National Halothane Study: a Study of the Possible Association Between Halothane Anesthesia and Postoperative Hepatic Necrosis; Report. Edited by John P. Bunker [and Others] (1969)

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CHAPTER III-1. OVER-ALL RESULTS OF THE STUDY OF HEPATIC NECROSIS William H. Forrest, Jr. Stanford University School of Medicine, Palo Alto, California This chapter describes the data on massive hepatic necrosis. It also includes discussion of some of the limitations of interpretation due to problems in the collection of necropsy data; tables relating such variables as operation, age, and institution to incidences of massive hepatic necrosis; and descriptions of special studies at- tempting to determine the etiology of massive hepatic necrosis. Subsequent chapters in Part III deal with interpretation in more detail, including the Pathology Panel's review of massive hepatic necrosis, the statistical analysis of hepatic data, and the clinical syndromes associated with post- operative hepatic necrosis. NECROPSY RATES AND THE IMPLICATIONS OF MISSING NECROPSY INFORMATION TABLE 1 .— COMPARISONS OF ANESTHETIC PRACTICE BY YEAR (PERCENTAGE DISTRIBUTION) Anesthetic practice** Estimated Year total Hal N-B Cyclo Ether Other adminis- 1959 11.0 35.5 20.5 17.3 15.7 207,261 trations 1960 22.7 28.4 18.8 14.3 15.8 211,421 1961 35.1 23.4 16.4 9.6 15.5 210,728 1962 48.5 15.5 13.4 6.9 15.7 227,105 Percent of 4-year total 29.8 25.5 17.2 11.9 15.6 4-Year total 254,896 218,221 147,358 102,014 134,026 856,515 *ln this and subsequent tables, numbers nay vary and may not add to thsir totals because of rounding. **For comparison, anesthetic agents were separated into the follow- ing anesthetic practices: (1) halothane (often abbreviated as "Ha1"), (2) nitrous oxide-barbiturate ("N-B"), (3) cyclopropane ("Cyclo"), (4) ether, and (5) Other. Combinations of halothane, cyclopropane, and ether were placed in the "Other" category. General anesthetics not included In the first four classes were also classified as "Other." Necropsy Rates During the 4-year period of study, general anesthetics were administered approximately 856,500 times in the 34 participating institutions (Table 1). Records of 16,840 deaths were examined during the Study. In 11,289 of these, necropsy had been performed, and in 10,171 cases, necropsy included examination of the abdomen (Fig. 1). Necropsy including the abdomen will be referred to as "complete," and necropsy excluding the ab- domen will be referred to as "partial." The over-all rate* of complete necropsies was 60.4 percent (Table 2); it varied from 31.3 percent (institution 23) to 88.3 percent (institu- tion 30). The over-all rate of partial necropsies was 6.6 percent, with a range among institutions of 0 to 25.7 percent (institutions 34 and 32, re- spectively). The rate of partial necropsy among the five anesthetic practices varied from 2.7 to 9.3 percent; this wide range is probably related FIGURE I NECROPSY CLASSIFICATION 16,840- Deaths No Necropsy - 5, 551 I1,289-Necropsies Abdomeo Included- I0,I7I ("Complete"Necropsy) 1.118- Abdomen oot I ocluded ("Partial"Necropsy) Liver Mentioned on Abstract of Necropsy Report (Form IV)-5,967 Liver Not Mentioned oo Abstract of Necropsy Report (Form IV) - 4,204 •Rates for complete and partial necropsies are based on total deaths. 91

TABLE 2.—NECROPSIES BY ANESTHETIC PRACTICE AND INSTITUTION Inst . Hal N-B Cyclo Ether Other Total P C D P C D P C D P C D P C D P C D 1 12 80 189 2 17 55 0 5 7 0 4 5 3 12 38 17 118 294 2 0 93 226 0 44 94 4 77 177 0 11 22 1 45 95 5 270 614 3 3 17 25 6 52 106 0 15 20 0 1 1 0 32 49 9 117 201 4 13 54 105 7 47 98 10 118 223 2 62 94 15 111 197 47 392 717 5 20 155 333 16 138 267 6 185 346 3 29 55 9 94 196 54 601 1197 6 4 59 90 2 73 103 0 10 23 0 37 56 0 39 60 6 218 332 7 16 74 152 1 19 45 1 44 98 0 33 58 9 95 189 27 265 542 8 89 417 671 14 80 115 13 27 51 22 184 299 74 101 212 212 809 1348 9 13 188 261 9 149 256 1 89 121 1 166 235 6 60 103 30 652 976 10 27 144 228 10 95 152 8 187 295 2 29 42 5 50 82 52 505 799 11 1 75 128 0 40 71 1 40 84 5 69 122 1 90 150 8 314 555 12 14 111 178 2 17 30 0 135 173 1 5 7 16 75 116 33 343 504 13 4 61 71 0 10 12 1 84 98 0 2 2 0 55 63 5 212 246 14 2 18 28 0 7 11 4 32 56 1 5 6 3 28 40 10 90 141 15 2 39 64 0 75 129 3 114 190 0 48 61 2 99 142 7 375 586 16 7 49 67 3 206 253 4 72 81 1 2 3 5 84 115 20 413 519 17 11 39 52 2 5 8 0 17 19 5 13 18 22 55 89 40 129 136 18 3 58 73 3 54 75 0 86 124 0 7 10 3 29 45 9 234 327 19 45 154 228 3 60 80 3 79 97 0 2 2 10 56 79 61 351 486 20 2 25 43 0 25 41 3 172 245 5 89 131 10 181 267 20 492 727 21 7 125 248 5 110 185 0 105 185 0 15 20 5 99 177 17 454 815 22 9 146 243 4 47 92 1 70 138 1 6 8 4 84 133 19 353 614 23 0 7 18 1 12 40 0 6 19 0 0 0 1 1 6 2 26 83 24 18 107 147 43 380 514 19 173 229 0 23 27 13 90 118 93 773 1035 25 6 63 126 2 25 50 3 87 166 1 9 23 2 98 213 14 282 578 26 1 63 125 2 74 131 0 51 78 0 6 10 1 25 48 4 219 392 27 6 41 98 0 16 30 1 67 113 0 2 6 2 29 49 9 155 296 28 1 7 10 0 4 5 0 0 0 0 1 2 1 1 2 2 13 19 29 10 70 89 1 13 15 it 27 35 0 2 2 1 27 30 16 139 171 30 9 112 130 4 41 47 0 25 26 0 0 0 0 19 20 13 197 223 31 7 32 59 1 16 23 2 43 79 1 0 1 2 12 18 13 103 180 32 41 66 137 8 5 14 3 47 68 0 0 0 19 31 57 71 149 276 33 48 106 210 50 60 140 9 69 106 16 36 63 50 73 162 173 344 681 34 0 5 11 0 2 5 0 32 75 0 2 5 0 23 84 0 64 180 Total 451 2860 4863 201 2018 3292 104 2390 3845 67 900 1396 295 2003 3444 1118 10171 16840 0 of deaths 9.3 58.8 6.1 61.3 2.7 62.2 4.8 64.5 8.6 58.2 6.6 60.4 P = Partial. C = Complete. D = Death. to the more limited choice of anesthesia for op- erations that are likely to have partial necropsy. For example, necropsy following craniotomy is likely to be limited to examination of the head; because halothane is by far the most common agent (57 percent) for craniotomy, the high inci- dence of partial necropsy for halothane is ex- pected. Failure to Obtain Necropsy No necropsy was performed in 5551 deaths, only partial necropsy in 1118 deaths. These two groups represented the greatest loss of informa- tion in the study of massive hepatic necrosis. On the basis of clinical evidence, 13 of the nonne- cropsied deaths were classified by the principal investigator as "probable massive hepatic ne- crosis" on the death abstraction form (Form m).* Of these, one was in the halothane category, three in nitrous oxide-barbiturate, five in cyclopro- pane, and four in Other. A review** of the death- certificate diagnoses (Form IV) and other infor- mation on Form m gave presumptive evidence of hepatic failure in an additional 241 of the nonne- cropsied deaths. Of these 241 patients, 20.8 per- cent had received halothane, whereas the over-all use of halothane in the Study was 29.8 percent. The possibility, implied by these data, that ne- cropsy may have been more likely to be per- formed in a patient with hepatic disease if he had received halothane is discussed in Chapter III-3. Necropsy Summaries with No Mention of the Liver Special attention was given to the possible loss of material in the 4204 necropsies whose abstracts did not mention the liver. Six institu- tions (1, 9, 19, 20, 22, and 27) were visited and 753 necropsy files were examined (approximately 18 percent of the 4204 cases). These institutions *See Chapter II-2 for details of the several forms men- tioned in this chapter. •By William Dozier, Sacramento, California.

taken as an appropriate cross section of partic- ipating institutions. The microscopic description of each of these cases recorded in the yearly, permanent records of the institution's pathology department was reviewed. Without exception, the necropsy reports that were examined were in order and readily available. Of the 753 cases reviewed, there were 28 with mention of some degree of necrosis in the necropsy protocol. Almost all necrosis appeared to be minimal, according to descriptive termi- nology. Three cases might have been in the in- termediate group if they had been reviewed mi- croscopically. No cases were diagnosed or described as massive hepatic necrosis. The rate of occurrence of massive necrosis in the 5967 cases in which the liver was mentioned was ap- proximately 1.4 percent. If this rate had pre- vailed in the necropsies whose abstracts did not mention the liver, 59 cases of massive hepatic necrosis would have been expected in this group of necropsies. That none was found provides ad- ditional confidence in the reporting procedures of the Study and gave documentary support to the opinions of the members of the Pathology Panel, who considered it unlikely that massive hepatic necrosis could be overlooked in this group of necropsies. The extent of confirmation and support was, of course, limited because the sample was not to be regarded as 753 of 4204 cases with no mention of the liver, which would be a large sample, but rather as six of 34 hospitals. If one hospital of the 34 had missed cases of massive hepatic necrosis, the chance was 0.82 that the sample of six hos- pitals visited would not include that hospital. If two hospitals had missed cases, the chance was 0.67 that the sample would not include either. For three hospitals, the chance was 0.55; for four, it was 0.44; and for ten, it was 0.10. Thus, it would have been easy for a sample of six not to include any of a small number of hospitals that had missed cases. If such a hospital existed among the 34, it could readily have missed several cases. The weakness of the evidence supplied by the small sample emphasizes the importance of the opinions of the pathologists in reaching a conclusion as to the chances of over- looking massive hepatic necrosis. Finding three cases in the six hospitals that might have fallen into the intermediate necrosis group was not surprising, inasmuch as the pro- tocol was designed to retrieve only massive he- patic necrosis. The opinions of the pathologists and the results of the sampling suggest that the probability of massive hepatic necrosis among the cases whose necropsies did not mention the liver was small. MASSIVE HEPATIC NECROSIS Identification of Cases of Massive Hepatic Necrosis Possible cases of massive hepatic necrosis were collected for pathology review by the series of steps outlined in Chapter II-2 and schematized in Fig. 2. Fewer than half the finally verified cases of massive hepatic necrosis (31 of 82) were elicited by the initial request for all cases of massive hepatic necrosis (Table 3). Prescreening for ne- crosis by the principal investigators introduced a bias not originally recognized and therefore not anticipated in the original protocol. The investi- gators' knowledge of the severity of the surgical procedure seemed to constitute the largest bias- ing factor, but knowledge of the anesthetic agent may also have contributed to this bias. Fortu- nately, bias was recognized soon enough to allow additions to the multistage review of necropsy reports, which ensured collection of slides of even remotely suspicious cases. The small number of verified cases of mas- sive hepatic necrosis accrued from the relatively large number of possible cases submitted also reflects difficulties in nomenclature and diagnosis (discussed in Chapter III-2). In examining the liver, each Panel member substantiated the existence of necrosis and in- dicated its degree. The degree of necrosis was arbitrarily classified as: 1+, not more than 25 percent of the lobular parenchyma affected; 2+, between 25 and 50 percent of the parenchyma affected; 3+, approximately 75 percent of the pa- renchyma destroyed; or 4+, almost all or all the parenchyma destroyed. For each case, the ne- crosis ratings of all five pathologists were averaged, and the cases were separated into three categories: massive necrosis, average score 2.6 or greater; intermediate, 1.5 to 2.5; and min- imal, 0 to 1.4. There were 82 cases of massive hepatic ne- crosis out of 10,171 necropsies, or approximately one in 125 necropsies and approximately one in 10,000 administrations of general anesthesia. There were 115 cases of intermediate hepatic ne- crosis and 25 cases of minimal necrosis col- lected as a byproduct of the search for massive necrosis cases. These accrued because of the leniency in interpretation of degree of necrosis prescribed to the "local selector" and the pathol- ogist who reviewed the 4204 necropsy summaries. Because the intent of the protocol and its addenda was not to collect cases of intermediate and min- imal necrosis (and there is no assurance that all were collected), these cases are generally ex- cluded from the comparisons that follow. * Massive Hepatic Necrosis in Relation to Anesthetic Practice Observed occurrences of massive necrosis after all operations (Table 4) for the five anes- thetic practices ranged from 5.9 below the ex- pected (nitrous oxide-barbiturate) to 10.9 above •Data from the two-way comparisons presented in this sec- tion cannot be fully interpreted unless multiple adjustments are made simultaneousiy. The small number of cases of massive hepatic necrosis precludes this type of analysis. 93

FIGURE 2 SCHEMATIC FOR PATHOLOGY DATA FLOW NECROPSY REPORTS 11,289 LIVER NOT MENTIONED 4,204 PARTIAL NECROPSY 1,118 DATA COLLECTION CENTER REVIEW (FORM IV1-11,289 CLASSIFICATION OF NECROSIS COMPLETE NECROPSY (FORM IV) 5,967 CHARTS & BLOCKS 184 CHARTS & BLOCKS 42 FIRST SUBMISSION 226 SECOND SUBMISSION 720 INTERFERING VARIABLES- 150 SECOND YIELD I46 INTERFERING VARIABLES--574 NECROSIS CATEGORY* SECOND YIELD Ma I Mi 51 80 15 FIRST YIELD 76 1 (9) NECROSIS CATEGORY FIRST YIELD Ma 1 31 35 • Mi I0 LEGEND: Step 1 Necropsy reports classified by principal investigator or designate. Step 2 For cases thought to be massive hepatic necrosis, complete charts were sent to Data Collection Center. Slides or blocks of liver were 3ent to AFIP, Washington, D.C. Step 3 Necropsy summary (Form IV) for all necropsy reports completed by principal investigator. Step 4 Hepatitis aod possible necrosis charts and slides or blocks requested. Step 5 Form IV categorized at Data Collection Center. Step 6 Slides prepared for circulation, charts abstracted. Step 7 Form IV summaries reviewed by consultant pathologist. Slides requested from participating institutions on the basis of the above review. Step 8 Submissions screeoed for interfering variables by consultant pathologist. Step 9 Necrosis and other morphologic variables rated by Pathology Panel. 'Necrosis Category: Ma = Massive, I - Intermediate, Mi - Minimal 94

