jaundice following open-heart surgery

Jaundice Following Open-Heart Surgery

RicHARD G. SANDERSON,* M.D., JOHN H. ELLISON,*" M.D.,JOHN A. BENSON, JR.,*' ' M.D., ALBERT STARR,+ M.D.

From the University of Oregon Medical School Hospital, Portland, Oregon

TRANSIENT jaundice after major surgicalprocedures, particularly lengthy operationsinvolving poor-risk patients, hypotension,and multiple transfusions, is not uncom-mon. Occasionally, however, hepatic dis-ease associated with postoperative jaundiceis of such magnitude that massive hepaticnecrosis and death result. With two pa-tients as an impetus to investigation, wehave reviewed our experience with jaun-dice following open-heart surgery.

MaterialAs jaundice is seldom detected clini-

cally at serum bilirubin levels lower than3 mg.%, only patients with higher levelswere included in this study. From the 1958onset of the open-heart program at theUniversity of Oregon Medical School Hos-pital to October 1, 1965, 736 proceduresusing cardiopulmonary bypass have beenaccomplished. Of this group, 411 patientshad congenital heart defects and 325 hadacquired heart disease. Serum bilirubin de-terminations were routinely performed be-fore operation, on the first postoperativeday, and twice weekly thereafter for amonth. The age range of patients was 5months to 75 years. Many had advanced

Submitted for publication July 14, 1966.* Chief resident in cardiopulmonary surgery.

Current address: Section Chief, Cardiac Surgery,Veterans Administration Hospital, San Francisco,California 94121.

* Clinical instructor of medicine.Professor of medicine; Head, division of

gastroenterology.f Professor of surgery; Head, division of car-

diopulmonary surgery.

217

lesions and long-standing cardiac disease;cardiac cachexia was common.Cardiopulmonary bypass was accom-

plished with high-flow perfusion (2.4 L./M.2/min.) with a prime of whole blood,drawn from voluntary donors within 24hours prior to operation. Mannitol was theonly routine additive to the prime. Manyoperations were done during moderate hy-pothermia (320 to 280 C.). Most aorticvalve replacements were done during car-diac standstill produced by intermittentperfusion of the coronary arteries with icedblood. Halothane was the anesthetic agentin most cases.

Postoperatively, pulmonary support witha mechanical respirator was commonly pro-vided in patients with pulmonary hyper-tension, cardiac cachexia, or major arrhyth-mias. Further support with isoproterenol,digitalis, vasopressors (adrenalin and nor-adrenalin) and steroids was given when in-dicated. Postoperative fever to 390 to 40.50C. without signs of infection was common.The only significant, potentially hepato-toxic drug used in the postoperative coursewas trifluoperazine (given for postcardi-otomy delirium), and usually the appear-ance of postoperative jaundice preceded itsuse. The following factors were evaluatedon each patient who developed jaundice:1) previous hepatic disease and pre-opera-tive liver function studies; 2) cardiac cathe-terization data (including right atrial andright ventricular pressures, cardiac index,and arteriovenous oxygen difference); 3)bypass time, total anesthesia time, andhalothane time; 4) serum pCO2 while on

218 SANDERSON, ELLISON, BENSON AND STARR

cardiopulmonary bypass; 5) number ofunits of blood used and serum hemoglobinlevels; and 6) operative and postopera-

tive hypotension and the use of vasopres-

sors. A graph of levels of serum bilirubinand serum glutamic oxaloacetic transami-nase (SGOT) was made for each patient.

Results

Postoperative jaundice (serum bilirubinof 3 mg.% or greater) was detected in 63patients (8.6%), 58 of whom had acquiredheart disease. These patients were catego-rized as to type of operation and depth ofbilirubinemia.

As can be seen from Table 1, patientswith acquired heart disease had postopera-tive hepatic dysfunction far more oftenthan did those with congenital disease(17.8% vs. 1.2%o). The jaundiced patientsin the congenital group, however, were alladults; their average age was 35 years, theyoungest being 24 years old. Average age

of the acquired heart disease patients was

45 years.

