% (n ~ 12/1 03), an d the main caus es of death were respiratory and multiorgan failure an d acute pulmonary hemorrhage. Univariate and multivari ate analyses of risk factors for hospital morbidity (i. e. reperfusion edema, respiratory insufficiency and ventilator dependency) an d mortality in these patients (7) could identify failur e to lower pulmonary res istance by more than 50%, the numb er of blood products required postoperatively, prolonged cardiopulmonary bypass times , presence of as cites, and decreased arterial pOz while breathing room air as predictors of perioperative complications . Only ascites as a sign of chronic right hear t failur e was proved as an independant predictor of ventilator depend en cy. The preoperative level of pulmona ry vascular resistan ce approached significance for hopspit al mortality. Older age, assoc iated disease, and severe symptomatology (NYHA IV) were tr end s th at did not reach sta tistical significance. Moser (12) has reported a long term follow-up (mean 28 month s, range 7 months to 16 years) of35 patients. Only one of the pati ents remain ed in NYHA functional group III! IV. In 17 of these 35 patients a repeat right heart catheterization 4 to 12 months postoperatively revealed further decrease of pulmonary vascular resistance. In no instance was there a deteriorati on of the primary postoperative result. but maximum clinical improvement was often delayed for up to one yea r after surge ry. The dat a of followup although not complete, suggest a three year survival of 85.3% (6). Conclusion
Fig.2 Theoperativespecimenfromthesamepatientreflectstheanatomy of thepulmonary arterytree.The intimawith thethromboembolicobstructions havebeen dissectedfromallsegmentalarteriesoftheright lungand the left lower lobe, secondary thrombus formation issuperimposed inthe lumen
Thus, pulmonary thromboend arterectomy has emerged as an effective measure in the tr eatment of chro nic th romboemb olic pulmonary hypertension at an acceptab ly low operative risk. The results also indicate that all patients suffering from pulmon ary hypertension should be screened for a thromboembolic etiology and evaluated for surgical tr eatm ent as ea rly as possible. Literature
2
Cabro l. Ch., A. Cabral. J. Acar, I. Gandj bakhch, G. Guiraudan. L. Laughlin. M.-F. Matt ei. and P. Gadea u: Surgical correction of chronic postembolic obstructions of the pulmonary arteries. J. Thora c. Cardiovasc. Surg. 76 (197 8) 620 - 628 Chitwood . ltV, R., D. C. Sobtston. and A. S. Wechs ler: Surgical treat-
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5 (1984) 507 -53 6 Daily, P.O.. G. G. Johnsto n. C. J. Simmons. and K. M. Moser:
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ment of chronic unresolved pulmonaryembolism. C1in. Chest. Med. Surgical management of chronic pulmonary embolism. Surgical management and late results. J. Throac. Cardiovasc. Surg. 79 (1980) 523 - 531 .. Daily. P.O., W, P. Dembitsky, K. L. Peterson. and K. M. Mos er:
S
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Fig. 3 Thepostoperativepulmonary angiogramreveals complete restoration ofpulmonaryblood flow
Modifications of techniques and early results of pulmonary thromboendarterectomy for chronic pulmonary embolism. J. Thcrac. Cardiova sc. Surg. 93 (1987) 22 1-2 33 Daily , P. O., ltV, P. Dembit sky. and S. Ivers en: Technique of pulmonary thromboendarterectomy for chronic pulmonary embolism. J. Cardiac. Surg. 4 (1989) 10- 24 Daily. P. O.. ltV, P. Dembits ky . S. lvers en. K. M. Mos er. and ltV, Auge r: Current early results of pulmonary thromboendarterectomy for chronic pulmonaryembolism. Eur. J. Cardiothorac. Sorgo(1990) in press
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Thom e. cardiovasc. Surgn 38 (1990)
Thoracic Res earch Scholarship 1988
Thome. eardiovase. Surg n38 (19901 7
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Daily . P. O.. W P. Dembitsky, S . /ve rsen. K. M . Moser, and W. Auger: Hisk factors for pu lmona ry thromboen darterectomy. J. Thorac . Cardiovasc . Surg. ( 990 ) in press Dalen. J. Ii.. and J. S. Alpe rt: Natural history of pulmon ary embo lism . Prog. Cardiovasc. Dis. XVII (1975) 259 - 270 Dar. v. . J. Jourdan . H. Sc hmitt. M. Saba tier . J. J. Amuif. and P. Kreitmann: Delayed pulm onary thro mbectomy via a periphe ra l a pproac h in the treatment of pulmonary embo lism and sequa lae. Thora c. Cardiovasc . Surgeo n 29 (1981) 227 -232 Leoinso n, H. M.. D. Shure, and K. M. Moser: Heper fusion pulmonary ede ma after pulmonary thromboenda rte recto my. Am. Rev. Respi r. Dis. 134119861124 1-1242 Mose r. K. M. . H. G. Spragg, J. Utley. and P. O. Daily : Chronic thrombotic obst ruction of major pulmon ary ar teries. Ann. Intern . Med. 99119831 299- 305 Moser, K. M., P. O. Daily, K. L. Pete rson, W. P. lJembilsk y, 1. M. Vap nek, D. S hure, J. Utley . and C. A rchibald: Throm boend arter ectomy for ch ronic, major vessel thro mboe mbo lic pulmonary hypertens ion in 42 patie nts: Immediate an d long-term results. Ann . Intern . Med . 10711987) 560-565 Ntcod. P., K. M. Peterson, M. S. Lev ine, Ii. Dittrich. M. Buchbinder. F. Chappuis, and K. M. Mose r: Pulmonary angiogra phy in severe chro nic pulmonary hypertension. Ann. Intern . Med . 107 (1987 )
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Satter. P.: Pulmonary em bolecto my with the aid of ext raco rporea l circulation. Thor ac. Cardiovasc . Surgeo n 30 (1982 ) 31-35 Shure. D.. G. Gregorates. and K. M. Moser: Fibero ptic angiosco py: Role in the diagnosis of chron ic pulmona ry arterial obstruction. Ann. Intern . Med. 103 (1985) 84 4-850 Snyder, 1\.. D. C. Ken t. and B. F. Bais ch: Successful endarterecto my of chron ically occlusive pulmon ary artery. J. Thora c. Card iovasc . Surg. 45 11 9631482 Riedel. M. . V. Stanek, J. W idims ky. and I. Prerovs ky : Long term follow-u p of patie nts wit h pulmona ry embolism. Late prognos is and evolution of hemodynam ic and respiratory data. Chest 81 ( 98 2) 15 1-158 Wage fwoort . C. 1\.. and N. Wagefwoort : Pathology of pulmonary hypertension . John Wiley & Sons Medical Pub lication , New Yor k, 1977
Dr. med. S tein loers en
Klinik fur lIerz -, Tho rax- und GefaBchir urgic am Klinikum de r Joha nnes Gute nberg-Unlversitat Langen beckstr. 1 D-650 0 Mainz lIFHG Downloaded by: Universite Laval. Copyrighted material.
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