TABLE 3.—PATHOLOGY PANEL RATINGS OF HEPATIC NECROSIS BASED ONLY ON SLIDES Hal N-B Cycle Ether Other Total Massive necrosis Intermediate necrosis Minimal necrosis TOTAL 26 (13)* 15 (3) 25 (9) 5 (l) 11 (5) 82 (31) 48 (13) 19 (4) 24 (14) 8 (2) 16 (2) 115 (35) 6 (3) 8 (2) 3 (1) 3 (2) 5 (2) 25 (10) 80 (29) 42 (9) 52 (24) 16 (5) 32 (9) 222 (76) *Numbers in parentheses are numbers of cases originally selected by principal in- vestigators (first yield). TABLE 4.—OBSERVED AND EXPECTED OCCURRENCE OF MASSIVE HEPATIC NECROSIS FOLLOWING HIGH-, MIDDLE-, AND LOW-DEATH-RATE OPERATIONS Operation Group Hal N-B Cyclo Ether Other Total Necrosis observed 2 0 1 0 0 3 Low -death-rate Necrosis expected* 0.7 0.9 0.6 0.4 0.5 3 operations EA** (in thousands) 86.7 105.3 67.5 50.1 57.4 367.0 Number of deaths 234 209 175 63 163 844 Rates/10,000 EA 0.23 0 0.15 0 0 0.08 Rates/1,000 deaths 8.55 0 5.71 0 0 3.55 Middle-death-rate operations High-death-rate operations Operations unknown Necrosis observed 13 6 17 4 7 47 Necrosis expected 16.1 11.1 7.5 4.9 7.4 47 EA (in thousands) 146.2 101.3 68.1 44.3 67.5 427.4 Number of deaths 2562 1757 2397 837 2073 9626 Rates/10,000 EA 0.89 0.59 2.50 0.90 1.04 1.10 Rates/1,000 deaths 5.07 3.41 7.09 4.78 3.38 4.88 Necrosis observed 11 9 7 1 4 32 Necrosis expected 11.3 6.0 6.1 3.9 4.7 32 EA (in thousands) 21.8 11.6 11.7 7.6 9.1 61.7 Number of deaths 2066 1323 1270 492 1205 6356 Rates/10,000 EA 5.05 7.78 5.99 1.31 4.40 5.18 Rates/1,000 deaths 5.32 6.80 5.51 2.03 3.32 5.03 EA (in thousands) 0.2 0.1 0 0 0.1 0.4 Number of deaths 1 3 3 4 3 14 All operations Necrosis observed 26 15 25 5 11 82 Necrosis expected 24.4 20.9 14.1 9.8 12.8 82 EA (in thousands) 254.9 218.2 147.4 102.0 134.0 856.5 Number of deaths 4863 3292 3845 1396 3444 16840 Number of complete necropsies 2860 2018 2390 900 2003 10171 Rates/10,000 EA 1.02 0.69 1.70 0.49 0.82 0.96 Rates/1,000 deaths 5.35 4.56 6.50 3.58 3.19 4.87 Hates/1, 000 necropsies 9.1 7.4 10.5 5.6 5.5 8.1 LEGEND: The numbers of necroses expected were computed by distributing the observed necrosis cases proportional to the number of estimated administrations. For example: , /„ ,, total necrosis X estimated administrations (Hal) Necrosis expected (Hal) = total estimated administrations 3 X 86.7 367.0 0.7 **Estimated administrations. the expected (cyclopropane). (The number of ne- croses expected was calculated by means of the formula given in the legend of Table 4.) Of the five anesthetic practices, cyclopropane and halo- thane were associated with the highest massive hepatic necrosis rates per 1000 necropsies: 10.5 and 9.1, respectively. Operations were grouped for purposes of analysis on the basis of low, middle, and high death rates. The low-death-rate category con- sisted of operations on the mouth and eye, her- niorrhaphy, dilatation and curettage, hysterec- tomy, cystoscopy and plastic procedures. The high-death-rate group included craniotomy,

TABLE 5.--OBSERVED AND EXPECTED OCCURRENCE OF MASSIVE HEPATIC NECROSIS FOLLOWING SINGLE PROCEDURES Hal N-B Cyclo Ether Other Total Necrosis observed 13 13 21 5 5 57 Necrosis expected 16.8 15.3 9.9 6.9 8.3 57 EA (in thousands ) 228.6 207.4 134.6 93.6 110.7 775.1 Number of deaths 3859 2822 2924 1135 2424 13164 Number of necropsies* 2595 1892 1890 785 1595 8757 Rates/10,000 EA** 0.6 0.6 1.5 0.5 0.5 0.7 Rates/1000 deaths 3.4 4.6 7.2 4.4 2.1 4.4 Rates/1000 necropsies 5.0 6.9 11.1 6.4 3.1 6.5 *Complete and incomplete. **Estimated administrations. were open-heart operations, exploratory laparo- tomy, and large-bowel procedures. All other operations were arbitrarily categorized in the middle-death-rate group. Massive hepatic necrosis occurred more frequently after operations associated with high death rates: there were three cases of massive necrosis after 366,992 low-death-rate operations (or approximately 0.1 per 10,000); 47 after 427,355 middle-death-rate operations (1.1 per 10,000); and 32 after 61,719 high-death-rate op- erations (five per 10,000). The rates of massive hepatic necrosis after single procedures within 6 weeks of death are shown in Table 5. The occurrence ranged from 11.1 above the expected (cyclopropane) to 3.8 below the expected (halothane). Cyclopropane is high with a massive hepatic necrosis rate of 11.1 per 1000 necropsies. Massive Hepatic Necrosis in Relation to Type of Operation Massive hepatic necrosis occurred most frequently after open-heart surgery (Table 6). Nearly one-fourth (19) followed open-heart op- erations with cardiopulmonary bypass, although these procedures accounted for only 1 percent of all operations in the Study. That massive hepatic necrosis following open-heart operations appeared predominantly in the second yield,* i.e., were not submitted by local selector, supports the inference that there were screening biases at the local institutions. Thus, easily explained or seem- ingly easily explained necrosis (such as that fol- lowing open-heart surgery) was rejected initially but collected later as part of the second yield. Operations on the large blood vessels (pri- marily the aorta), on the stomach, and for ex- ploratory laparotomy (such as lysis of adhesions for relief of intestinal obstruction, confirmation of inoperable neoplasm, control of hemorrhage, and drainage of abscess) were also associated with relatively high incidences of massive ne- crosis (nine, eight, and nine cases, respectively). Contrary to expectations, an increased in- cidence of massive hepatic necrosis following biliary tract operations did not occur. An esti- mated 27,677 patients underwent cholecystectomy with or without common-duct exploration and other major surgery. Massive hepatic necrosis occurred in only six of these, a rate somewhat less than that for most other abdominal opera- tions. One of the six patients had received halo- thane, whereas halothane was administered for approximately 30 percent of the cholecystec- tomies with or without common-duct exploration. Massive hepatic necrosis occurred in an addi- tional three patients who had undergone a biliary tract procedure at a previous operation within 6 weeks of death, and one of these had received halothane. Massive Hepatic Necrosis in Relation to Multiple Administrations of Anesthesia There were 25 massive hepatic necroses in the 81,400 patients who had two or more opera- tions that qualified them for the multiple proce- dure category.** Table 7 shows that the incidence of massive hepatic necrosis was considerably higher in patients who had undergone multiple procedures (25 of 81,400 or 3.1 per 10,000) than in patients who had not (57 of 775,100 or 0.7 per 10,000, as shown in Table 5). Those who received halothane for at least two procedures had higher rates than expected (10 cases, rather than 4.3); those who had cyclopropane for the last procedure had the expected rates; and those who had nitrous oxide-barbiturate, ether, or Other for the last procedure had lower than the expected rates. The 25 patients in the multiple procedure category underwent 27 types of operations. Of these 27, 14 were abdominal and represent 13 deaths. No other region*** contributed more than three deaths. It •See Fig. 2 for definition of first and second yields. **To qualify for this category, it was arbitrarily agreed that two or more operations should occur within 6 weeks. The selection of patients to meet this criterion was approximate, and included patients who had at least two operations under general anesthesia in the same month if the last operation was done after the 15th of that month, or two operations in the same month or consecutive months if the last operation was done on or before the 15th day of the month. **«"Regions" were the abdomen, chest, extremities, head, neck, soft tissue, and genitourinary tract. 96

^e 3 a«ffo.«S3 CM \O r»\ \O in O \O Ov ^ i! | OrHO>trHrH>J-rH C\. CM CM O ^ in C^ O O CM c*-fl t^- Nf O rH O O O i O in r H i CD c 3 i CM t-H rH CM CM rH rH C-n CMi-nfli-Hi-H rHCM f^ ,-^ rH rHf»lrH>tCTirHCMCM CM rH CM rH O\«D >J-rHrHO\rH>J-r H rHrHrHrHCM CM it W o 0 g CMi0 C-OC-O>CMtO O-\. \O CM Nf rH ^ O\ CM CM CM rH in >O in 00 Nf Nt Nt in 1 a SO r H r H rH ' ' rHrHr H rHl-HrH-JCMm rH OJ in to m o STHETIC -P > CMrH rH rH In CO -H i Pi bo CM rH 1 CMCM rH C^ rH tH 03 „. c 3 & 1 Si rH O f»l O CM O O • • • • P • CO CM O O 1 >J- I| r H -P O n I rH 1 - 1 S 0 rH i Pi rH 0 rH rH rH rH in Si! a 1 >d 8 CO O -H w co d d o i CM C rH . 0) OF MASSIVE HEPATIC NECR 1-1 es originally selected b A because entries are mac rH r H rH rH rH CM in t^ OJ , — ( 'xt rH i — 1 r- 1 in 1 O CM in>fOrHrHrHr H O ! C^ rH CQ - \O rH O d >t r H rH In 'r7 In ^\ CM CM i m 83 1 CM O\ CO M z CM t»> CM CM ro rH CM 1 1 § 3 rH rH tO i CM *! r H CO 00 — INCIDENCE J! |~~ CM--' — - — - n rH rH \D rH r-H oj o .i n 1-HrHrH rH rH rHCMIrH rHCMCM rHrHCM rHrHCM \D J1 CM co in ^ CM -H 0) OCMrH fOO\D tOrHO O\ CO CO C -tf O -tf «0 CM O o iu \o S OMr»t i^ n >J- Ip r H m CM c.) 0) S Operation I t. Pi C -p C QJ I O rHrHOiHO>> O-OCi) 0) O • VCUTHOlPiTH -P 0) S fl C0 -P pi >rj 03 Pi [C S -P Pi T3 i — 1 TH ^1 CO CO Q) Pi *In thousands. **Massive hepatic ***Numbers in pare Note: Columns anc | tp, i oj S -a >> & rt -p -p Pi 3 -H CO CO CD COQJCCQ03 OOcd bo cd P4 C H O to p> Q) H O O 1 CO O O >H -PC O £(iM pl-HrHrH O-PP]O O OJrH-cTojtlOCO-P -H+J CO } 97

TABLE 7. —OBSERVED AND EXPECTED OCCURRENCES OF MASSIVE HEPATIC NECROSIS FOLLOWING MULTIPLE PROCEDURES Hal on previous operations No Hal on previous operations Hal last op. No Hal last op. Hal last op. No Hal last op. Necrosis observed 10 0 3 12 25 Necrosis expected 4.3 2.8 3.7 14.1 25 EA (in thousands) 14.1 9.1 12.2 46.0 81.4 Number of deaths 480 455 524 2217 3676 Number of necropsies 352 312 364 1504 2532 N-B last op. No N-B last op. N-B last op. No N-B last op. Total Necrosis observed 0 10 2 13 25 Necrosis expected 0.5 6.6 2.8 15.1 25 EA (in thousands) 1.6 21.6 9.0 49.2 81.4 Number of deaths 74 861 396 2345 3676 Number of necropsies 51 613 276 1592 2532 Cyclo last op. No Cyclo last op. Cyclo last op. No Cyclo last op. Total Necrosis observed 0 10 4 11 25 Necrosis expected 0.6 6.6 3.4 14.5 25 EA (in thousands) 1.8 21.4 11.0 47.2 81.4 Number of deaths 150 785 771 1970 3676 Number of necropsies 100 564 504 1364 2532 Ether last op. No Ether last op. Ether last op. No Ether last op. Total Necrosis observed 0 10 0 15 25 Necrosis expected 0.3 6.8 2.3 15.5 25 EA (in thousands) 0.9 22.3 7.6 50.6 81.4 Number of deaths 19 916 242 2499 3676 Number of necropsies 9 655 173 1695 2532 Other last op. No Other last op. Other last op. No Other last op. Total Necrosis observed 0 10 6 9 25 Necrosis expected 1.5 5.6 5.7 12.2 25 EA (in thousands) 4.9 18.3 18.4 39.8 81.4 Number of deaths 212 723 808 1933 3676 Number of necropsies 152 512 551 1317 2532 is striking that none of these 25 patients was jaun- diced before the last administration of anesthesia (Table 8). Two patients had pre-existing hepatic disease and 11 developed jaundice after the final anesthetic and before death. All but one died within 11 days of operation. Incidence of Massive Hepatic Necrosis for Each Institution Table 9 displays the rate of massive hepatic necrosis for each institution. Eleven institutions had no massive hepatic necrosis (3, 7, 13, 14, 23, 26, 27, 28, 31, 32, and 34). They contributed 191, 400 cases to the 856, 500 studied. Seven insti- tutions had five or more necrosis cases (8, 10, 20, 21, 22, 24, and 30) and contributed very heavily (283, 900) to the total cases in the Study. Two institutions, 24 and 30, stand out as having high massive necrosis rates (6. 5 and 12.5 per 10,000 administrations, respectively). These institutions also had large numbers of operations associated with high rates of massive hepatic necrosis* and high death rates. These factors undoubtedly contributed to the high rates of massive hepatic necrosis in the two institutions. •Four operation categories had notably higher rates of mas- sive hepatic necrosis than all others: heart with pump, laparotomy, stomach, and great vessels. 98

