Circulatory and respiratory changes in patients with Laennec's cirrhosis of the liver

irwlatory and respiruto ith lmennec‘s cirrhosis

Ike hepa:osplanchnic hemodynamic changes associated with cirrhosis of The liver are well known. They consist of a -educed total hepatic blood flow, portal :lypertension, and the extensive formation tif collateral venous system that bypasses :he hepatic bed. The collateral vessels are, perhaps: largely the consequence of portal ?ypertension. On the other hand, the cardiovascular and respiratory changes that occur in patients with cirrhosis of the ‘iver have not received the same attention. In recent years, special endeavor to elicit
espire~ory

ehcmges

The pulmonary ventilatory changes associated with cirrhosis of the liver were studied by Heinemann and associates,l and :>y us9 (Table I). There are no consistent Aanges in mechanical ventilatory function ,.>r lung volume2 noted in patients with

severe liver disease (TaLe i 1” 7h~ C23:~mg3 observed most often are rclaivd 11) non!lepatic disorders of the respirator!, q-&n). However, in he presence of sever<~iwzites, :he vital capacity may ‘be reduceG :lmder-itely. In the presence of ~beGt> a:ld :narked ascites, compression of the 111ng vollume also results in a decrease in the diameter of the airways and a degree of 35struction to airflow. FurtherI-tore, all ventilatory capacity values are expecled :o be reduced in the presence of pu!monar:$r congestion, which may- ‘be associai ed with severe liver disease. The most striking alterations it: gas exhange which llave been noted in ~irt~uall~~ d!f patients \\?th severe 1ive.i. &ea~e are jlyperventilation with respirator>- ~l~~alosis~ a:ld hypoxia of variabIe proporCoI)s. Tal)le iI summarizes the gas exchange d ita froul d group cf patients with cirrhosis of the iiver that was studied i.n our iaho!-atory. Ws is representative of a nu cn!~r of studies previously reported1*‘3~6” The degree 2 hyperventilation and respirator:,- a&iosis is roughly proportional to the severit? of the liver disease, but did not <.orrelate with either the degree of arteriai ~desati~r;tLion or the magnitude of vt~:i0ar~~i+d ad-

570

Bash.osr, McConnell, and M&Y

2370 1900 2000 1400 1450 1720 2250 2000

52 49 43 SO 48 75 SO 49

4600 4000 365.5 2800 3000 2270 4490 2900

108 99 89 62 80 70 112 8.5

67 zt S.8 *FEVo.e,

0.5 second forced

expiratory

volume:

100 * FVC,

forced

vital

capacity;

None None + None ++ None None None 11

PVC, predicted

vital

capacity.

FEVo.5 x 100 tFEVo.6 % = FVC . $FVC % =

FVC

x 100 PVC .

Table 11. AlveoZur ventilation

24 2.89 - 9.16 S.56 zt 1.5 4.44 * 1.08

NO.

Range Mean * SD Normal

Pa02

26 45 - 89 71.3 zt 12.6 >85

and gas exchange in patients with cirrhosis of the liver

I

A-a

PH

I

26 23 - 72 43 + 12 13+ 6

27 80 - 96 91.6+ 4.1 >95

24 5.52 - 13.5 9.66 * 2.3 6.32* 1.5

I

25 7.3.5 - 7.50 7.44 Lt 0.04 7.37 - 7.43

HCOr

24 12,s - 28 21.3 23 -21

PA, aIve&r ventilation (L./min.); VE, minute ventilation (L./min.); S-02, systemic arterial 02, saturation 02 and CO* tensions in the systemic arterial blood on room air breathing (mm. Hg) ; A-a, alveolar-arterial room air breathing (mm. Hg); pH, arterial pH (base excess in mEq./L); HCOi, plasma bicarbonate.

mixture. The observed alveolar ventilation represented 58 Z!C 10 per cent of the total minute ventilation and it was significantly lower than the predicted ratio of 70 per cent, indicating that the physiological dead space is increased in patients with cirrhosis of the liver. The $~A/VE tended to decrease with increased ascites (Fig. 1), which was largely the result of increased dead space ventilation. This is particularly significant

27 18 - 40 32.2 zt S.2 37 - 44

Base

excess

24 -11 to+5 -2.4 - 2to+4 (%); Pa02 and P&O*, 02 tension gradient on

in the light of the expected change with ascites being a decrease in VD as noted in obesity where VE tends to decrease with increased obesity instead of an increase as noted here. Hyperventilation was present at all levels of consciousness and persists apparently unrelated to the presence of anemia, fever, pulmonary disease, or hypoxia. The mechanism of hyperventilation seen

* tn e.