The more serious the valvular pathologiclesions, the higher was the percentage of

Annals of SurgeryFebruary 1967

jaundiced patients. Jaundice developed in8%/o of patients undergoing open mitralcommissurotomy, 13% with aortic replace-ments, 16o with mitral replacements, 33%/oreceiving double valve replacements, and53% subjected to triple valve replacement.In general, the degree of postoperative hy-perbilirubinemia followed a similar ascend-ing scale. Patients with isolated aortic val-vular lesions were unusual in that most (12of 17) had only minimal bilirubin eleva-tions. In patients receiving mitral and mul-tiple valvular replacements, elevations weredistributed through all levels of severity.Of patients who developed postoperative

jaundice, only five had previously con-

sumed alcohol moderately or heavily andnone had postoperative bilirubin levelsgreater than 4.8 mg./%. Three patients withpostoperative jaundice were known to havehad jaundice prior to open-heart surgery.

At elective cholecystectomy, one was notedto have a cobblestone liver (serum bilirubinwas 3.2 mg.% after open-heart operation).Another had long-standing hepatic cirrho-sis secondary to chronic congestion, with a

bromsulfalein retention of 20%0 (postop-

TABLE 1. Jaundice Afler Open-Ileart Surgery

Operalions-UOMS 1958-1965Jaun(liced Pts. Level of Jaundice-Mg.%

AverageBilirubin

Type of Operation No. No. '7o Mg.%C/o 3-5 5-10 1(0-25 >25

Tetralogy of Fallot-total corr. 77 2 1 1Repair of V.S.D. 88with infundibulectomy 14 1 1

Repair of A.S.D. 118 2 1 1Pulmonic 37

ValvotomyAortic 45

Misc. congenital defects 32

411 5 1.2 13.8 2 0 2 1

Mitral plastic procedures 36 3 8.3 5.3 1 2Misc. acquired defects 11 1 9.1 3.6 1Valve replacement

Aortic 131 17 13.() 5.1 12 4 1Mitral 84 13 15.5 9.7 4 5 3 1Double 46 15 32.6 13.3 6 7 2*Triple 17 9 52.9 12.2 4 3 1 1

325 58 17.8 9.3 28 21 5 4

Totals 736 63 8.6 9.7 3(0 21 7 5

* Deaths from hepatic (lisease.

JAUNDICE FOLLOWING OPEN-HEART SURGERY

erative bilirubin, 35.2%o. Another had hadjaundice 25 years before (postoperativebilirubin, 3.0 mg. %). Finally, two patientswere clinically jaundiced at the time ofthe open-heart procedures, both at thelevel of 3.6 mg. %. Their maximal postop-erative bilirubin elevations were 8.8 and9.5 mg.%.

In the entire group, there were only fivepatients with icteric serum hepatitis, an in-cidence of 0.7%. In these patients malaise,anorexia, nausea, mild fever, and jaundiceappeared after 30 to 90 days (average 66days). SGOT elevations ranged from 920to 4,080 units. All five patients survived;three had received prophylactic gamma

globulin. (These five patients are not in-cluded in this study.)Attempts were made to correlate levels

of postoperative bilirubinemia with pos-

sible etiologic factors in the operative ex-

perience. Surprisingly, the pre-operativelevel of bromsulfalein retention was unre-

lated to postoperative bilirubin levels. Theseverity of the patient's pre-operative heartdisease, as measured by arteriovenous oxy-

gen differences and cardiac index did notcorrelate. Patients with elevated right atrialand right ventricular pressures experiencedno deeper jaundice than those with nor-

mal pressures. Postulation that erythrocytebreakdown products were a source of post-operative jaundice was also unrewarding,for operative plasma hemoglobin concen-

trations taken at the end of cardiopulmo-nary bypass showed a wide scatter whengraphed against postoperative peak bili-rubin levels. For example, one patient hada plasma hemoglobin of 69 mg.% and a

postoperative bilirubin of 52.4 mg.%, whileanother had 390 mg.% of plasma hemo-

globin and only 4.2 mg.% of serum bili-rubin. Finally, in all 63 cases, the direct-reacting bilirubin was much higher thanthe indirect fraction, usually in a ratio of3: 1 or 4: 1. Other factors which were

shown to have no direct correlation topostoperative bilirubin levels were the

length of time of cardiopulmonary bypass,the time of halothane anesthesia, arterialpCO2 and pH levels while the patient was

on bypass, and the use of vasopressors inthe postoperative course.