TABLE 8.--SUMMARY OF MASSIVE HEPATIC NECROSIS CASES WITH MULTIPLE PROCEDURES Anesthetic practice prev. ope. Anesthetic practice Pre-exist, hepatic disease Jaundiced Jaundiced before last op. Day of death after last op. Case Age Sex last op. Alcoholism before death 1 67 U Hal Hal Unknown No Yea No 3 36 25 U Hal Hal Unknown No Yes No 5 44 64 V. Hal Hal Yes No Ye s No 3 55 72 M No Hal Other Unknown No No No 2 68 42 U No Hal Other Unknown No Yes No 1 91 66 F Hal Hal Unknown No Yes No 8 93 63 U No Hal Cyclo Unknown No No No 3 97 67 M Hal Hal Yes No Yes No 9 99 21 U Hal Hal Unknown No No No 5 100 39 U Hal Hal Unknown No Yes No 10 122 58 r Hal Hal Unknown No Yes No 5 156 41 M No Hal Cyclo Unknown Unknown Unknown No 2 185 57 U No Hal Hal Unknown Yes Yes No 1 345 34 U No Hal Hal Yes No Yes No 7 616 81 U No Hal Other Unknown Yes •a No 3 636 55 M Hal Hal Unknown No No No 3 649 65 M No Hal Other Yes No No No 3 675 80 F No Hal Cyclo Unknown No No No 27 687 48 M No Hal N-B Unknown Bo XM No 4 691 64 M Hal Hal Unknown No No No 11 707 21 M No Hal Other Unknown No No No 3 709 37 r No Hal N-B Unknown Unknown No No 2 711 33 u No Hal Hal Unknown No No No 7 717 66 M No Hal Other Unknown No No No 2 719 62 F No Hal Cyclo Unknown No No No 8 TABLE 9.—INCIDENCE AND RATES OF MASSIVE HEPATIC NECROSIS BY INSTITUTION AND ANESTHETIC PRACTICE Institution Halothane N- B Cyclo Ether Other Total Rate of MHN/ 10,000 EA KA* MHN EA MHN EA UHN EA MHN EA MHN EA MHN 1 16.6 2(2)«» 39.9 2 (2) 0.3 2 1.9 2 (1) 9.5 2 (1) 2.1 3 0 4 3.5 3 29.2 3 1.0 5 15.8 3 (2) 32.9 3 (2) 0.91 6 7.2 1 (1) 30.3 1 (1) 0.33 7 0 8 36.3 3 (2) 16.0 1 1.4 1 25.5 1 11.9 2 91.2 8 (2) 0.88 9 7.3 2 (2) 19.4 1 3.3 1 (1) 55.5 4 (3) 0.72 10 13.5 1 (1) 5.7 2 5.2 3 (1) 3.1 1 29.2 7 (2) 2.4 11 4.3 2 (1) 2.7 1 4.0 1 26.3 4 (1) 1.5 12 8.2 1 (1) 11.9 2 (2) 25.1 3 (3) 1.2 13 0 1 4 0 15 9.6 2 3.3 1 30.3 3 0.99 16 8.2 1 (1) 16.1 1 (1) 0.62 17 5.5 2 (2) 19.8 2 (2) 1.0 18 2.4 1 (1) 8.9 1 (1) 1.1 19 7.2 1 (1) 18.3 1 (1) 0.55 20 3.0 1 21.8 2 (1) 7.0 1 (1) 10.7 1 (1) 47.5 5 (3) 1.1 21 22.4 2 15.1 3 (1) 12.7 1 13.4 1 (1) 65.1 7 (2) 1.1 22 14.1 4 (1) 3.8 2 31.2 6 (1) 1.9 23 0 24 2.5 3 (1) 11.2 3 0.9 1 0.2 1 0.6 2 15.3 10 (1) 6.1 25 2.1 1 8.4 1 1.2 26 0 27 0 28 0 29 2.5 2 (1) 3.9 2 (1) 5.1 30 2.3 3 0.3 2 4.4 5 12.5 31 0 32 0 33 5.7 1 (1) 26.8 1 (1) 0.38 34 0 TOTALS 254.9 26 (13) 218.2 15 (3) 147.4 25 (9) 102.0 5 (l) 134.0 11 (5) 856.5 82 (31) 0.96 *In thousands. ""Numbers in parentheses are numbers of cases originally selected by principal investigators (first yield). Note: Columns and rows need not total for EA because entries are made only if MHN occurred in a given category. 99

Massive Hepatic Necrosis in Relation to Preoperative Physical Status Preoperative "physical status" is fre- quently not entered on the anesthesia record. Nine of the 82 cases of massive hepatic necrosis occurred in patients whose physical status had not been assigned preoperatively. In addition to the nonassignment problem (discussed in Chapter II-2), the designation of physical status varies considerably among institutions and anesthesiol- ogists, because the criteria are so general. As an example of the unreliability of this classifi- cation, Table 10 lists five patients who suffered massive hepatic necrosis and who were evaluated preoperatively as physical status 1, i.e., "no complicating systemic disturbance." Of the five patients, three had severe debilitating disease for which they were to undergo definitive surgery, the fourth was 70 years old and had arterioscle- rotic heart disease, and the fifth had a recent history of perforated duodenal ulcer. Clearly, none of these cases should have been classified as physical status 1. In spite of the serious limitation imposed by inaccurate or absent assignment of physical status, there was a clear pattern of increasing massive hepatic necrosis rates for patients in poorer preoperative physical status (Table 11). For nonemergency cases, the rates of massive hepatic necrosis for "good-risk" patients (phys- ical status 1 and 2) were 0.12 and 0.84 per 10,000 administrations, whereas the rates for "poor- risk" patients (physical status 3 and 4) were 3.6 and 12.7 per 10,000. A similar pattern was ob- served for emergency operations, and patients listed preoperatively as "moribund" (physical status 7) had the highest rate of massive hepatic necrosis, 22.6 per 10,000 estimated administra- tions. Incidence of Massive Hepatic Necrosis for Each Year of the Study There was an increase in over-all incidence of massive hepatic necrosis during the period of study, from 15 cases in 1959 to 24 in 1962 (Table 12). At the same time, the use of halo thane in- creased markedly, from 13 percent in 1959 to 50 percent in 1962. Many suspected that the increase in total incidence of necrosis might be caused by the increased use of halothane. The data failed to support this possibility, because, although the number of cases of massive hepatic necrosis following halothane increased during the 4-year period, this increase was roughly in proportion to the increase in over-all use of halothane. In •The physical status of patients was recorded preoperatively in accordance with the classification of the American Society of Anesthesiologists, as follows: 1, no complicating systemic disturbance; 2, moderate complicating systemic disturbance; 3, severe complicating systemic disturbance; 4, extreme complicating systemic disturbance; 5, emergency classes 1 and 2; 6, emergency classes 3 and 4; and 7, moribund. fact, the rates of massive hepatic necrosis fol- lowing halothane and following all agents com- bined were approximately the same for the 4 years individually, as well as combined. By con- trast, the incidence of massive hepatic necrosis following cyclopropane remained approximately the same, but the rate was rising because the over-all use of cyclopropane dropped by 25 per- cent from 1959 to 1962. The absence of massive hepatic necrosis following nitrous oxide- barbiturate in 1962 is puzzling. No good alternate explanation for the increase in massive hepatic necrosis during the 4-year period is apparent from the data. It seemed likely that the number of difficult operations, such as open-heart procedures, which are followed more frequently by hepatic necrosis, might be increas- ing, but that proved not to be the case (Table 13). In the absence of any better explanation, it is reasonable to assume that the increase in post- operative necrosis observed in this Study may simply reflect the over-all increase in viral and other forms of hepatitis that have been reported for recent years. Massive Hepatic Necrosis in Relation to Other Variables Age Massive hepatic necrosis occurred in all age groups (Table 14), but the rates were lowest in the youngest (0 to 9 years) group and highest in the oldest (80 to 89 years) group. Sex Tabulation of the incidence of massive ne- crosis by sex (Table 14) shows a ratio of 51 males to 31 females; and the rate of necrosis for males was twice that for females. However, the over-all death rate for males was 2.56 and for females it was 1.44; thus the necrosis rates par- allel the death rates, and the rates calculated on the basis of estimated administrations are mis- leading. Duration of Anesthesia The rate of massive hepatic necrosis in- creased with the duration of anesthesia (Table 15). These rates varied from 0.28/10,000 estimated administrations for procedures lasting under % hr to 10.5/10,000 estimated administrations for pro- cedures lasting over 6/s hr. The type of operation and preoperative physical status probably con- tributed more heavily to these rates than the duration of anesthesia. This assumption is based on the fact that multiple adjustments tended to minimize the effect of duration of anesthesia on death rates. Day of Death Necrosis by day of death is shown in Table 16. There were 54 deaths in the massive necrosis group within 1 week of surgery; this represents about 66 percent of all massive necrosis deaths. 100

TABLE 10.—CASES OF MASSIVE HEPATIC NECROSIS CLASSIFIED AS PHYSICAL STATUS 1 y£f pj Preoperative diagnosis Comment * 67 Cancer esophagus Ulcerating lesion lower third esophagus 49 Duodenal ulcer Had perforated ulcer with surgery 6 weeks before 70 Elective choleoystectomy Arteriosclerotic heart disease 13 Atrial septal defect 13 I.V. septal defect, patent ductus Cyanotic on admission TABLE 11. —INCIDENCE AND RATES OF MASSIVE HEPATIC NECROSIS BY PHYSICAL STATUS AND ANESTHETIC PRACTICE Physical Halothane N-B Cyclo Ether Other Total Rate/ EA* MHN EA MHN EA MHN EA MHN EA MHN EA MHN 1 121.9 3 (2)«* 109.9 1 65.0 1 (1) 421.7 5 (3) 0.12 2 60.2 7 (5) 48.8 4 (1) 27.3 3 (1) 20.1 1 184.0 15 (7) 0.84 3 15.9 4 (1) 12.5 3 7.0 7 (1) 5.7 2 (1) 9.1 2 50.2 18 (3) 3.6 4 2.3 5 (1) 1.3 3 (1) 6.3 8 (2) 12.7 5 14.1 3 (3) 38.2 3 (3) 0.79 6 4.2 4 (2) 3.4 1 (1) 6.2 8 (2) 3.3 4 (2) 18.2 17 (7) 9.3 7 0.7 1 0.5 1 1.1 3 (2) 0.7 2 (1) 3.1 7 (3) 22.6 Not recorded 39.4 2 (2) 34.6 2 22.5 1 15.7 2 22.6 2 (1) 134.8 9 (3) TOTALS 254.9 26 (13) 218.2 15 (3) 147.4 25 (9) 102.0 1 (1) 134.0 11 (5) 856.5 82(31) 0.96 *In thousands. **Numbers in parentheses are numbers of cases originally selected by principal investigators (first yield). TABLE 12.— INCIDENCE AND RATES OF MASSIVE HEPATIC NECROSIS Halothane N-B Cyclo Ether BY YEAR AND ANESTHETIC PRACTICE Other Total Rates/ Year EA* MHN EA MHN EA MHN EA MHN EA MHN EA MHN 10,000 EA 1959 22.8 2 (l)*» 73.6 t. 42.6 6 (3) 35.9 2 (1) 32.5 1 (1) 207.3 15 (6) 0 72 1960 48 0 6 (3) 60 0 4 (2) 39 8 6 (1) 30 3 1 33 3 2 211 4 19 (6) 0 90 1961 74 0 5 (3) 49 4 7 (1) 34 5 7 (2) 20 2 1 32 7 4 (1) 210 7 24 (7) 1 14 1962 110.2 13 (6) 35.2 o 30.5 6 (3) T5.7 1 35.5 4 (3) 227.1 24 (12) 1.06 TOTALS 254.9 26 (13) 218.2 15 (3) 147.4 25 (9) iro.n -i (1) 134.0 11 (5) 856.5 82 (31 ) n.Ofi *In thousands. **Numbers in parentheses are numbers of cases originally selected by principal investigators TABLE 13.— ANNUAL INCIDENCE OF OPERATIONS WITH HIGH MASSIVE HEPATIC NECROSIS» Year (first yield). Estimated 1959 1960 1961 1962 administrations 11,500 13,400 12,100 12,300 "Heart with pump, laparotomy, stomach, great vessels. 334-553 O-69—8 101