* . e

ASCf FIN. I. Relation between the degree of ascites in patients rho& of the liver*

rffs ratio with

VA/GE

and

the

Laennec’s cir-

in cirrhosis of the liver remains obscure. Certain factors, singly or combined, have ‘been assumed to stimuIate the respiratory center and to perpetuate the respiratory drive. In the unanesthetized dog, the infusion of nonacidifying ammonium salt increased respiratory drive and led to respiratory alkalosis.’ Hyperventilation with respiratory alkalosis, in turn, has been observed to increase the blood ammonia concentration8 and to enhance the ammonia toxicity through impairment of oxygen utilization at the tissue level.g Whether this increase in blood ammonia level of hyperventilation is solely the result of an increased muscular activity remains to be seen..lOJr However, the poor correlation, between the circulating level of blood ammonia and the level of ventilation, casts some doubt on the role of ammonia. It was suggested that the ratio of the diffusible to nondiffusible ions determine the magnitude of the respiratory drive rather than i-he absolute value of the ammonia blood level.lJ* While the role of ammonia in the respiratory drive remains unclear, other primary aminesr3 of intestinal origin also :llave been implicated. These compounds peached the systemic circulation by the 2 tUypes of shtints described below. The decreased arterial oxygen tension?

bhaL lb dllc ~~~y&mrliil~rkJ s,L;%~tx36: w ial &untingr may play an additive ?o!e in the respiratory. drive that is associad with 5rrhosi.s of the liver. However* t,vith the exception of a few patients, the arterial oxygen tension is not sufficiently low to be !he singular cause for this increaseo ventilap:ion.r4 Furthermore~ there is a poor CorreIaGon between the observed s>Tsternic arterial oxygen tension and minute ventilation which suggests again that additional or G~dependent factors are responaib~~? for the increased respiratory drive.ls Such a COW elusion is further substantiated b>. the observation that the breathing of pure oxygen for 30 minutes failed to decrease alveolar ventilation. The arterial CD2 ten&on in 24 paGents with cirrhosis of the her was 32 + 5 mm. Hg on breathing of room air and 31 in 4 mm. Hg on breathing of 100 per cent oxygen. lt is interesting to note that. in oiir studies ;‘Table lI), the mean plasma bicarbonate is low 21.3 mEq./l,., and the base def’cit is slightly increased (base excess = -.%a, ranging as Iow as - 11). lY!loreover* we were able to calculate from the data of VEmxinee and associate3? whose patients had more severe lives disease and more severe hyper,” v-entilation, that the base d&cit was greater- The average was ---4*$ in patients Gthout coma and -5.1 in patients in coma. A decrease in blood bu8er base would :end to increase the sensitivity oi both the peripheral and central chemoreceptors to !lydrogen-ion (H+) stimuli. The decrease ;n plasma bicarbonate* presan&Gy, would indicate a decrease in cerebral spinal fluid ,CSF) bicarbonate which is likely to be accompanied by a lower CSF pH {normally 7.32 at ‘blood pH 7.4). Vnder these &cumstances, hyperventilation wouId tend to be lnaintained, since any reduction in ventilaGon with a subsequent rise in CQZ tension ivill raise CSF H+ concentra.tion and. stimulate breathing.lG This would tend to Qrevent the expected decrease in ventilation when the patient is placed on 1Ol1 per cent oxygen breathing, if one assumees that the :iypoxia were a factor in the su3tained ‘lyperventilation. This, apparently8 is the ‘eason our patients showed no decrease in ventilation on 100 per cent 0t breathing sn spite of the iact that in some insCa.nces r,he I%.O~ was as low as 45 mm. 13g. The

cause of the sustained low bicarbonate is not clear, but it is known to occur in chronic hyperventilation in subjects that experience altitude hypoxia and in persons who are subjected to prolonged hyperventifation by mechanical ventilation. Thus, the primary cause of hyperventilation remains obscure; but certainly, the possibility of an interdependence of multiple factors, which include increased circulating metabolites and hypoxia in the presence of a reduced bicarbonate in the blood and spinal fluid, seems to offer the best possibility of an explanation of the sustained hyperventilation. Circulatory