The pattern of hyperbilirubinemia inthese patients fell into two distinctivegroups, early and late. In the early group

(59 patients), jaundice appeared in thefirst few days after operation, reached itshighest level by the seventh to tenth day,then receded rapidly, falling below 3 mg.%by the twelfth to fifteenth day. Serum trans-aminase levels were generally elevated to50 to 150 units. Although dark urine was

common, seldom were there acholic stoolsor hepatosplenomegaly. None of these pa-

tients succumbed from hepatic disease,even though concentrations of serum bili-rubin rose as high as 52.4 mg.%. Figure 1illustrates a typical course.

In the late group (4 patients), the earlypostoperative course was relatively benign.Hepatic dysfunction did not appear untilthe twelfth to fourteenth day, but then pro-

gressed rapidly. Two of these patients sur-

vived, despite SGOT elevations to 6,300and 1,350 units, respectively; their peakserum bilirubin levels were 16.0 and 3.2mg.%., respectively. The only two deaths

E.D. Replacement of Mitral Valve

400

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FIG. 1. Early jaundice following open-heartsurgery.

Volume 165Number 2 219


in the series came from this late group.Both patients succumbed to massive centri-lobular hepatic necrosis after double valvereplacement. Bilirubin levels before deathreached 29.6 and 100.6 mg.%,. and SGOTlevels rose to 4,100 and 2,120 units, re-spectively. Vasopressors were used in onepatient who died (100 minutes of epineph-rine and 9 hours of levarterenol on the firstpostoperative day) and in one survivor (35hours of levarterenol). Illustrative case his-tories will focus on the problems involved.

Case ReportsCase 1. A 50-year old Indian woman had been

nearly incapacitated by recurrent bouts of con-gestive heart failure. Mixed mitral and aortic le-sions were demonstrated by preoperative cardiaccatheterization and cine-angiocardiography. Therewas no history of liver disease or alcoholic intake.Preoperative BSP retention was 13%.

With high-flow cardiopulmonary bypass, re-placement of mitral and aortic valves with Starr-Edwards prostheses was accomplished withoutindicent. Pump time was 2 hours and 57 minutes,anesthesia time, 9 hours 45 minutes, and halothanetime 7 hours 40 minutes. Plasma hemoglobin oncardiopulmonary bypass reached a maximum of147 mg.%. Serum pH and pCO2 were normalon bypass. There was no operative hypotensionand isoproterenol was the only cardiac agent used.

A dilute solution of epinephrine was used for1 hour and 40 minutes upon return to the recoveryroom. Later that day, levarterenol drip was neces-sary for 9 hours to support the blood pressure. Afever of 40.30 C. on the second and third post-operative days was controlled with intravenoussalicylates and steroids. Postoperative cardiac indexwas 3.5 L./M.'/min. as compared to 1.85 L./M.'/min. at preoperative cardiac catheterization. Oralintake was resumed on the fourth day and pro-gressive ambulation started on the seventh day.

On the fourteenth postoperative day, jaundicewas noted for the first time, accompanied byanorexia, malaise, and lethargy. Within 4 days,serum bilirubin had risen to 35 mg.%, SGOT to2,120 and SGPT to 3,500 (Fig. 2). During thisperiod, she was treated with diet, vitamins, andsteroids (24 mg. dexamenthasone/day). By thenineteenth postoperative day, signs of moderatehepatic coma appeared. Hypotension on the twen-tieth day was treated briefly with isoproterenoland then 68 hours of high concentration levar-terenol. From day 21 to 24 she showed clinical

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FIG. 2. Late jaundice following open-heart surgery.Case 1-Death from hepatic failure.

improvement and was alert and responsive despitesteadily mounting serum bilirubin levels (73mg.%). Gradual deterioration ensued as the bloodurea nitrogen started to rise. Ecchymoses, pete-chiae, and gastrointestinal bleeding heralded thereturn of hepatic coma. Peritoneal dialysis was per-formed on days 28 to 30 for uremia. The patientfinally expired on the 31st postoperative day, theterminal event being massive bleeding from thegastrointestinal tract and many other sites. Onthat day, serum bilirubin level reached 100.6mg.%o.