TABLE 14. —INCIDENCE AND RATES OF MASSIVE HEPATIC NECROSIS BY SEX AND ANESTHETIC PRACTICE Sex Halothane N-B Cyolo Ether Other Total Rates/ 10,000 EA EA* HHN EA MHN EA MHN EA MHN EA MHN EA MHN Male 120.6 134.3 17 (8)** 83.2 9 (5) 135.0 7 (2) 49.6 8 (1) 97.8 U (5) 50.3 11 (4) 51.7 4 (1) 65.7 1 68.3 9 (4) 369.4 2 (1) 487.1 51 (20) 1.38 31 (11) 0.64 TOTALS. 254.9 26 (13) 218.2 15 (3) 147.4 25 (9) 102.0 5 (l) 134.0 11 (5) 856.5 82 (31) 0.96 INCIDENCE AND RATES OF MASSIVE HEPATIC NECROSIS BY AGE GROUP AND ANESTHETIC PRACTICE Halothane N-B Cyolo Ether Other Total Rates/ 10,000 EA Age EA MHN EA MHN EA MHN EA MHN EA MHN EA MHN 0-9. 10 - 19. 20 - 29. 30 - 39. 40 - 49. 50 - 59. 60 - 69. 70 - 79. 80-89. 26.6 27.0 36.8 42.2 37.7 32.4 13.0 2.5 (1) (2) (2) (1) (2) (4) (1) 19.0 31.9 38.8 41.6 34.4 28.9 (1) (1) (1) 13.7 23.0 26.6 27.2 19.8 16.5 7.9 2.3 1 (1) 1 (1) 3 (1) 8 (4) 7 (1) 3 (1) 1 35.4 12.0 2 (1) 1.0 45.5 10.6 9.5 16.1 15.7 13.1 7.7 1.9 137.1 O) (1) (1) 75.8 9 (2) 98.7 8 (4) 126.2 8 (3) 139.1 10 (6) 119.1 17 (8) 100.9 17 (5) 47.0 6 (3) 11.4 4 0.22 1.2 0.82 0.64 0.72 1.4 1.7 1.3 3.5 TOTALS. 254.9 26 (13) 218.2 15 (3) 147.4 25 (9) 102.0 5 (l) 134.0 11 (5) 856.5 82(31) 0.96 *In thousands. **Numbers in parentheses are numbers of cases originally selected by principal investigators (first yield). Note: Columns and rows need not total for EA because entries are made only if MHN occurred in a given category. TABLE 15.—INCIDENCE AND RATES OF MASSIVE HEPATIC NECROSIS BY DURATION OF ANESTHESIA AND ANESTHETIC PRACTICE Length of Halothane N-B Cyolo Ether Other Total . . Rate/ EA» MHN EA MHN EA MHN EA MHN EA MHN EA ^ 10,000 EA 0 - 1/2 hr 23.0 2 (2)«* 55.0 2 (1) 79.4 4 (3) 71.2 11 (5) 20.6 3 (2) 4.8 4 54.9 26 (13) 20.8 1 (1) 34.7 3 (1) 53.1 1 44.1 8 (3) 41.8 6 (1) 38.1 8 (3) 15.0 2 8.2 4 (1) 3.3 6 (2) 1.2 1 218.2 15 (3) 147.4 25 (9) 108.2 209.7 248.5 2L3.5 61.7 12.4 856.5 3 (3) 0.28 5 (2) 0.24 18 (8) 0.73 30 (11) 1.41 13 (4) 2.10 13 (3) 10.5 82 (31) 0.96 1/2 - 1 hr 1-2 hr 33.2 2 38.7 3 (2) 33.0 5 (2) 2 4 hr 4-6 1/2 hr 7.7 1 10.0 3 (1) 1.2 2 (1) 102.0 5 (1) 134.0 11 (5) Over 6 1/2 hr TOTALS J *In thousands. **Numbers in parentheses are numbers of cases originally selected by principal investigators (first yield). Note: Columns and rows need not total for EA because (1) entries are only made if massive hepatic necrosis occurred in that category, and (2) there were some cases in each common practice in which length of anesthesia was not recorded. Five died on the day of surgery and half of the massive hepatic necrosis deaths occurred before day 4. Except for the ether category, in which there were so few deaths, the pattern of day of death for the common anesthetic practices is very similar. Occurrence of Jaundice Before Death Jaundice was not observed in all patients who died of massive hepatic necrosis (Table 17). The clinical pathologic implications of this are discussed in Chapter m-4. Of the 26 patients in me halothane group who died from massive hepatic necrosis, 16 were jaundiced, whereas jaundice was recorded for only 15 of the 56 who had not received halothane. Possible explanations for this considerable excess in clinical jaundice in the halothane cases of massive hepatic necro- sis include the following: (1) jaundice occurs as a late manifestation of massive hepatic necrosis more frequently after halothane than after other agents; (2) jaundice occurs equally for all agents, so many patients who had massive hepatic necro- sis and received agents other than halothane were not necropsied; and (3) the physician was more 102

TABLE 16. —INCIDENCE OF JUSSIVE HEPATIC NECROSIS BY POSTOPERATIVE DAY OF DEATH AND ANESTHETIC PRACTICE Day of death Halothane N- 9 Cyclo Ether Other Total 0 1 4 5 1 4 (1)» 2 1 (1) 2 (1) 9 (3) 2 4 2 6 (3) i 2 (1) 15 (4) 3 5 (2) 1 2 (1) 4 (1) 12 (4) 4 1 3 1 (1) 5 (1) 5 3 (3) 1 1 (1) 5 (4) 6 1 ^ 7 1 (1) 2 (1) 1 (1) 7 (4) a 1 (1) 2 (1) 3 (1) • 1 (1) 1 (1) 2 (1) 4 (3) 10 1 (1) 1 2 (1) 11 1 1 (1) 1 (1) 3 (2) u 1(1) 1 2 (1) 15 1 1 17 1 1 19 1 1 20 1 (1) 1 (1) 22 1 (1) KD 25 1 1 2 27 1 1 35 1 (1) 1 (1) 42 1 1 TOTALS 26 (13) 15 (3) 25 (9) 5 (1) 11 (5) 82 (31) •Numbers in parentheses are numbers of cases originally selected by principal investigators (first yield). TABLE 17.—JAUNDICE BEFORE DEATH IN CASES OF MASSIVE HEPATIC NECROSIS Hal N-B Cyolo Ether Other Total Jaundice before death 16 (11)" 4 (2) 9 (5) 1 (1) 1 (1) 31 No Jaundice befora death ID (2) 11 (1) 16 (4) 4 (0) 1C (4) 51 •Numbers in parentheses are numbers of owes originally selected by principal investigators (first yield). likely to look for, and record or measure, jaun- dice in terminal patients with hepatic failure if those patients had received halothane. The data do not show any basis for discriminating among these possibilities, whose statistical implications are similar to those discussed in Chapter III-3. ETIOLOGY OF NECROSIS Pathology Panel Review After the members of the Pathology Panel reviewed the histologic sections from the cases culled by the local selectors, they were given clinical abstracts* that contained details of the clinical cases (knowledge of the anesthetic was withheld). Using this information and their knowledge of the histologic features, they stipu- lated the etiology of hepatic necrosis and placed the cases into one or more of the following cate- gories: (1) halothane, (2) any hepatotoxin, (3) drug sensitization, (4) viral hepatitis, (5) shock, (6) anoxemia or sepsis, and (7) auto- lysis, etc. The pathologists worked independently and used their own criteria to determine the proper category. After the data had been reviewed, items 2, 3, 4, 5, and 6 were found suitable for survey and were grouped for convenience into the three categories shown in Table 18. Thirty abstracts** of massive hepatic necro- sis were available for review (Table 18). Five cases (64, 98, 99, 100, and 328) were considered by at least three of the five panelists who completed the review to be consistent with drug-induced hepatic injury, and five (64, 91, 122, 205, and 255) to be consistent with viral hepatitis. Four cases in each group involved halothane; only one (64) appeared in both groups. Twenty-three cases were considered by at least three of the five panelists to be consistent with the effects of shock, anoxemia, or sepsis. Of these, seven involved halothane, three nitrous oxide-barbiturate, eight cyclopropane, one ether, and four Other. Of the 23 cases, two of the halo- thane cases (98 and 100) appeared in the drug injury category as well, and one of the nitrous oxide-barbiturate cases (205) appeared in the viral hepatitis category. It is worth noting (1) that, although the Pa- thology Panel was allowed to enter a given case in more than one category, only four cases (64, 98, 100, and 205) consistently appeared in more than one category; and (2) that there was more conformity of scoring in the category of shock, anoxemia, or sepsis. •*One chart submitted too late for Panel review (345). TABLE 18.--ETIOLOGY OF MASSIVE HEPATIC NECROSIS ASSESSED BT PATHOLOGY PANEL Number of pathologiats scoring* C«ae Aneethetic Consistent with drug-induced hepatic injury Consistent with effects of shook, anoxemia, or sepsis qonsistent with effects of viral hepatitis practice .1 Hal 2 9 0 36 Hal 2 9 0 44 Hal 2 4 1 51 Other 2 2 39 Other 9 0 64 Hal 1 3 68 Other 5 0 72 Cyolo 9 1 74 Cyclo 4 1 81 Cyolo 3 2 91 Hal 1 1 9 93 Cyclo 1 9 0 97 Hal 2 4 2 98 Hal 4 3 0 M Hal 3 2 0 100 Hal 4 3 2 122 Hal 2 0 9 127 Other 1 4 0 131 Cyolo 1 4 0 156 Cyolo 1 9 0 1B5 Hal 1 4 0 209 N-B 1 3 3 222 Ether 2 4 0 223 Other 0 4 1 334 N-B 0 4 0 255 Hal 2 0 4 328 Cyolo 3 0 1 338 N-B 1 5 0 349 Hal NOT SOORJ 352 Cyolo 0 4 0 363 Cyolo 1 4 0 •Prepared by William Dozier, Sacramento, California. •May score 5. •"Patient's chart submitted late. 103

TABLE 19.—niQLOOI OP INTffllimiATE HEPATIC HEBOSIS ASSESE) BT PATHOLOGY PANEL Number of pathologists scoring* Case ta esthetic practice Conalatent with! drug-Induced hepatic Injury Consistent with effects of shock, anoxenia, or sepele Consistent with sff acts of viral hepatitis 27 "-—io 0 3 0 34 I*>.-. 2 2 0 73 Hal 0 3 0 86 Hal 2 3 3 87 Hal 1 3 3 89 N-B 1 2 1 92 Cycle.. 1 4 0 102 Other 1 5 0 111 Hal 2 1 4 112 Qyclo 1 4 0 118 2 4 2 119 Hal 1 3 0 130 Ether 0 4 0 134 Cyclo 1 0 188 Hal 0 0 190 Other 0 0 196 Hal 1 0 200 O~-i - 1 0 206 Hal 1 0 207 Hal 0 5 0 220 Cyclo 0 1 2 224 Cyclo 0 3 1 248 Cjrolo 0 4 0 249 Hal 1 5 0 268 Cyclo 0 3' 1 269 Hal 0 1 3 271 N-B 1 2 0 304 Hal 1 5 0 308 CJrolo 0 3 3 330 N-B 2 2 1 344 Cyclo 1 5 0 346 Ether 3 9 0 348 Qyolo 0 4 0 369 N-B CHART NOT AVAILABLE> 3C6 Cyclo 0 5 0 •May score 5. Thirty-five abstracts of intermediate hepatic necrosis were available for review (Table 19). Twenty-seven cases were considered to be con- sistent with shock, anoxemia, or sepsis. One case (346) was also considered to be consistent with drug-induced hepatic injury. Five cases (86, 87, 111, 269, and 308) were consistent with the effects of viral hepatitis. Of these five, three (86, 87, and 308) also appeared in the shock category. Clinical Review The chart abstracts* of cases of hepatic ne- crosis were reviewed by an ad hoc group com- posed of one member of each of four medical dis- ciplines.** Their purpose was to judge whether the degree and pattern of hepatic injury could be explained by a primary or contributory cause in the clinical history, necropsy summary, or both. Three members of the committee independently surveyed 193 abstracts (four missing) of mas- sive and intermediate necrosis, and one member separately reviewed the 80 massive hepatic ne- crosis abstracts. Thus, all four members of the ad hoc committee reviewed 80 of the 82 cases of massive hepatic necrosis, and three members reviewed the abstracts of 113 cases of inter- mediate necrosis.*** In most of the cases there appeared to be adequate clinical explanation for the massive hepatic necroses observed at necropsy: shock, especially with prolonged use of vasopressors; overwhelming infection; severe and prolonged congestive heart failure; and pre-existing he- patic disease. In several cases, however, no adequate explanation was evident. Of the 80 mas- sive hepatic necrosis cases, seven were con- sidered unexplained by one member of the group (two involved halothane, four cyclopropane, and one Other); eight additional cases were con- sidered unexplained by two members of the group (four involved halothane, one nitrous oxide- barbiturate, two cyclopropane, and one Other); and nine cases were considered to be unexplained by three or four members of the group (Table 20). Of those nine, seven patients had received halo- thane for the final operation, one cyclopropane, and one Other. Of the nine patients, five had undergone one or more previous operations within 6 weeks of the final procedure. Of those five, four had received halothane on at least two occasions and the fifth had received ethylene for the final operation and ether for a previous operation. Of the 113 cases of intermediate hepatic ne- crosis reviewed by three members of the group, 10 cases were considered unexplained (Table 21) by two or three members of the grOup; seven of the 10 patients had received halothane. Four of the 10 had undergone one or more previous operations within 6 weeks of the final procedure, and two of those four had received halothane more than once. Table 22 summarizes the 71 cases of death from massive hepatic necrosis that were con- sidered by more than one member of the group to be explained by clinical circumstances. This group included a high proportion of complicated operative procedures, and one-third were known to have hepatic disease or gave a history of alcoholism before operation. Table 23 summarizes the 103 cases of death with intermediate necrosis that were considered by more than one member of the group to be ex- plained by clinical circumstances. This group also contained a high proportion of complicated operative procedures. History of hepatic disease or alcoholism was prominent. Thirty of the 103 patients had pre-existing hepatic disease and six had a history of alcoholism; 35 underwent thoracic or cardiac surgery. HALOTHANE LESION Because considerable data were available on the histologic features of the 82 cases of massive hepatic necrosis, attempts could be made to as- cribe a specific lesion to halothane. One approach is discussed in Chapter III-2. This section dis- cusses the use of discriminant analyses to identify •Summaries of 80 cases of massive hepatic necrosis are appended to this chapter. **J. P. Bunker, C. G. Child, C. Davidson, and E. Gall. »**No clinical histories for cases 647 and 817 (massive) or 365 and 811 (intermediate). 104

TABLE 20.—SU1MARY OF "UNEXPLAINED" CASES OF MASSIVE HEPATIC NECROSIS* Case Age, years Sex Anesthetic practice Contributing factor Operative procedure(s ) Total no. ops. with- in 6 wks Day of postop. Jaundice** Day of death following operation** Previous exposure to halothane 55 72 U Other* ** Cholecystectomy; control 2 No Jaundice 2-2 postop. hemorrhage 64 70 F Hal Cholecystectomy and biopsy 1 14 20 liver-normal 91 66 F Hal Excision skin ca., popliteal 2 26-3 31-8 Yes - 1 area; debridement and graft 97 67 U Hal Alcoholism Closure perf . ulcer; subtotal 2 19-9 19-9 Yes - 1 gastrectomy 98 16 F Hal Repair lacerated tendons of 1 No jaundice 14 wrist 99 21 M Hal Craniotomy with biopsy; 2 No Jaundice 14-5 Yes - 1 ventriculojugular shunt 122 58 F Hal Bndosoopy; cholecystectomy 4 30-24-5-1 34-28-9-5 Yes - 3 and repair of hiatus hernia; debride, & pack, of wound; resuture wound dehlscence 255 45 F Hal Laparotomy and biopsy 1 28 35 352 75 M Cyclo Laparotomy and release of 1 11 adhesions "Three or four examiners were unable to explain the extent of hepatic necrosis on the basis of patient's underlying disease, surgical procedure, or recognizable postoperative complication. Evaluation was without knowledge of anesthetic agents used, although four cases had been publicized in the literature. **Time following each operation listed. »*»Cholecystectoiny, nitrous oxide and ether; control postoperative hemorrhage, ethylene. TABLE 21.--SUMJARY OF "UNEXPLAINED" CASES OF INTERMEDIATE HEPATIC NECROSIS Age, ^ years Anesthetic practice Contributing factor Total no. Day of Day of death Previous Operative procedure(s) ops. within postop. following exposure to 6 weeks Jaundice operation halothane 71 F Hal Jaundice 1-1/2 yrs before sur- Open red. femur 1 5 24 33 M H»l gery Carotid arteriogram-brain 3 11-2-1 19-10-7 Yes - 1 biopsy; carotid arteriogram; ventriculogram pneumoence- phalogram-brain biopsy 40 U Hal Excision of tumor-shoulder; 2 7-3 10-6 Yes - 1 re -exploration for nemos tasis 39 F Ether Recent transfu- Radical hysterectomy 1 No jaundice 13 63 F Hal sions D t C 1 3 29 63 P N-B Jaundice Cholecystectomy common duct 1 Preop. 7 43 F ao. Sigmoid colostomy 169 Yes - 1 39 F Ether Transfusions 4 months before Biopsy of the pelvic mass; expl. 2 No Jaundice 13-12 lap., biopsy of peritoneal implant 44 M Hal surgery Right upper lobectomy; closure 2 No Jaundice 32-22 of dehiscence 60 F Hal Recent cytoxan therapy Open femur 1 No Jaundice 29 105