shanges

Mechankn of pep$heyal artekal desatuyatie%. Peripheral arterial desaturation of oxyhemoglobin is frequently encountered in patients with advanced cirrhosis of the liver. The degree of hypoxemia is usually mild; but in some instances, marked peripheral cyanosis, associated with clubbing of the digits, is observed. This has been a clinical entity with obscure mechanism. It was first recognized by Fluckiger in 1884, in a woman with no evidence of cardiorespiratory dysfunctionl’. Subsequently, similar observaGons were reported in both children and adults18-zo. SnelP reported the presence of systemic arterial desaturation and observed a close relationship between the acuteness and the severity of the liver disease and the degree of arterial desaturation. He postulated that an abnormality of the red blood cell (hemoglobin) could be responsible for the observed hypoxemia. Later, Keys and §nellzl ascribed the cause of the hypoxemia to a shift in the oxyhemoglobin dissociation to the right. Their finding of altered hemo-

globin dissociation, wljich was denied by subsequent investigators,lxa was recently confirmed.ZZ The magnitude of this displacement was consistent, but small, and it would neither explain the described large alveoiar-arterial OZ tension (A-a) gradient (Table III) nor the marked degree of arterial desaturation that was observed in some patients with advanced disease of the 1iver.z5 These observations could, however, be best explained on altered exchange of pulmonary gases. In the patient with chronic alcoholism, impaired diffusion might be conceivable as the result of a recurrent pulmonary infection with subsequent interstitial pulmonary fibrosis. The demonstration of a decrease in the A-a gradient on low oxygen-air mixture suggested that this mechanism played no significant role in the observed hypoxemia of cirrhosis of the liver.!6 Whereas, the finding of a large A-a gradient on 100 per cent 02 breathing suggested the existence of a venoarterial admixture.z5*26 In cirrhosis of the liver, 2 sites of venoarterial admixture (shunting) were described both anatomicallys’J8 and physiologically.~~~2g~30The portopulmonary pathway, the consequence of portal hypertension, diverted the porta venous bIood into the pulmonary vein via the periesophageal and mediastinal veins. Theoretically, it is not possible for these shunts to carry the calculated amount of blood that bypasses the alveol? or to produce marked arterial oxygen desaturation owing to the high oxygen content of the portal venous blood.31 These theoretical considerations coupled with the finding of an estimated blood flow through this pathway (averaged 45 ml. per minute per square meter)32 pointed

Table III, Alveolar-arterial (A-a) 02 tension gradients of the liver (q*oom aiy byeathzkg)

Mean

No. Abelman Rodman Heineman Bashour

and associateP and associate? and associates1 and associateP

5 18 10 1.5

(mm. Hg) in patients with cirrhosis

35 32.8 31.2 43

* 4.3 + 11.2 * 9.3 * 16

Normal 9.7 0 0 13

nukes * 4.3 - 1.5 - 1.5 * 6

LO the second possible site7 pulmonary a~tei-ioles-to-ve~~~les. The existence of this pulr~~o~~ary site was further substantiated f>y demonstrating that mild to model-ate exercise increased the degree of venoLb:terial admixture.zG Furthermore, the finding of a significant positive correlation, between the extra hepatic shunted blood zj~ld portal venous pressure (judged from ‘lepatic wedge pressure), suggested that the portal hypertension played an import- injecting the pulmonary artery with a microopaque gelatin suspension. Instead, Berthe:ot and coworkersS3 found marked arterial dilatation of the fine peripheral branches of the pulmonary artery within the lung parenchyma (in the alveolar wall) and on I:he pleural These later resembled the