At postmortem examination, the liver was ex-tensively involved with centrilobular necrosis.More than half the hepatic cells were necrotic(Fig. 3). Erythrocytic debris, canalicular bilestasis and polymorphonuclear leukocytic infiltra-tion were present. Periodic acid-Schiff stainingdemonstrated severe glycogen depletion.

Case 2. A heart murmur was discovered soonafter birth in this 24-year-old Oriental housewife.Her only complaint was easy fatigability. Cardiaccatheterization showed a large atrial septal defectwith moderate pulmonary hypertension. She hadno previous history of liver disease.

With high-flow cardiopulmonary bypass, re-pair of the defect was accomplished using a peri-cardial patch. Halothane anesthesia for 5 hourswas necessary. Plasma hemoglobin was 92 mg.%,and pCO2 and pH were maintained within normallimits. There was no operative hypotension. Asidefrom a 12-hour temperature rise to 400 C. on thesecond postoperative day, her course was uncom-


FI:: 3.i;b:u- :is

FIG. 3. Centrilobular hepatic necrosis. Case 1.

plicated. She was discharged from the hospitalon the ninth day in excellent condition.

Two days later, she returned because of ma-

laise, fever to 39.40 C., headache, and upper res-

piratory infection. The only abnormal physical find-ing was a slightly tender liver. Thirteen days afteroperation, SGOT was 6,300, serum bilirubin 6

FIG. 4. Late jaundice following open-heart surgery.Case 2-Survivor.

mg.%, and prothrombin and proconvertin ac-

tivity was 11% (without anticoagulants; Fig. 4).Massive steroid therapy (1,000 mg. prednisonein the first 24 hours, tapering rapidly thereafter),bed rest, vitamins and dietary support were given.

Within 4 days, the SGOT had fallen to 300 unitsand to less than 100 units after 5 more days. Pro-thrombin and proconvertin activity returned tonormal with vitamin K support and jaundice dis-appeared. Throughout this period the patient feltwell and had an excellent appetite.

When steroids were withdrawn (after 19days), daily temperature elevations to 37.7 to38.30 C. resumed and splenomegaly first becameapparent. Serum bilirubin remained at 4 mg.%.Blood smears showed abnormal lymphocytes char-acteristic of the febrile postcardiotomy lympho-cytic splenomegaly syndrome. Salicylate therapywas effective and she was soon discharged.

Since that time she has been in excellenthealth. A bromsulfalein test done 6 weeks afterthe onset of jaundice was 30%o retention. Onemonth later, there was 12%o BSP retention.

DiscussionChanges in liver function and morphol-

ogy after surgical procedures have been



reported by many authors. Tagnon et al.19found a significant rise in bromsulfalein re-tention in 14 of 20 patients, free of mal-nutrition or previous liver disease, who hadundergone extra-abdominal surgical proce-dures. In 22 patients undergoing abdomi-nal operation, Geller and Tagnon 7 ob-served 17 to have elevated bromsulfaleinretention postoperatively. Zamcheck 20 etal. detected liver impairment not only bychanges in liver function, but also by mor-phologic changes in hepatic biopsies. In 15patients undergoing upper abdominal op-erations, liver biopsies were obtained whenthe abdominal cavity was first entered (6patients) and at the close of the surgicalprocedures (all 15 patients). Every closingspecimen showed signs of acute inflamma-tion while none of the earlier biopsy speci-mens had such changes. Schmidt et al.16collected 12 cases with bilirubin elevationsabove 5 mg.% early in the postoperativecourse. A majority showed a preponderanceof conjugated bilirubin, bilirubinuria andminor transaminase elevations. Hepatic bi-opsies in each of these patients showedcanaliculi with bile plugs, bile pigment inthe cytoplasm of the adjacent liver cells,and bile in the Kupffer cells. Fahrlanderet al.5 also reported intrahepatic cholestasiswith little or no injury to liver cells in 8cases of severe bacterial infections. Theyconcluded that operation or severe infec-tion caused a temporary disturbance of ex-cretory function of the liver.Although a high percentage of our pa-