TABLE 22.--SUJ*IARY OF EXPLAINED CASES OF MASSIVE HEPATIC NECROSIS Case Anes. prac. Last gen. anes . to death Oper. No. of ops . in last 4 yrs Mas. to prev. surg. Prev. hal. History of alcohol Preop. hepatic die. and/or Jaundice Jaundice before death 1 Hal 3 20 2 1j1 1 Unknown No Yes 36 Hal 5 90 4 1, 1,1*1 5 Unknown No Yes 44 Hal 3 27 2 1,1 1 Yes No Ye s 100 Hal 10 44 1 1 1 Unknown No Yes 185 Hal 1 59 1 1 0 Unknown Yes Yes 345 Hal 7 12 1 1 0 Yes No Yes 609 Hal 2 33 0 0 0 No No No 636 Hal 3 34 1 1 1 Unknown No No 653 Hal 2 33 0 0 0 Unknown No No 657 Hal 1 33 0 0 0 No No No 658 Hal 3 33 0 0 0 Unknown Tes Yee 660 Hal 1 34 0 0 0 Unknown No No 666 Hal 4 33 2 2,2 0 Yes Yes Yes 667 Hal 3 44 1 6 0 Unknown No Yea 681 Hal 2 58 0 0 0 Unknown No No 691 Hal 11 71 1 1 1 Unknown No No 711 Hal 7 45 2 1,1 0 Unknown No No 716 Hal 2 59 0 0 0 Unknown Yes Yes 723 Hal 42 12 1 27 0 Unknown Yes Yes 205 N-B 8 42 0 0 0 Unknown Y«s Yes 222 N-B 5 33 0 0 0 Unknown No Yes 234 N-B 11 57 0 0 0 Unknown No Yes 338 N-B 9 33 0 0 0 Unknown No No 619 N-B 1 33 0 0 0 No No No 664 N-B 1 33 0 0 0 Unknown Yes No 665 K-B 0 42 0 0 0 Unknown Yes No 687 N-B 4 44 1 1 0 Unknown No Yes 689 N-B 8 27 0 0 0 No No No 709 N-B 2 33 4 1,2 0 Unknown Unknown No 712 N-B 5 33 0 0 0 Unknown No Yes 713 N-B 2 33 0 0 0 No No No 724 N-B 4 33 1 22 0 Unknown Unkown No 807 N-B 15 27 0 0 0 Yes No No 824 N-B 3 33 0 0 0 No No No 72 Cyelo 2 44 0 0 0 Unknown No No 74 Cyclo 9 45 0 0 0 Unknown Yes Yes 81 Cyclo 8 40 0 0 0 No Yes Yes 93 Cyclo 3 44 2 1,1 0 Unknown No No 135 Cyclo 2 57 0 0 0 Unknown No No 156 Cyclo 2 44 1 1 0 Unknown Unknown Unknown 328 Cyclo 40 62 0 0 0 Unknown No Yes 363 Cyclo 4 47 0 0 0 Yes Yes Yes 609 Cyclo 9 41 0 0 0 Unknown Yes Yes 620 Cyclo 3 33 0 0 0 No No No 645 Cyclo 8 57 0 0 0 No No No 650 Cyolo 19 27 1 20 0 Unknown No Yes 651 Cyclo 2 44 1 13 0 No Yes Ye s 669 Cyclo 0 45 0 0 0 Unknown Yes No 670 Cyclo 0 57 1 26+ 0 Unknown Yes No 673 Cyclo 1A 48 1 3 0 Unknown Yes No 675 Cyclo 27 80 2, 1,2 0 Unknown No No 680 Cyclo 17 01 0 0 0 Unknown No No 686 Cyclo 0 36 0 0 0 Unknown No No 688 Cyclo 2 47 1 47 0 Unknown No No 692 Cyclo 0 57 0 0 0 Unknown No No 719 Cyclo 8 44 1 1 0 Unknown No No 802 Cyclo 2 59 0 0 0 Yes No Yea 812 Cyclo 6 45 0 0 0 Yes Yes No 618 Ether 2 44 0 0 0 No No No 685 Ether 7 47 0 0 0 Unknown No No 718 Ether 10 45 0 0 0 Unknown No No 51 Other 11 45 1 2 1 Yes No Yes 68 Other 1 44 2 1,1 0 Unknown No No 127 Other 8 47 0 0 0 Unknown No No 223 Other 3 57 0 0 0 Unknown No No 616 Other 3 45 1 1 0 Unknown Yes No 628 Other 1 33 0 0 0 No No No 632 Other 2 33 1 13 1 No No No 649 Other 3 57 1 1 0 Yes No No 707 Other 3 36 2 1,7 0 Unknown No No 717 Other 25 57 2 1,1 0 Unknown No No 106

TABLE 23.--SIMIARY OF EXPLAINED CASES OF INTERMEDIATE HEPATIC NECROSIS Last gen- anes. to death No. of Mos. to prev. surg. History of alcohol Preop. hepatic dis. and/or Jaundice Jaundice before death Case Anes. prac. Oper. ops . in last 4 yrs Prev. hal. 73 Hal 1 76 2 1,1 0 No No Yes 87 Hal 7 41 3 10,11,26 1 No Yes Yes 119 Hal 17 16 1 1 1 No No Yes 188 Hal 5 34 1 1 0 Yes No No 196 Hal 2 34 1 1 1 No No No 206 Hal 8 48 1 13 0 No Tea No 207 Hal 2 45 0 0 0 No No No 249 Hal 5 42 0 0 0 No No Yes 601 Hal 10 65 0 0 0 No No No 607 Hal 6 33 0 0 0 No No No 611 Hal 28 34 0 0 0 No Yes Yes 612 Hal 5 45 1 16 0 No No No 617 Hal 6 66 3 5,7,16 1 No No No 622 Hal 15 12 2 1,17 1 No No Yes 626 Hal 0 33 0 0 0 No No No 629 Hal 5 33 0 0 0 No No No 630 Hal 1 33 0 0 0 No No No 631 Hal 0 33 0 0 0 No No No 633 Hal 1 33 1 1 1 No Yes No 634 Hal 3 12 0 0 0 No No No 635 Hal 3 33 0 0 0 No No No 637 Hal 3 33 0 0 0 No No No 648 Hal 6 36 1 1 1 No No No 652 Hal 15 99 0 0 0 No No No 654 Hal 3 33 1 2 1 No No No 661 Hal 2 27 4 1,1,5,8 0 Mo No Yes 668 Hal 1 57 0 0 0 No No No 676 Hal 9 27 0 0 0 No No No 678 Hal 28 27 0 0 0 No No No 684 Hal 7 02 1 42 0 No No No 690 Hal 4 88 1 1 1 No No No 695 Hal 11 75 2 1,3 2 No No No 696 Hal 1 33 2 6,23 0 No Yee No 697 Hal 8 33 0 0 0 No No No 703 Hal 0 34 0 0 0 No Yes No 721 Hal 4 27 0 0 0 No No No 801 Hal 11 80 1 53 0 No No No 803 Hal 2 33 0 0 0 No Nr No 805 Hal 13 41 0 0 0 No Yes Yes 821 Hal 9 34 0 0 0 No Yes Yes 823 Hal 13 05 1 1 0 No No No 89 N-B 24 41 0 0 0 No Yes Yes 330 N-B 1 45 0 0 0 No Yea Yes 621 N-B 14 52 1 1 0 No No No 624 N-B 2 12 0 0 0 No No No 625 N-B 1 47 3 1,1,1 0 No No Yes 640 N-B 25 70 1 3 0 No No No 644 N-B 2 16 0 0 0 No No No 655 N-B 1 25 0 0 0 No Yes No 706 N-B 2 33 1 1 1 No No No 710 N-B 9 73 1 10 0 No No No 725 N-B 4 33 0 0 0 No No No 804 N-B 7 48 0 0 0 No No Yes 806 N-B 4 48 1 1 0 Yes No No 814 N-B 3 47 0 0 0 No No No 815 N-B 2 33 0 0 0 No Yes No 816 N-B 1 33 2 7,27 0 No Ye s No 7 Cyclo 12 50 0 0 0 No No No 34 Cyclo 19 59 0 0 0 No Yes Yes 92 Cyclo 5 33 2 17,17 0 No Yes Yes 112 Cyclo 5 44 1 1 1 No No Yes 134 Cyclo 13 33 0 0 0 No Yes Yes 200 Cyclo 5 60 0 0 0 No Yes No 107

Table 23 (Cont'd) Case Anes. prac. Last gen. anes. to death Oper. No. of ops. in last 4 yrs. Itos. to prev. Prev. hal. History of alcohol Preop. hepatic dis. and/or Jaundice Jaundice before death surg. 220 Cyclo 6 45 1 24 0 No Yes Yes 224 Gyclo 8 20 0 0 0 Yea Yes Yes 248 Cyclo 2 44 0 0 0 Yea Yes Yes 268 Cyclo 2 44 0 0 0 No Yes Yes 308 Cyclo 3 44 0 0 0 No No Yes 344 Cyclo 2 47 0 0 0 No No No 348 Cyclo 2 44 0 0 0 No Yes Yes 366 Cyclo 2 45 0 0 0 No No No 608 Cyclo 23 52 3 2,7,9 0 Yes No No 615 Cyclo 10 88 1 14 0 No No No 671 Cyclo 4 57 0 0 c No No No 672 Cyclo 5 33 1 22 0 No No No 693 Cyclo 7 36 0 0 0 No No No 694 Cyclo 1 33 1 29 0 No No No 702 Cyclo 4 65 0 0 0 No Yes Yes 704 Cyclo 2 34 2 1,1 0 No No No 715 Cyclo 41 50 2 10,19 0 No Yes No 822 Cyclo 7 95 3 1,1,3 2 No Yes No 639 Ether 7 57 0 0 0 No No No 642 Ether 18 75 0 0 0 No No No 679 Ether 0 33 0 0 0 Yes Yes Yes 698 Ether 3 44 0 0 0 No Yes Yes 808 Ether 4 47 0 0 0 No No No 820 Ether 38 58 0 0 0 No No No 102 Other 1 44 0 0 0 No No No 190 Other 7 33 1 1 1 No No No 600 Other 2 42 1 9 1 No Yes Yes 604 Other 2 92 2 1,36 1 No No No 613 Other 2 57 1 1 0 No No No 614 Other 2 33 0 0 0 No Yes No 623 Other 2 33 0 0 0 No Yes No 627 Other 9 70 0 0 0 No No No 638 Other 1 44 0 0 0 No No No 659 Other 4 36 1 1 1 No No No 663 Other 1 22 2 1,1 0 No No No 674 Other 12 88 1 2 0 No No No 683 Other 33 27 0 0 0 No No No 699 Other 4 44 0 0 0 No No No 722 Other 32 12 0 0 0 No No No 818 Other 5 40 0 0 0 No No No 108

the histologic variables that are the best index of discrimination between two groups. For this analysis, the 82 cases of massive hepatic necro- sis were divided into a halothane group* and a "no halothane" group. Within these groups, the scores of the Pathology Panel were pooled for each histologic variable (Form IV). The initial scoring by the Pathology Panel was done without specific instruction on protocol; therefore, there were blanks on the forms for many of the variables. It is difficult to tell whether the blanks represent zero scores or missing information. Consensus scores for each variable (five pathologists scoring) were calcu- lated. Most of the variables on Form VI were scored on the basis of presence or absence, but some** were scored on the basis of degree (0 to 4+). •Exposure to halothane any time within 6 weeks before death. **Autolysis, necrosis, lobular inflammation, lobular bile stasis, portal inflammation, and portal bile stasis. Six of the 53 histologic variables tested seemed to help discriminate between the two groups. They were, in order of significance: (1) lipofuscin pigmentation in Kupffer's cells, (2) lobular polymorphonuclear cytosis, (3) acidophilic bodies in necrotic areas, (4) degree of inflammation in portal triads, (5) lobular lymphocytes is, and (6) portal triad lymphocytosis. Lobular polymorphonuclear cytosis was the only significant variable oriented with "no halo- thane." Many of the cases selected preferentially by this analysis did, in fact, involve halothane, and most of these are the unexplained cases of mas- sive hepatic necrosis. The inherent weakness of this analysis is that, when the number of factors (53) approaches the number of individuals studied, random variations may easily be mistaken for real differences, and there is no statistical or practical way of resolving this problem without accumulating more cases. 109