574

Bashour, McConnell,

and M,iller

clubbing, occasionally associated with cirrhosis of the liver, is not clear. Clubbing of the digits from various causes was uniformly accompanied by a small peripheral (across the hand) arteriovenous O2 and CO2 differences,34 a decreased digital capillary blood flow,36 and digital oxygen consumption,36 which suggest the presence of blood shunting across the fingers from digital arterioles to venules through the existing arteriovenous anastomosis.34,37-3g Similar peripheral gaseous exchanges were noted in the patient with cirrhosis of the liver with marked palmar erythema.~4~QJ This latter clinical finding shares the same pathogenesis and it is believed to precede clubbing of the digits in some patients with cirrhosis of the liver.41 In addition to the peripheral site of blood shunting, an intrapulmonary right-to-left blood shunting was also described.34 The disturbed circulations in both lung and peripheray are interrelated, and after the resection of the primary lung lesion, 4zr43 they returned to normal. A recent finding by Hall and Laidlaw strongly indicated that reduced ferritin had bypassed the lungs and produced peripheral vasodilatation. In cirrhosis of the liver, the vasoactive substance, whether it is a ferritin compound or not, may gain access to the systemic circulation through either the intrahepatic shunts32 and then through the pulmonary shunts or by the way of the portopulmonary shunts. The former is the larger; therefore, it would represent the most significant site. Cardiac output and blood vokmes. A hyperkinetic state may be associated with disease of the liver. The increased cardiac output results presumably from peripheral vasodilatation with increased peripherai blood flow.45s4s This is suggested by the frequent occurrence of warm hands, wide pulse pressure and capillary pulsations in these patients, and supported by the finding of an increased blood flow to the hand.4g These circulatory changes at the periphery occurred independentIy of vascular changes in other vascular beds (splanchnic, renal, and cerebral) and in spite of an increased cardiac output, the blood to these vascular beds may either be normal or diminished. Again, as in the presence of clubbing of the digits, a circulating vasoactive substance(s)

Am. Hmrt ?. October. 19b7

is postulated to produce peripheral vasodilatation in patients with disease of the liver, On the basis of the findings of 3 distinct circulatory patterns, Kontos and coworkers5a suggested a number of factors (neurogenic, metabolic, hypocapnea, and even bradykinin), rather than a single cause, to be responsible for the observed changes at the periphery as to whether the process of vasodilatation was limited to the skin, to the muscle, or to both. Elevated cardiac indices have been observed clinically, in the presence or absence of ascites and in patients with only fatty infiltration of the liver.45 Clubbing of the digits is usually associated with high cardiac output, but this is not necessarily true for palmar erythema or spider nevi.46 This hyperkinetic state has been likened to that associated with beriberi, Paget’s disease, and systemic arterio-venous fistula.5i The generalized arteriolar vasodilatation may indeed be acting as multiple arteriovenous fistulae in parallel.45 The increase in total blood volume that is seen in cirrhosis of the liver is primarily the result of an increase in plasma volume with little or no change in red cell mass.5z*53 Using red cell labelled radioactive chromium, Eisenberg54 studied the relationship of the total blood volume and the presence of esophageal varices and/or peripheral cyanosis. He observed a significant increase in the plasma volume in patients with esophageal varices and of the red cell mass in patients with peripheral cyanosis; in their absence, patients with cirrhosis of the liver had normal plasma volume and red cell mass. Thus, the hypervolemia of cirrhosis of the liver is related to the eryth= ropoietic factor in the cyanotic patient and to the expanded capacity of the vascular bed in the presence of varices. This hypervolemia is reminiscent of that seen in clinical conditions associated with decreased peripheral resistance (i.e., pregnancy and systemic arteriovenous fistula). Myoccwdial changes. The increased cardiac output and total blood volume might conceivably lead to cardiac hypertrophy. Indeed, in the study of Lunseth and coworkersE5 and in our study (Table V), myocardial hypertrophy was frequently observed at postmortem examination of patients with Laennec’s cirrhosis. In one

rhitd 13 our patients, the heart weighed snore than 400 grams. in 19 patients, the inyocardial hypertrophy could not be ex$ained by the known causes of heart disease. Thirteen of these 19 patients had varying degrees of myocardial fibrosis ;l?ig. 3)* ln the remaining 6 patients, the >increased heart weight was at least, in part9 due to interstitial and/or myocardial edema, which was previousiy reported in cirrhosis of the live? and observed by us. .Nese microscopic changes were limited

::ig. .T. Diffuse myocardial fibrosis !,aennec’s cirrhosis of the liver.

in a patient

with

Ige$ 29 to 82 years (average 56) Sex: male, 54; female, 36 %ace, 75 Ca;rcasians, 20 Negroes, S Latin Americans Yistory of excessive intake of alcohol in 80 Xearts weighing at least 400 grams in 33 patients Etiology of hypertrophy unexplained 19 Coronary atherosclerosis 5 Hypertension and valvular disease 7 Car puhnonale 1 Metastatic tumor 1 %yocardial fibrosis seen in 20 hearts A. With unexplained hypertrophy 13 FS. With myocardiaf infarction 5 C. With other causes 2 EuJocardiai thickening, 2 cases, both tvith unexplained hypertrophy. Clinical and pathological evidence of heart failure (in the absence of known heart disease) 4

1~0 ,;he ,.~I:~& ;
a.

9.

10.