tients experienced postoperative fever of390 to 40.50 C. on the first to third days,none showed signs of true sepsis. No focusof infection could be found, blood cultureswere negative, and white blood cell countswere usually normal. The pattern of clini-cal and laboratory findings in the patientsin our early group of jaundiced patients isvery similar to those described by Schmidtet al.16 Cholestasis may play an importantrole in this group. Unfortunately, our alka-


line phosphatase data is insufficient forcritical interpretation.The low-output syndrome complicated

the early postoperative period in many ofour patients, particularly those with mitraland multivalvular replacements. Hepaticcongestion and anoxemia are natural se-quelae which may help explain the highincidence of jaundice in the multivalvularreplacements and its low incidence inaortic replacements when this syndrome isinfrequently seen. Sluggish return of he-patic venous blood because of obstructinginferior vena caval catheters on cardio-pulmonary bypass may also contribute tohepatic vascular congestion.

Massive hepatic necrosis is uncommon.Rodgers et al.14 found only 18 instancesamong 11,341 autopsies at Boston CityHospital. Of these, only six were associatedwith surgical operation and all were latedeaths attributed to viral hepatitis. Miyaiand Ruebner's 11 series listed only 45 casesin 45,000 autopsies and Caravati andWooten2 reported nine among 9,960 autop-sies. Herber and Specht 8 found jaundicein only 13 patients among 20,000 under-going general anesthesia. Seven patientshad serum bilirubin levels less than 6.8mg.%, and six exceeded that value; therewere three deaths among the latter. Rubin-son et al.'5 reported only one death in 24patients who developed icteric serum hepa-titis after open-heart surgery. Descriptionsof the pathologic findings of massive he-patic necrosis be Ellenberg and Osserman 4and by Caravati and Wooten 2 were in closeagreement with our observations. Archi-tectural disruption was greatest centrally,decreasing towards the periphery of thelobule. The line of demarcation from rela-tively unaffected cells was usually well-defined. Congestion of the central veinand nearby sinusoids, nuclear degenerationand vacuolization, neutrophilic infiltrationand glycogen depletion were prominentfeatures.

Caravati and Wooten 2 listed viral hepa-


titis, drugs and chemicals, endogenoustoxins, circulatory disturbances with anoxia,toxemia of pregnancy, and experimentaldietary necrosis as possible causes of acute

massive hepatic necrosis. Sims et al.17 alsorelated hypercarbia to postsurgical hepaticdamage. Of these possibilities, circulatorydisturbances and drugs seem most relevantto our experience.The use of halothane as a nonexplosive

anesthetic agent in open-heart surgery iscommonplace in many centers. Morris andFeldman 12 showed a close association ofpostoperative hepatic dysfunction withhalothane anesthesia when combined witheither hypercarbia or hypotension. Herberand Specht 8 noted an increase in the inci-dence of hepatic necrosis since halothanewas introduced as an anesthetic agent, butLittle et al."o contend that halothane hasno greater hepatotoxicity than other anes-

thetic agents. Slater et al.', found the inci-dence of deaths from hepatic necrosis tobe one in 4,895 with halothane and one in4,605 with other anesthetics in a reviewof 46,923 general anesthetics at the Massa-chusetts General Hospital. To date, no di-rect evidence has been offered to substan-tiate halothane hepatotoxicity. More re-

cently, our patients with disease of threeheart valves, severe cachexia, ascites or

preoperative liver dysfunction have under-gone open-heart procedures with anes-

thesia consisting of narcotics, relaxants andnitrous oxide and no halothane. Four ofthese patients have become jaundiced post-operatively (serum bilirubin levels of 4.0,4.7, 8.8, and 9.5 mg.%o).