APPENDIX TO CHAPTER m-1 SUMMARIES OF 80 CASES OF MASSIVE HEPATIC NECROSIS* SUMMARY OF CASE 1 History: This 67-year-old man entered the hos- pital with a 6-week history of dysphagia, 20-lb weight loss, and hoarseness. X-rays taken before he came to the hospital showed ulcerating lesion in the lower third of the esophagus. Before he entered the hospital, pro- cedure 1, consisting of esophagoscopy and biopsy, which showed carcinoma, had be en done on an out- patient basis. This procedure was done under general anesthesia with premedication of: atro- pine, 0.4 mg; Phenergan, 25 mg; and Demerol, 25 mg. The anesthesia lasted 10 min and was general. Blood pressure at this time was 160/80, and the procedure was well tolerated. Physical Examination: He was thin, was not jaundiced, had unequal pupils, and had no abdom- inal mass or tenderness. Clinical Course: Twelve days after procedure 1, he underwent procedure 2, consisting of insertion of a Celestin tube as a palliative measure into the esophagus via a laparotomy performed under general anesthesia. After this, he was confused and anorectic, ate poorly, coughed poorly, and cooperated poorly. He was given radiation therapy with cobalt in 14 treatments from the 9th to the 25th day after procedure 2. On the 25th day after procedure 2, x-rays showed that the tube was out of place, lying above the lesion in the esophagus, and he underwent procedure 3, consisting of esophagoscopy under general anesthesia, only to remove the tube. Very shortly after, he developed a marked shivering and tachycardia, with a pulse rate as high as 140 and wide swings in his temperature from 99 to 103 down to 94 F. He developed abdominal rigid- ity, but no crepitus in the neck or definite evi- dence of perforation of the esophagus. He was treated with oral fluids, intravenous fluids, and tetracycline, and was first noted to be jaundiced on the day he died, i. e., the 3rd day after pro- cedure 3, or 28 days after procedure 2. Necropsy Findings: 1. Recent insertion of Celestin tube for car- cinoma of the esophagus. 2. Carcinoma of the esophagus with no gross extension locally or lymph node involve- ment. 3. Subhepatic abscess in the region of the pylorus and involving the lesser peritoneal cavity. 4. Pulmonary edema. 5. Extensive central necrosis of liver. SUMMARY OF CASE 36 History: This 25-year-old man was well until 4 hr before admission, when his shirt caught fire while he was pouring gasoline into the carburetor of an automobile. Physical Examination: He was well nourished and had third-degree burns estimated at 55 to 60 percent of his body surface area, including face, chest, back, and arms. There was no jaundice. The abdomen was not examined because of the presence of burns. The blood pressure was never taken because of the presence of burns on the upper extremities. Clinical Course: He was treated with fluids and electrolytes, blood, and several dressing changes. Sixteen days after admission to the hospital, he had autografting from both thighs to the right arm. Six days after this, he started to have hallucina- tions and at this time was first noted to be jaun- diced. This was thought to be due either to septi- cemia or to a transfusion reaction. Seven days postoperatively, an x-ray showed free air under the diaphragm and he was thought to have per- foration of a Curling's ulcer. He died shortly after this, 7 days after operation, 23 days after admission to the hospital. Necropsy Findings: 1. Third-degree burns of 60 percent of body surface area. 2. Severe central necrosis of liver, toxic. 3. Multiple superficial mucosal erosions of the stomach and duodenum. 4. No perforation of the gastrointestinal tract or other explanation of the free air under the diaphragm seen by x-ray was found at necropsy. SUMMARY OF CASE 44 History: This 64-year-old man had a history of alcoholism, a myocardial infarction 5 years pre- viously, and angina pectoris since the myocardial infarction. He had been studied in another hos- pital 3 weeks before and been found to have a left upper lobe lesion in his chest. He was admitted for elective surgery. Physical Examination: He was not jaundiced and there was no abdominal mass or tenderness. Blood pressure was 140/90. Clinical Course: One day after admission to the hospital, he had bronchoscopy under local anes- thesia, which showed an irregularity of the orifice of the left upper lobe; this area was biopsied and •Anesthetic agent not included in these summaries to allow unbiased clinical and pathologic review. Anesthetic practices are listed in Tables 20 and 22 of Chapter iII-1. 110

showed only chronic inflammation. Three days after admission to the hospital, he underwent procedure 1, consisting of left upper lobectomy for what proved to be a chronic granuloma. After this, he had confusion thought to be due to delir- ium tremens, chest pain, fever, continued drain- age leaking and bubbling in his chest tube, and transient hypotension the 1st and 2nd days to a pressure of 70, for which a cause was never found. He also had transient atrial fibrillation. Eleven days after procedure 1, x-rays showed a left hydropneumothorax with a radiopaque for- eign body remaining in the chest. Twelve days after procedure 1, he under- went procedure 2, consisting of a removal of a surgical sponge. After procedure 2, he remained febrile, hypotensive, cyanotic, confused, incon- tinent, and unable to clear secretions effectively. On the 4th day, he vomited blood, complained of chest pain, and died 1.5 hr after the final com- plaint of chest pain, 3 days after procedure 2, 14 days after procedure 1, and 18 days after ad- mission to the hospital. He was jaundiced only during the last day of life. Necropsy Findings: 1. Left serosanguineous pleural effusion, 200 cc. 2. Bilateral pulmonary atelectasis. 3. Pulmonary edema. 4. Recent thromboemboli in branches of both lower lobe pulmonary arteries. 5. Aspiration of gastric contents. 6. Acute hepatitis with marked acute cen- tral hemorrhagic necrosis. 7. Healed myocardial infarction. SUMMARY OF CASE 51 History: This 49-year-old man entered the hos- pital the second time for elective surgery for duodenal ulcer. He had been in the same hospital 6 weeks previously for closure of a perforated ulcer. This first operation, procedure 1, was done under general anesthesia, lasting 1 hr and proceeding uneventfully. His postoperative course was un- eventful and he was discharged in 10 days. A BSP test during that hospitalization showed 36 per- cent retention in 30 min. No other studies per- taining to liver function were done. He also had a history of alcoholism in the past, but allegedly the alcoholic intake had been moderate recently. He was re-admitted for elective, definitive surgery for his duodenal ulcer after being treated with Pro-banthine, Gelusil, and phenobarbital be- cause of continuing abdominal distress. Physical examination was negative except for the presence of moderate follicular acne. Blood pressure was 110/80. Clinical Course: He was studied and treated in the hospital for 4 days before surgery. He was treated with antibiotics (penicillin and tetracycline) because of the presence of acne. On the 5th day, under anesthesia, he under- went a 4-hr operation, strengthening the closure of the duodenal stump and gastrojejunostomy. The operation entailed a 600-cc blood loss; no blood was given, but a transfusion of 500 cc of albumin. This operation also proceeded unevent- fully. On the 2nd postoperative day, he was found to be jaundiced. The jaundice deepened and he had chills and fever, and developed liver flap and coma, and finally upper gastrointestinal bleeding. He continued to have bile in his nasogastric re- turn, as well as in his stool. His treatment in- cluded steroids, blood, gastric cooling, and fibrinogen, but he died 10 days after the second operation. Necropsy Findings: 1. Acute atrophy of liver, etiology viral hepatitis. 2. Peritonitis, localized lesser peritoneal sac. 3. Incompetent duodenal stump, etiology surgical operation with perforation of duodenal stump and drainage of duodenal contents into lesser peritoneal sac. 4. Necrotizing bronchopneumonia with abscess formation left and right lungs. 5. Acute and chronic bronchitis. 6. Pulmonary emphysema. 7. Pleural effusion, bilateral. 8. Acute congestion of kidney, marked, bi- lateral. 9. Cholemic nephrosis. SUMMARY OF CASE 55 History: This 72-year-old man entered the hos- pital for elective cholecystectomy. Two months earlier, he had been in the hos- pital for resection of a carcinoma of the sigmoid colon; at that time he was found to have an acute cholecystitis for which a cholecystostomy had been done under an unknown type of anesthesia; no details about that hospitalization are available. Postoperatively he did well, and the chol- ecystostomy tube had come out 2 weeks before the final admission. He had been on no medica- tions and had not been jaundiced. Physical Examination: He was well developed and well nourished and had no abdominal mass, tenderness, or jaundice. Blood pressure was 140/75. Clinical Course: On the day after admission, a cholecystectomy and biopsy of a suspicious nodule in the liver were performed under general anes- thesia, and proceeded uneventfully. Postopera- tively, on the afternoon of surgery, he became hypotensive and showed abdominal distention, so 111

he was returned to surgery for a second opera- tion that same night, also under general anes- thesia. At this operation, he was found to be bleeding from multiple points throughout the abdomen. In spite of transfusion of a total of at least 14 units of blood, he showed bleeding from the rectum, the mouth, the wound, the nasogas- tric tube, and needle puncture sites; he died 36 hr after the second operation. He was hypoten- sive on vasopressors most of this time and was oliguric after the second operation. He never became jaundiced. Necropsy Findings: 1. Hemoperitoneum, 3000 cc, associated with generalized bleeding tendency. 2. Acute massive necrosis of hepatic paren- chyma. 3. Bilateral pleural effusions, total 3000 cc. 4. Bilateral pulmonary atelectasis, edema, congestion, and hemorrhage. 5. Generalized ecchymosis of peritoneum, liver, diaphragm, small and large in- testine, omentum, and mesentery. 6. Hemorrhage into spleen. 7. Ecchymosis of skin at injection sites. SUMMARY OF CASE 64 History: This 70-year-old woman entered the hospital for elective cholecystectomy with a his- tory of several years of right upper quadrant dis- tress and intolerance of fatty foods. She had never been jaundiced, and was known to have arteriosclerotic heart disease, Meniere's syndrome, and seborrheic dermatitis of the scalp, for which she had been on unknown medications. She had been studied in an out-patient clinic, whose records are not available, and there had had x-rays and blood tests that were completed 4 weeks before her hospital admission. Physical Examination: She was well nourished, was not jaundiced, and had no abdominal mass or tenderness. Blood pressure was 170/80. Clinical Course: One day after admission to the hospital she underwent cholecystectomy and liver biopsy. The liver biopsy showed "minimal lipid infiltration." After surgery she did quite well, and was discharged on the 7th day. Seventeen days after surgery she was read- mitted with a history that 14 days postoperatively she had become jaundiced and after that had de- veloped light stools, nausea, vomiting, and ab- dominal pain, and had vomited dark blood. She was admitted in coma, with no abdominal mass or tenderness, passing dark bloody material by rectum, with a stiff neck, and with paralysis of the right side of the face and left lower extre- mity. She was thought by a neurologic consultant to have intracranial hemorrhage; lumbar punc- ture showed 40-50 RBC per high-power field. After her admission, 17 days following sur- gery, the stiff neck cleared, the paralysis ex- tended to all four extremities, and she became hypotensive in spite of the transfusion of blood. She became more deeply jaundiced, gradually deteriorated, became oliguric, and died 21 days after her original admission to the hospital, 20 days after surgery, 3 days after her readmission to the hospital, and 6 days after the onset of jaun- dice. Necropsy Findings: 1. Severe acute hepatitis with fatty infiltra- tion of the liver. 2. Massive melena due to acute gastric ulcers (six) and petechiae. 3. Hemorrhagic ascites, 300 cc. 4. Acute erosive esophagitis. 5. Aspiration of gastric contents. 6. Right pleural effusion, 300 cc. 7. Examination of brain not permitted. SUMMARY OF CASE 68 History: This 42-year-old man was transferred from another hospital 2 days after he had been in- jured in a crushing injury when an automobile fell off the jack while he was lying under it working. In the original hospital he arrived in shock and was found to have a compound fracture of the left radius, separation of the pubic symphysis, separation of the right iliac joint, hemoperitoneum, and disruption of the small intestine with mas- sive intraperitoneal and retroperitoneal hem- orrhage. He was taken to surgery under general anesthesia, and underwent open reduction and internal fixation of the fracture of the radius, evacuation of massive hemoperitoneum, and small bowel resection. This operation lasted 4.5 hr and during this time he had no blood pressure for at least 1 hr. During this procedure, he received 15 units of blood. Postoperatively, he was completely anuric, had considerable respiratory difficulty, and re- quired four more units of blood. After 48 hr in the first hospital, he was transferred by air, with blood, oxygen, and Levophed running, to the second hospital. Physical Examination: He was obese, was semi- comatose, and had inadequate respirations. Blood pressure was 100/7. Pulse was 110. Abdomen was hidden by dressings. Clinical Course: He immediately received res- piratory assistance by means of endotracheal in- tubation and very shortly had tracheostomy per- formed under local anesthesia. Because of a rising potassium level, he had hemodialysis on an artificial kidney. After 1 day in the second hospital he developed cardiac arrest; he re- sponded to cardiac massage, but immediately after this was found to have abdominal distention and hypotension thought to be due to progressive intra-abdominal bleeding. Accordingly, he had his second operation, again under general anesthesia, with the evacua- tion of 1500 cc of intraperitoneal and retroperi- toneal blood, but without transfusion. After this 112

operation, he remained hypotensive and again, because of a rising serum potassium level, a second hemodialysis was started 9 hr after the end of the second operation. He became hypo- tensive and suffered cardiac arrest during his second hemodialysis and died 11 hr after the end of the second operation. Jaundice was not re- ported in life but was noted at necropsy. Necropsy Findings: 1. Acute massive necrosis of the liver. 2. Hemorrhagic necrosis of the gallbladder. 3. Multiple small infarcts, large and small intestine. 4. Acute tubular necrosis of the kidneys, bilateral. 5. Fracture of the pubic symphysis. 6. Fracture of the left radius. 7. Multiple intracerebral petechiae. 8. Cerebral edema. SUMMARY OF CASE 72 History: This 43-year-old woman was admitted to the hospital with a history of an abdominal mass developing over a period of 9 months. There had been a 10-Ib weight loss but no other symptoms. Physical Examination: She was thin and not jaundiced. A large, rounded mass filled the entire abdomen. The liver, as such, was not palpable. Clinical Course: She was studied and prepared in the hospital for 7 days, her preparation in- cluding transfusion of 1500 cc of blood. After a week in the hospital, she underwent exploratory laparotomy in which a tumor mass was found ex- tending from the diaphragm to the pelvis. This was interpreted as being bilateral horseshoe kidneys with fusion in the midline. Nothing de- finitive was done and the abdomen was closed. After the operation, the patient had prac- tically no urine output and remained hypotensive and unresponsive in spite of intensive manage- ment for renal failure. She was not noted to be jaundiced in life. She died 48 hr after surgery, 8 days after admission to the hospital. Necropsy Findings: 1. Retroperitoneal sarcoma, low-grade ma- lignant schwannoma, 9270 g, unrelated to any intra-abdominal viscera. (The kidneys were normal.) 2. Massive necrosis of the liver (shock). 3. Hemoglobinuric nephrosis. 4. Moderate left hydronephrosis and hydro- ureter. 5. Focal adrenal cortical necrosis. 6. Pulmonary atelectasis, congestion, and edema. SUMMARY OF CASE 74 History: This 36-year-old woman entered the hospital because of vomiting blood. For the pre- ceding 6 months, she had been ill with fever, anemia, edema, joint pains, muscle tenderness, paresthesias, and muscle spasms. She had been admitted and studied extensively on the medical service 1 month before the final hospital ad- mission. Laboratory tests at that time included: total protein, 4.4; albumin, 3.1; globulin, 1.3; BSP retention. 22 percent; alkaline phosphatase, 7.5; SCOT, 76; and SCPT, 42. She had bone mar- row, skin, and muscle biopsies, but the only di- agnosis reached was "collagen disease." She was discharged on prednisone, 60 mg/day, as- pirin, and antacids. On this medicine, she de- veloped hirsutism, increased appetite, obesity, and a buffalo hump. For 2 weeks before the final hospital admission, she had recurrent epigastric pain developing on an empty stomach, particularly in the middle of the night, and relieved by ant- acids. Two hours before the final admission, she abruptly vomited blood and began to pass blood by rectum. This was her first episode of gas- trointestinal bleeding. Physical Examination: She was pale but not jaundiced. Blood pressure was 110/60. Pulse was 170. She had a round face and increased body hair; the liver was palpable three finger- breadths below the right costal margin. Clinical Course: She was given 7500 cc of blood but the gastrointestinal bleeding continued. On the day of admission, she underwent her only operation, consisting of vagotomy, pyloroplasty, gastrostomy, suture ligature of a bleeding duodenal ulcer, and liver biopsy. The liver was said to be "enlarged and abnormal." Immediately after the operation, she became jaundiced and continued to ooze from her inci- sion. She continued febrile with temperature as high as 40 C and evidence of left lower lobe pneu- monia. Jaundice deepened and on the 8th day she became hypotensive to 70/50 and developed leak- age of dark brownish fluid around the gastros- tomy. Her urine output was always good. She died 9 days after admission to the hospital, 9 days after surgery. Necropsy Findings: 1. Centrilobular hemorrhagic necrosis of the liver, advanced with biostasis and re- generation of surviving liver plates. 2. Intrahepatic endophlebitis of hepatic veins with focal, partly organized mural and occlusive venous thrombi. 3. Acute intrahepatic pericholangitis, ad- vanced. 4. Active duodenal peptic ulcer with bleed- ing. 5. Unhealed abdominal wound and wounds of pyloroplasty and gastrostomy (pyloro- plasty separated at necropsy). 6. Generalized fibrinopurulent peritonitis. 7. Nonspecific focal myopathy, various muscles. 113