11.

12. 13. 14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

Roberts, K., Thompson, G., Poppell, W., Vanamee, P. : Respiratory alkalosis accompanying ammonium toxicity, J. Applied Physiol. 9:367, 19.56. Berry, J., Owen, E., Flanagan, J., Tyor, M.: The effect of acute hyperventilation on the blood ammonia concentration of patients with liver disease. J. Lab. & Clin rMed. 55:849, 1960. Karr, N., and Hendricks, E.: The toxicity of intravenous ammonium compounds, Am. J, M. SC. 2X3:302, 1949. Parnas, J., Moyolowski, W.! and Lewinski, W.: uber den Ammoniagehalt und die Ammoniakbildung im Blute: Mitterlung der zusammen des Blutammoniaks mit der Muskelarbeit, Biochem. Ztschr. 188:15, 1927. Schwartz, A., Lawrence, W., and Roberts, K.: Elevation of peripheral blood ammonia following muscular exercise, Proc. Sot. Exper. Biol. & Med. 98:%8, 1958. Bandy, P.: Some metabolic abnormalities in liver disease. Am. J. IMed. 24:428, 19.58. Sherlock, S.: Pathogenesis and management of hepatic coma, Am. J. Med. 24:805, 1958. Schmidt, C., Comroe, J.: Functions of the carotid and aortic bodies, Physiol. Rev. 20:115, 1940. Snell, R., and Luchsinger, P.: Relation of arterial hyperventilation of chronic liver disease, Am. J. M. SC. 245:289, 1963. Mitchell, R. A.: Cerebrospinal fluid and the regulation of respiration, zjz Care, C. G., editor: Advances in respiration physiology, Baltimore, 1966. The Williams & Wilkins Comnanv. Fluckiger, M. : Vorkommen vor; tiommelschlagelformigen Fingerendphalangen ohne chronische Veranderungen an den Lungen oder am Herzen, Wien. Med. Wchnschr. 34:1457, 1884. Gilbert, A., and Fournier, L.: La cirrhose hypertrophique avec ictere chez les enfants, Compt. rend. Sot. de Biol. 2:419, 1895. Hijmans, van den Bergh, A.: Osteo-arthropathie hypertrophiante bij hypertrophische levercirrhose, Nederl. Tijdschr. v. Geneesk. 317:761, 1901. Gilbert, A., and Lereboullet, P.: Le doigt hippocratique dans les cirrhoses biliaires, Gaz. hebd. Med. Chir., Paris 49:l. 1902. Keys, A., inell, A.: Respiratory properties of arterial blood in normal man and in patients with disease of the liver: position of oxygen dissociation curve, J. Clin. Invest. 17:59, 1938. Caldwell, P., Fritts, H., and Cournand, A.: Oxyhemoglobin dissociation curve in Iiver disease, J. Applied Physiol. 20:316, 1965. Abelman. W.. Verstraeten, T., Frank, N., McNeely, W., ‘and Kowalskil H.: The alveolararterial oxygen pressure gradient in parenchymatous disease of the liver, Clin. Res. Proc. 2 :47, 1954. Rodman, T., Sobel, M., and Close, H.: Arterial oxygen unsaturation and the ventilation-perfusion defect of Laennec’s cirrhosis, New England J. Med. 263:73, 1960. Bashour, F., Miller, W., and Chapman, C.: Pulmonary venoarterial shunting in hepatic cirrhosis, AX HEART J. 42:350, 1961.

26

27.

28.

29.

30.

3t.

32.

33.

34,

35. 36.

37.

38. 39.

40.

41.

42.

43. 44.

4.5.