Shock and anoxia have been cited bymany authors 2-4, e, 12, 14 as a cause of liverdamage. Lack of oxygen in the central area

of the hepatic lobule may be responsiblefor the massive hepatic necrosis. Ellen-berg and Osserman 4 noted that 32 of 34instances of centrilobular hepatic necrosiswere associated with shock, 25 being hypo-tensive for 24 hours or more. Even in cases

of congestive failure, massive necrosis did

not occur unless shock was also present.

Their pathologic studies indicated that gly-cogen depletion, as seen in hypotensivestates, was characteristic of massive livercell necrosis.

Using photoelectric dropmeter measure-

ments, Corday and Williams 3 demonstratedthe effect of hypotension and vasopressors

upon blood flow to the liver. At least two-

thirds of the hepatic blood flow under nor-

mal conditions is from the portal vein andone-third from the hepatic artery. With a

fall in systemic blood pressure, portal veinand hepatic artery blood flow are de-creased. Administration of vasopressors fur-ther depresses portal vein flow while he-

patic artery flow increases slightly. Thenet effect is a further decrease in total he-patic blood flow. Caravati and Wooten 2

also postulated that shock causes not onlymesenteric venous spasm, but also spasm

in the hepatic vein which reduces outflowof blood from the liver and adds furtherto stasis, hypoxemia, and necrosis. Cells atthe center of the lobule (central vein) re-

ceive blood at an oxygen tension lowerthan do those at the periphery (hepaticartery). This observation is substantiatedby the pathologic findings of centrilobularhepatic necrosis.

Hemolysis of red blood cells did notseem to be an etiologic factor. The highestserum hemoglobin levels on cardiopulmo-nary bypass did not correlate with post-operative bilirubin elevations. Most jaun-dice preceded the time that Coombs-positive acquired hemolytic anemia aftervalve replacement is thought to occur.13A review of our experience with jaundice

after open-heart surgery leads to certaintherapeutic corollaries. Particular attentionshould be focused upon patients under-going mitral or multiple valvular replace-ment. Bypass flow rates, perfusion pres-sures, and oxygen saturation should bemaintained at high levels to avoid hepatichypoxemia. Halothane has been avoided inthese patients and in those with previous


224 SANDERSON, ELLISON, BENSON AND STARR Annals of Surgeryliver disease or hypercarbia from poor pul-monary function. Support with glucose,B-complex vitamins, and. adequate oxy-genation is encouraged. The use of isopro-terenol, digitalis, mechanical respirator as-sistance, and blood volume support mayavoid vasopressor therapy. Massive steroidtherapy in the treatment of the late-appear-ing hepatic necrosis may be helpful.

SummaryOf 736 open-heart procedures at the

University of Oregon Medical School Hos-pital from 1958 to October 1, 1965, 63 pa-tients had postoperative jaundice. Fifty-eight of these had operations for acquiredheart disease and five (all adults) for con-genital heart disease. The incidence andseverity of postoperative jaundice increasedwith the degree of valvular involvement.There were two deaths from massive centri-lobular hepatic necrosis.The pattern of bilirubinemia fell into an

early group in which jaundice appearedearly and receded rapidly and a late groupin which hepatic dysfunction appeared atabout 2 weeks postoperatively and pro-gressed rapidly. Two case histories of pa-tients in the late group are presented. Jaun-dice of the early group may be related tointrahepatic cholestasis.

Attempts to correlate the level of post-operative hyperbilirubinemia with variousfactors in the operative experience wereunrewarding. Probably many different fac-tors contribute to postoperative jaundice.Of possible etiologic agents, halothane andshock seemed most relevant. The effect ofshock and vasopressors on hepatic bloodflow is discussed in relation to the charac-teristic pathologic findings of centrilobularhepatic necrosis. Therapeutic suggestionsare offered.