8. Focal nonspecific glomerulitis of kidneys. 9. Confluent hemorrhagic necrosis of the spleen. 10. Atelectasis of lungs, advanced. 11. Bilateral serosanguineous pleural effu- sion; right, 550 cc; left, 600 cc. 12. Chronic passive congestion of the liver and spleen. SUMMARY OF CASE 81 History: This 59-year-old man was admitted with right upper quadrant distress. Two months before the final admission, he had surgery in another hospital under an un- known type of anesthesia for bleeding duodenal ulcer. A subtotal gastrectomy was done. Ten units of blood were given. Further details con- cerning this hospitali zation are not available. One month before, he had a 5-day illness considered to be influenza, with chills and fever but no jaundice. Physical Examination: He was well nourished, not jaundiced, and in moderate distress. Tem- perature was 99 F. Blood pressure was 120/80. There was moderate right upper quadrant ten- derness, but no definite mass. During his first 3 days in the hospital, he had chills and fever as high as 104 F, as well as hiccups, nausea, and vomiting. He was described as critically ill, and was treated with nasogastric tube and antibiotics. Clinical Course: On the 3rd day, a cholecystos- tomy was performed under anesthesia in a pro- cedure lasting 0.5 hr. The gross appearance of the liver was not stated. He tolerated the proce- dure well, but in the recovery room it was thought, in retrospect, that he had been severely depressed by the procedure, in that it took him about 13 hr to recover from the anesthetic. On the 1st post- operative day, he was noted to be jaundiced, al- though the serum bilirubin level had been rising up to the time of surgery. He was treated with antibiotics and was able to eat, but developed pro- gressive jaundice with dark urine and ecchymosis. On the 7th day, he was confused, and on the 8th day he abruptly became hypotensive with marked hyperventilation and acidosis. He was treated with vasopressors, steroids, and antibiotics, but died 8 days after the second operation and 11 days after the final hospital admission. Necropsy Findings (provisional necropsy diag- nosis based only on gross exam): 1. Acute hepatic necrosis, probable homol- ogous serum hepatitis. 2. Acute cholecystitis with necrosis and gangrene of the gallbladder. SUMMARY OF CASE 91 History: This 66-year-old woman entered the hospital for elective surgery for carcinoma of the right leg. Forty-four years before, at the age of 21, she had sustained a burn in the right popliteal fossa that had never healed completely. There re- mained a small ulcerated area that had been en- larging for 4 months before the final admission to the hospital. She had been known to Have dia- betes mellitus for 16 months before the final ad- mission and had been taking Orinase. It is not known whether she had it at the final hospital ad- mission. Physical Examination: She was obese but not jaundiced. Blood pressure was 130/70. There was no abdominal mass or tenderness. There was a 12 x 12-cm ulcerated fungating lesion in the right popliteal fossa. Clinical Course: The first biopsy done under local anesthesia was not positive, but suggested early squamous cell carcinoma. A second biopsy done under local anesthesia was positive for squamous cell carcinoma. Twenty-three days after admission to the hospital she had operation 1, consisting of ex- cision of the lesion in the right popliteal region, including partial resection of the gastrocnemius muscle and application of split-thickness skin grafts. After this, she had a low-grade fever and was seen to have 75-80 percent take of the skin graft with some infection, which cleared with conservative treatment. Twenty-three days after operation 1, she had operation 2. Both operations were under general anesthesia. Operation 2 consisted of debridement of the right popliteal region and split-thickness skin graft with pinch grafts. Three days after this, she became confused and then comatose. She developed jaundice with dark urine and a tempera- ture of 103 F. The jaundice became deeper and in the last 3 days of life she was oliguric and the last day hypotensive. She died 54 days after ad- mission to the hospital, 31 days after operation 1, and 8 days after operation 2. Necropsy Findings: 1. Acute diffuse hepatic necrosis, etiology undetermined. 2. Diabetes. 3. Bilateral atelectasis, partial. 4. Mild pulmonary congestion. 5. Interstitial pancreatitis. SUMMARY OF CASE 93 History: This 63-year-old man entered the hos- pital for elective repair of an abdominal aortic aneurysm that had been known to be present for 4 years. He had a history of cardiac disease with angina and was taking digitalis and nitroglycerin. Physical Examination: Blood pressure was not stated. There was no mass or tenderness in the right upper quadrant. A 14 x 17-cm aortic aneu- rysm was palpable in the abdomen. 114

Clinical Course: He was found to have a mild urinary tract infection and was treated with Gantrisin and Chloromycetin and maintained on digitalis. After 2 weeks in the hospital, he under- went operation 1 under spinal plus "general" an- esthesia, consisting of resection of the abdom- inal aortic aneurysm and replacement with Tef- lon graft. During this procedure, he was given 10 million units of penicillin intravenously, and after this became abruptly hypotensive for a period of at least 45 min and was thought to have had a penicillin reaction. Postoperatively, he was hypotensive and passed several bloody stools. One day later he was returned to surgery for operation 2, again under general anesthesia, and had evacuation of retroperitoneal hematoma and repair of an aortic suture line. Several dusky areas in the small intestine appeared to improve after procaine was infiltrated about the celiac plexus. After this operation he became hypoten- sive again with evidence of bleeding in the flank. - One day after the second operation he was returned to surgery for operation 3, under "gen- eral" anesthesia, and had laparotomy, evacuation of retroperitoneal hematoma, and tracheostomy. He was thought to have a coagulation defect and was given 2500 cc of bank blood and 1000 cc of fresh red blood. After operation 3, he did well for 2 days, but he died suddenly 3 days after the last operation and 5 days after the first operation, with a cardiac arrhythmia. He was not noticed to be jaundiced. Necropsy Findings: 1. Intraperitoneal hemorrhage, 1100 cc. 2. Retroperitoneal hemorrhage, 700 cc. 3. Pseudomembranous enterocolitis involv- ing the entire small intestine, cecum, and rectum, probably on an ischemic basis. 4. Central lobular necrosis of the liver. 5. Acute tubular necrosis of the kidney. SUMMARY OF CASE 97 History: This 67-year-old man entered the hos- pital with acute severe abdominal pain that be- gan 8 hr before admission. He had a long history of heavy alcohol in- take, although allegedly this had been reduced recently. He had been having abdominal pain for 2 weeks and had been receiving Sparine, anta- cids, and laxatives in unknown amounts. Physical Examination: He appeared acutely ill and was cyanotic. Temperature was 97 F, pulse was 60, and blood pressure was 110/70. He was not jaundiced. There was marked epigastric and right lower quadrant tenderness. Clinical Course: He was taken to surgery on the day of admission and a perforated duodenal ulcer was closed under anesthesia. Aside from some respiratory problems, he did well for 10 days. Then, on the 10th day, he developed acute mas- sive upper and lower gastrointestinal bleeding and was taken to surgery for a second operation, under anesthesia, in which a bleeding posterior duodenal ulcer was suture-ligated and a gastrec- tomy was performed. The procedure lasted 4.5 hr and he received 2000 cc of blood during sur- gery. After this operation, he did well for about 4 days and then developed fever, then cyanosis, then oliguria. On the 9th postoperative day he was noted to be jaundiced. The fever, oliguria, and jaundice persisted in spite of antibiotics, fluid and electrolyte management, steroids, and blood, and he died 9 days after the second opera- tion and 19 days after the first operation. Necropsy Findings: 1. Acute submassive necrosis of the liver. 2. Nephrosis, marked. 3. Paraduodenal abscess, in continuity with a blown-out duodenal stump. 4. Recent coronary thrombosis with heal- ing myocardial infarction. 5. Bilateral bronchopneumonia with pul- monary edema, congestion, and atelec- tasis. SUMMARY OF CASE 98 History: This 16-year-old girl entered the hos- pital shortly after she fell through a glass door, sustaining a deep laceration of the right wrist. Physical Examination: There was a deep lacera- tion of the right wrist with evidence of laceration of several tendons. Blood pressure was 110/80. There was no jaundice or abdominal mass or tenderness. Clinical Course: There was surgery shortly after admission and she had a 4-hr operation under general anesthesia, involving repair of eight lacerated tendons and a partial laceration of the median nerve. After this, she did well until the 9th postoperative day, when she developed a fever as high as 105 F. She continued with high fever, became more lethargic, and developed nausea, vomiting, and confusion. She never de- veloped jaundice or abdominal mass or tender- ness. She died 14 days after admission to the hospital. Necropsy Findings: 1. Acute massive necrosis of the liver. 2. Nephrosis, severe. SUMMARY OF CASE 99 History: This 21-year-old man entered the hos- pital with a 6-year history of headaches, which had become more severe in the preceding year. He also had recent onset of blurred vision, complete loss of vision, and transient staggering gait. 115

Physical Examination: He was moderately nour- ished and had no jaundice. Blood pressure was 120/80. He was mentally slow, and showed papil- ledema and bilateral visual field defects. Clinical Course: In his first 2 weeks in the hos- pital, he underwent lumbar punctures and carotid arteriograms, then ventriculograms, then con- trast ventriculograms, then bilateral ventriculos- tomy with subgaleal shunts, all performed under local anesthesia. His studies showed increased cerebral spinal fluid pressure and x-ray evidence of a tumor in the region of the third ventricle. He was started preoperatively on radiation therapy, about 300 r/day, along with INK, 100 mg three times a day, as an adjunct to radiation therapy. He became agitated and confused. On the 13th day under anesthesia, he had right frontal craniotomy and was found to have an inoperable brain tumor. After this, he had fever, continuing evidence of increased spinal fluid pressure, and more confusion, incontinence, and poor nutrition. He was treated with steroids. Nine days after the first operation, he had a second operation, again under anesthesia, con- sisting of a ventriculocaval shunt, shunting spinal fluid from ventricles through the jugular vein to the vena cava. After this, he remained confused, incontinent, difficult to manage, and hypotensive, with continuing evidence of spinal fluid pressure. On the last day of life, he bled from the nose and showed retinal hemorrhages, hemiplegia, bilateral fixed pupils, and moderate hypotension in spite of steroids. He died 5 days after the second operation, and 14 days after the first operation. He was never noticed to be jaundiced in life. Necropsy Findings: 1. Astrocytoma, grade I I midline and third ventricle, persistent, replacing and ob- structing the third ventricle. 2. Intraventricular hemorrhage, right cere- bral hemisphere. 3. Massive liver necrosis (infectious hepa- titis^ 4. Cerebral edema. 5. Pulmonary edema and congestion. SUMMARY OF CASE 100 History: This 39-year-old Japanese man, who had been born in the United States but had lived in Japan for the last 15 years, had a 5-month his- tory of indigestion and pain on an empty stomach with a 15-lb weight loss. One month before the final hospitalization, a laparotomy was per- formed in a hospital in Japan, where it was found that he had carcinoma of the stomach ex- tending to the transverse colon, transverse meso- colon, and greater omentum. Nothing other than biopsy was done. No blood was given. One month after the laparotomy in Japan, he was admitted finally to a hospital in the United States for de- finitive surgery. Physical Examination: He was well nourished and not jaundiced. There was a healing upper abdominal incision. No abdominal mass or ten- derness was noted. Blood pressure was 140/80. Clinical Course: Preoperatively, he was treated with blood and antibiotics. Three days after ad- mission to the hospital, or 1 month after opera- tion 1, he underwent operation 2, consisting of a total gastrectomy, splenectomy, and resection of the transverse colon, tail of the pancreas, and greater omentum for carcinoma of the stomach. It was later found that carcinoma extended to the proximal surgical margin. Postoperatively he did well for the first 10 days, and then abruptly developed chills, fever to 40 C, and evidence of paralytic ileus or small bowel obstruction. He was treated with antibiotics and various small intestinal tubes. X-rays showed subphrenic abscess with associated small bowel obstruction. Twenty-three days after operation 2, or about 2 months after operation 1, he had opera- tion 3, consisting of incision and drainage of the left subphrenic abscess. Later, he deteriorated and became febrile. From the 3rd postoperative day onward, he was jaundiced, with confusion, depression, flapping, tremor, and finally con- vulsions and other neurologic symptoms. He died 10 days after after operation 3, 33 days after operation 2, 36 days after final admission to the hospital, and 2 months after operation 1. Necropsy Findings: 1. Acute hepatitis. 2. Pulmonary edema, diffuse, marked. 3. Diffuse bronchopneumonia. 4. Gastrointestinal hemorrhage, marked, terminal. 5. Left subdiaphragmatic abscess with drain in place. SUMMARY OF CASE 122 History: This 58-year-old woman entered the hospital for evaluation of multiple problems, in- cluding known cholelithiasis, a tumor of the left breast known for 20 years, and cardiac enlarge- ment. She had no history of jaundice, cardiac symptoms, or cardiac failure. Physical Examination: She was obese, had a palpable tumor in the left breast, had an umbil- ical hernia, was not jaundiced, had no abdominal mass or tenderness, and had a blood pressure of 160/90. Clinical Course: X-rays confirmed the presence of gallstones and a hiatus hernia. The chest film showed cardiac enlargement, suggestive of pericardial effusion. She had four operations under general anesthesia. The first was esoph- agoscopy, a brief, uneventful procedure. The second, 6 days after the first, was the largest 116