Bashour, F., and Cochran, P. : Alveolar-arterial oxygen tension gradients in cirrhosis of the liver, ANY. HEART J. 71:734, 1966. Rydell, R., and Hoffbauer, F.: Multiple pulmonary arterio-venous fistulas in juvenile cirrhosis, Am. J. Med. 21:450, 19.56. Calabresi, P., and Abelmann, W.: Portocaval and portopulmonary anastomosis in Laennec’s cirrhosis and in heart failure, J. Clin. Invest, 36:l257, 195’7, Wilson, R., Ebert, R., Borden, C., Pearson, R., Johnson, R., Falk, A., and Dempsey, M.: The determination of blood flow through nonventilated portions of the normal and diseased lung, Am. Rev. Tuberc. 68:177, 19.53. Fritts, H., Hardewig, A., Rochester, D., Durand, J., and Cournand, A.: Estimation of pulmonary arteriovenous shunt-flow using intravenous injections of T-1824 dye and KrB5. J. Clin. Invest. 39:1841, 1960. Smythe, C., Fitzpatrick, H., and Blakemore, A.: Studies of portal venous oxygen content in unanesthetized man, J. Clin. Invest. 30:674, 19.51. Nakamura, T., NaKamura, S., Kaneko, T., Suzuki, T., Tokita, K., Sire, A.: Measurement of extraheptaic shunted blood flow in liver cirrhosis, J. Lab. & Clin. Med. 60:889, 1962. Berthelot, P., Walker, J., Sherlock, S., Reid, L.: Artetial changes in the lungs in cirrhosis of the liver, lung spider nevi. New England J. Med, 274:29l, 1966. Bashour, F.: Clubbing of the digits-physiologic considerations, J. Lab. & Clin. Med. 58: 613, 1961. Hall, G,: The cause of digital clubbing-testing a new hypothesis, Lancet l:750, 1959: Bashour. F.. Shafik. A.. and Rogers. D.: Blood flow ancl o&gen consumption if the clubbed digits, Clin. Res. X:163, 1963. Grant, R., and Bland, E.: Observations on arteriovenous anastomosis in human skin and in the bird’s foot with special reference to the reaction to cold. Heart 15:386, 1929-31. Clark, E.: Arteriovenous anasiomosis. Physiol. Rev, 18:229, 1938, Hale, A., and Burch, G.: The arteriovenous anastomosis and blood vessels of the human finger, morphological and functional aspects. Medicine 39:191, 1960, Fischer, C., Eich, R,, Faloon, W., and Child, B,: Arteriovenous shunting in palmar erythema: the effect upon blood ammonia determinations, J. Lab. t?z Clin. Med. 51:1118, 19.58. Bean, W.: Vascular spiders and related lesions of the skin, Springfield, Ill., 1958, Charles C Thomas, Publisher, Semple, T., and McCluskie, R.: Generalized hypertrophic osteoarthropathy in association with bronchial carcinoma, Brit. M. J. 1:754, 195s, Bashour, F.: Hydatid cyst of the lung with clubbing, Ann. Int, Med. 54:326, 1961. Hall, G., and Laidlaw, C. D.: Further experimental evidence implicating reduced ferritin as a cause of digital clubbing, Clin. SC. 24:121, 1963. Kowalski, H., and Abelmann, W.: The cardiac

~~c,tpuL a: ~cbt it, Lae~~~iec’b cirrhoaih, J. Cii~k. ‘nvest. 32:lWS, lY53. Claypool, G., T>elp, M., and IA, -I’.: Hemudynzunic studies in patients with Laennec’s cirrhosis, Am. J. M. SC. 234:48, 19.57. Murray, J.? Lawson, A., and Sherlock, S.: Circulatory changes in chronic liver disease, s\nl. J. Med. 24:358, 19.58. johnson? G.- Dart, C., Peters, R., and MacFie, changes with cirrhosis of the aT.’ . Hemodynamic liver, Ann. Surg. 163:692, 1966. Abramson D., and Lichtman, S.: Influences of ergotamine tartrate upon peripheral blood flow in subiects with liver disease. Proc. Sot. Exper. Biol: & Med. 37:‘262, 1937. Kontos, H., Shapiro, W., Mauck, P., and Patterson, J. : General and regional circulator>. alterations in cirrhosis of the liver, Am. J. Med. 37526, 1964. Cohen, S., Edhohn, O., Howarth, S., McMichael, J., and Sharpey-Shaeffer, E.: Cardiac output and peripheral blood flow in arteriovenous zmeurysm, Clin. §c. 7:35, 1948. Perera, G.: The plasma volume in Laennec’s cirrhosis of the liver, A\nn. lnt. Med. 24:643$ 1946.

., lmyocardium in cases of Chro!!ic livklr disease, especially of liver cirrhosis, Jap. Circul:l tiori J. 28:163, 1964. Bollinger, P.: Lreber die HaAgkitund Ursachen der idiopathischen HerzbJzperkophie in Munchen, Deutche &Ied. V,‘chnscl~~. ~.Ozl?X!~ 1884. Abelmann, W., Kowalski, H., and Mc:Yeeiy, Ii’.: The hemodyanmic response tl) exercise in patients with Laennec’s cirrho$ ,j. Clin. Invest. 34~690, 1955.