Bibliography1. Bunker, J. P. and Blumenfield, C. M.: Liver

Necrosis After Halothane Anesthesia-Causeor Coincidence? New Eng. J. Med., 268:531,1963.

2. Caravati, C. M. and Wooten, P.: Acute Mas-sive Hepatic Necrosis With Fatal Liver Fail-ure. Southern Med. J., 55:1268, 1962.

3. Corday, E. and Williams, J. H., Jr.: Effect ofShock and of Vasopressor Drugs on the Cir-culation of the Brain, Heart, Kidney, andLiver. Amer. J. Med., 29:228, 1960.

4. Ellenberg, J. and Osserman, K. E.: The Roleof Shock in the Production of Central LiverCell Necrosis. Amer. J. Med., 11:170, 1951.

5. Fahrlander, H., Huber, F. and Gloor, F.: In-trahepatic Retention of Bile in Severe Bac-terial Infections. Gastroenterology, 47:590,1964.

6. Gadeholt, H. and Haugen, J.: CentrilobularHepatic Necrosis in Cardiac Failure. Acta.Med. Scand., 176:525, 1964.

7. Geller, W. and Tagnon, H. J.: Liver Dysfunc-tion Following Abdominal Operations. Arch.Int. Med., 8,6:908, 1950.

8. Herber, R. and Specht, N. W.: Liver NecrosisFollowing Anesthesia. Arch. Int. Med.,115:266, 1965.

9. Jones, W. M., Margolis, G. and Stephen, C.R.: Hepatotoxicity of Inhalation AnesthesiaDrugs. Anesthesiology, 19:715, 1958.

10. Little, D. M., Jr., Barbout, C. M. and Given,J. B.: The Effects of Fluothane, Cyclopro-pane, and Ether Anesthesias on Liver Func-tion. Surg. Gynec. Obst., 107:712, 1958.

11. Miyai, K. and Ruebner, B. H.: Acute YellowAtrophy, Cirrhosis and Hepatoma. Arch.Path., 75:609, 1963.

12. Morris, L. E. and Feldman, S. A.: Influenceof Hypercarbia and Hypotension Upon LiverDamage Following Halothane Anesthesia.Anesthesia, 18:32, 1963.

13. Pirofsky, B., Sutherland, D., Starr, A. andGriswold, H. E.: Hemolytic Anemia Com-plicating Aortic Valve Surgery. New Eng. J.Med., 272:239, 1965.

14. Rodgers, J. B., Mallory, K. and Davidson, C.S.: Massive Liver Cell Necrosis. Arch. Int.Med., 114:646, 1964.

15. Rubinson, R. M., Holland, P., Schmidt, P. J.and Morrow, A. G.: Serum Hepatitis AfterOpen-Heart Surgery. J. Thorac. Cardiov.Surg., 50:575, 1965.

16. Schmidt, M., Hefti, M. L., Galliker, R., Krist-ler, H. J. and Senning, A.: Benign Post-operative Intrahepatic Cholestasis. New Eng.J. Med., 272:545, 1965.

17. Sims, J. L., Morris, L. E., Orth, 0. S. andWaters, R. M.: The Influence of Oxygen andCarbon Dioxide Levels During AnesthesiaUpon Post-Surgical Hepatic Damage. J. Lab.Clin. Med., 38:388, 1951.

18. Slater, E. M., Gibson, J. M., Dykes, M. H. M.and Walters, S. G.: Postoperative HepaticNecrosis: The Incidence and DiagnosticValve in Association with the Administrationof Halothane. New Eng. J. Med., 270:983,1964.

19. Tagnon, H. J., Robbins, G. F. and Nichols,M. P.: The Effect of Surgical Operations onthe Bromsulfalein Retention Test. New Eng.J. Med., 238:556, 1948.

20. Zamcheck, N., Chalmers, T. C. and Davidson,C. S.: Pathologic and Functional Changes inthe Liver Following Upper Abdominal Op-erations. Amer. J. Med., 7:409, 1949.

jaundice following open-heart surgery

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