operation, including excision biopsy of multiple fibroadenomata of the left breast, cholecystectomy with operative cholangiograms, which were nor- mal, pericardial aspiration and pericardial biopsy performed through the diaphragm, hiatus hernia repair, and umbilical hernia repair. At this op- eration it was seen that the liver was normal. After the second operation, she did well until the 12th day, when it was noted that there was separation of the midline abdominal wound down to the fascia. The wound was irrigated with hydrogen peroxide. Then 19 days after operation 2, she had operation 3, a brief procedure in which the abdominal incision was debrided and packed with iodoform gauze. Operation 4 was 4 days after operation 3, and in this the packing was removed and the pre- viously placed retention sutures were tied. Shortly after this, she became febrile to 103 F, with confusion progressing to coma and jaundice, which became deeper and was accompanied by liver flap. She became hypotensive the last 2 days of life, her urine output ceased, she had a tracheostomy under local anesthesia, and she remained deeply jaundiced. She died 5 days after operation 4, 9 days after operation 3, 28 days after operation 2, 34 days after operation 1, and 43 days after admission to the hospital. Necropsy Findings: 1. Acute infectious hepatitis, with hepatic insufficiency and jaundice. 2. Pulmonary edema. 3. Diffuse fibrous pericarditis. 4. Edema of the kidneys. SUMMARY OF CASE 127 History: This 44-year-old white man had been in the hospital 1 month before, at which time he had a 4-month history of anorexia, weakness, weight loss, abdominal cramps, and constipation, and a 2-month history of dyspnea on exertion and left chest pain. Before admission to the hospital, he had been treated with hexylresorcinol, for an unknown period in unknown dosages, for intes- tinal parasites. He was emaciated and had two firm masses in the right side of the neck, the bi- opsy of which showed metastatic undifferentiated carcinoma. X-rays showed a left upper lobe in- filtrate and a 3 x 4-cm mass in the left In him. The small bowel series was interpreted as show- ing narrowing and ulceration of the terminal jejunum, most likely malignant tumor. Labora- tory tests included: PCV, 28; hemoglobin, 9.3; sedimentation rate, 60; WBC, 8600; alkaline phosphatase, 2.1; acid phosphatase, 0.441; SGOT, 8; SCPT, 6; BUN, 10; and uric acid, 3.1. Stool showed occult blood. Prothrombin time was 65 percent and rose to 100 percent with vitamin K. He was thought to have carcinoma, metastatic from the small intestine to the chest and cervical lymph nodes, and was treated with fluorouracil and then transferred to another hospital and finally to his home. One month later, because of continued weak- ness and weight loss, progressive dyspnea and chest pain, and particularly regurgitation of food or vomiting, he was admitted finally. Physical Examination: He was pale and cadav- erous, weak, hoarse, and confused. Blood pres- sure was 98/60. He was not jaundiced. There was no abdominal mass or tenderness. There was dullness over the left half of the chest. Clinical Course: On the 2nd hospital day, tho- racentesis of 2300 cc was performed, with little improvement in his dyspnea. He continued to vomit and was thought to have small bowel ob- struction. On the 4th hospital day he underwent exploratory laparotomy under general anesthesia and was found to have two obstructing lesions in the proximal ileum; these were bypassed with two side-to-side enteroenterostomies. He did well until the 6th postoperative day, when he de- veloped evidence of pericardial effusion with cardiac tamponade. Pericardiocentesis was per- formed twice and nitrogen mustard was instilled into the pericardium. He did poorly after this, and died 1 day after the pericardiocentesis, or 8 days after the operation. Necropsy Findings: 1. Adenocarcinoma, bronchogenic, left upper lobe bronchus, with metastases to hilar lymph nodes, pericardium, epicardium, adventitia of descending aorta, jejunum, mesenteric lymph nodes, periaortic lymph nodes, and right adrenal gland. 2. Pericardial effusion, 1100 cc; right pleural effusion, 600 cc; left pleural ef- fusion, 900 cc; ascites, 400 cc. 3. Bronchopneumonia, left lung. 4. Congestion and edema, right lung. 5. Congestion, central, with necrosis, mod- erately severe, liver. SUMMARY OF CASE 135 History: This 56-year-old white woman entered the hospital as an emergency because of acute pain in the right lower extremity. She had been well until 24 hr before the final admission, when she developed severe pain in the right shoulder and chest. This pain gradually decreased, but 12 hr before the final admission, she developed in- creasing pain in the right chest, the left side of the abdomen, and the right lower extremity. Physical Examination: She was well nourished and in considerable distress. She was not jaun- diced. Blood pressure was 140/80. There was no abdominal mass or tenderness. The right femoral pulse was absent. The right lower extremity was colder than the left . Clinical Course: She was thought to have had an embolism to the right femoral arteryand was taken directly to surgery. She had an embolectomy of the right common iliac artery and an appendectomy. 334-553 O-69—9 117

Following surgery, the pulse, color, and temperature of the right lower extremity re- mained good, but she was found to have different blood pressures in the two arms (95/60 on the right and 75/50 on the left), and systolic murmur beneath the left clavicle. On the 2nd day, the left radial and the right dorsal pedal pulses became weaker, the murmur became louder, and finally she was found to have no blood pressure in the right arm. She died 2 days after surgery and ad- mission to the hospital. She was never jaundiced. Necropsy Findings: 1. Generalized arteriosclerosis. 2. Dissecting aneurysm of the ascending aorta with rupture and cardiac tamponade, 120 cc. 3. Focal atelectasis. 4. Central necrosis of the liver. 5. Infarction of the kidney, recent, right. SUMMARY OF CASE 156 History: This 41-year-old man was readmitted to the hospital because of anemia and weakness. He had been known to have myelogenous leukemia for 4 years. He had previously received radiation therapy to the spleen, radioactive phos- phorus, Myleran, and numerous blood transfu- sions, although details of this treatment are not available. He had been admitted to the hospital 7 months before the final admission because of weakness and dyspnea on exertion. At that time, the WBC was 3900; RBC, 3.29 million; hemoglobin, 9.2; and platelets, 394,000. He was treated with blood and radiation. He had been admitted 4 months before the final admission. At that time, the WBC was 46,000; platelets, 700,000; and hemoglobin, 10.8. He was again treated with radiation to the spleen. Physical Examination: He was well nourished but appeared to be chronically ill. He was pale but not jaundiced. The spleen was greatly en- larged, filling most of the abdomen. Clinical Course: The patient had two operations, the first being an elective splenectomy and gas- trostomy. The details of the preparation of this operation, the course of the operation, and the postoperative course are not available, but it is known that the patient developed intraperitoneal bleeding and had a second operation in which, apparently, it was impossible to control the bleed- ing, so that numerous packs and drains were left in. Details of blood pressure, urine volume, and the presence or absence of jaundice are not avail- able. The chronologic relationships of surgery to death are not known, except for the fact that he died 3 days after the first operation. Slight jaundice was present at necropsy. Necropsy Findings: 1. Hepatic necrosis, diffuse, moderately severe. 2. Chronic myelogenous leukemia with anemia, thrombocytopenia, hemorrhagic diathesis. 3. Hemoperitoneum, 6000 cc. 4. Lower nephron nephrosis. SUMMARY OF CASE 185 History: This 57-year-old man entered the hos- pital for elective definitive surgery for a duo- denal ulcer, known to have been present for 5 years. He had been on medical treatment, the de- tails of which are not available. He gave a history of painless jaundice 5 years before admission, clearing in 1 week, for which he was not studied medically. Physical Examination: He was well nourished and not jaundiced. Blood pressure was 140/80. There was no mass or tenderness in the abdo- men. Clinical Course: After 2 days in the hospital he had an elective operation for a subtotal gastrec- tomy, gastrojejunostomy, and appendectomy, under spinal and general anesthesia. He did well postoperatively until the 4th day, when he became hypotensive and showed evidence of bleeding through his nasogastric tube. There was good response to transfusion of blood, dex- tran, and Levophed, and the bleeding apparently stopped. On the 6th day there was evidence of wound infection and more nasogastric bleeding. On the 7th postoperative day he was found to have both upper and lower gastrointestinal bleeding and was taken to surgery in shock; a laparotomy was performed under general anes- thesia. He was found to have blood in his stomach and in his free peritoneal cavity, although no source for bleeding was found. The procedure consisted of laparotomy, exploratory gastrotomy, and splenectomy, with transfusion of 3500 cc of blood. After this, he was hypotensive in spite of being given blood, Levophed, and dextran; was oliguric; and had poor clearing of his respira- tory tract, requiring a tracheostomy, which was done under local anesthesia. He was first noted to be jaundiced 18 hr after the second operation and died 19 hr after the second operation. Necropsy Findings: 1. Acute hepatic necrosis with jaundice. 2. Hemorrhage into the gastrointestinal tract. 3. Hemoperitoneum, with fibrinous perito- nitis. 4. Acute toxic nephrosis. 5. Severe coronary arteriosclerosis. 6. Pulmonary congestion, edema, atelec- tasis, and pneumonia. 118

SUMMARY OF CASE 205 History: This 58-year-old man, known to have rheumatoid arthritis, entered the hospital be- cause of fever. He had had arthritis for at least 3 years, involving his knees and ankles, and had been on adrenal steroids all that time. Nine weeks before admission, he developed increased pain in his back, as well as fever, was hospitalized else- where, and was given higher doses of adrenal steroids. One month before this admission, he was hospitalized elsewhere and was started on ACTH, four units/day, which had been continued until the time of admission, and had been given Chloromycetin for 4 days. Physical Examination: He appeared to be chronically ill, was slightly jaundiced, and was having a shaking chill. He had a maculopapular rash over his face. The liver was palpable two fingerbreadths below the costal margin and there was definite right upper quadrant tenderness. Clinical Course: In his first 4 days in the hos- pital, he was studied very extensively, prin- cipally for arthritis, jaundice, and high swinging fever, as high as 106 F. On the 5th day he under- went an operation because of the continuing fever, jaundice, development of a liver flap, right upper quadrant tenderness, and a palpable mass that was thought to be the gallbladder. The operation, performed under general anesthesia, consisted of a cholecystectomy, common bile duct exploration, and liver biopsy. There were stones in the gallbladder, but none in the common bile duct. The common bile duct was not dilated or thickened. The liver did not appear normal. Postoperatively, he did well the first few days, but became disoriented, more deeply jaun- diced, confused, and comatose, developed liver flap, passed dark blood through his nasogastric tube, passed practically nothing through his T-tube, and, terminally, became oliguric and developed peripheral edema and pulmonary con- gestion. He died 8 days after surgery, or 12 days after admission to the hospital. He was hypoten- sive throughout his entire hospital course, in- cluding before, during, and after the operation. Necropsy Findings: 1. Central lobular necrosis of liver, mas- sive, ? toxic etiology. 2. Fat necrosis of pancreas. 3. Chronic arthritis. 4. Hemorrhage, fresh, moderate, subarach- noid space, left frontotemporal region, Sylvian fissure over left cerebral hemi- sphere, source undetermined. SUMMARY OF CASE 222 History: This 44-year-old man entered the hos- pital for elective cardiac surgery for aortic stenosis. He had been known to have a heart murmur since the age of 6 and had had easy fatigue all his life, increasing in the past 5 years, and ac- companied by dyspnea on exertion. For 2 years he had had substernal pain with exercise, and had taken reserpine, 0.25 mg/day, as an "anti- thyroid" medication and Preludin, three times a day, for control of weight. He was allergic to sulfas. He had been in the hospital for 3 days, 4 months before, when cardiac catheterization per- formed under local anesthesia showed findings compatible with aortic stenosis. Laboratory find- ings at that time were: hemoglobin, 13.8; PVC, 46.5; WBC, 10,500; urinalysis, normal; BUN, 16; sodium, 139; potassium, 4.5; chloride, 104; CO2 combining power, 31; calcium, 10.8; phosphorus, 3.7; alkaline phosphatase, 2.2; bilirubin, total 1.4, direct 0.4, and indirect 1.3; BSP retention, 0; prothrombin time, 100 percent; and trans- aminase, 14. He was discharged with instructions to lose weight, which he did, and then was ad- mitted for elective surgery. Physical Examination: He was well nourished, had evidence of cardiac enlargement, had a sys- tolic murmur and a probable diastolic murmur, had no jaundice, and had no abdominal mass or tenderness. Blood pressure was 110/68. Clinical Course: After 5 days in the hospital, he had an aortic valvulotomy and open-heart pro- cedure, under general anesthesia, with unknown drugs, involving a rotating-disk pump oxygenator, with potassium-induced cardiac arrest. At the end of the operation, he had leaking from the aortic suture line, and ventricular fibrillation requir- ing several drugs and 27 defibrillating shocks. Time on the pump was 68 min. There was con- siderable bleeding from the chest wall during the closure. In the recovery room he became jaundiced and then cyanotic, had evidence of continued bleeding from his chest tubes, became hypo- tensive down to 80/60, and required a consider- able amount of blood. For the first 3 postoperative days, he re- mained jaundiced and oliguric, with no urine output, and on the 4th day he was dialyzed on an artificial kidney because of his rising serum potassium level. He developed atrial fibrillation, paroxysmal atrial tachycardia, and congestive heart failure, and died 5 days after surgery. He was not hypotensive in the last few days, but re- mained jaundiced and oliguric. Necropsy Findings: 1. Rheumatic heart disease with calcific aortic stenosis and cardiac hypertrophy. 2. Acute passive congestion of lungs and spleen. 3. Acute passive congestion of the liver with centrilobular necrosis. 4. Ischemic nephrosis. 119

SUMMARY OF CASE 223 History: This 55-year-old woman had been known to have an esophageal hiatus hernia for 3 years, manifested by pain after eating, with nausea and vomiting, but never with the vomiting of blood. Two months before her final hospital ad- mission, she had an exacerbation of her chronic stasis ulcers of her legs and was placed on bed- rest with the feet elevated. This made the symp- toms of the esophageal hiatus hernia much worse. After 2 months of elevation of the feet she was allowed to walk again; the symptoms of the hiatus hernia were still severe. Accordingly, she was admitted for study. Twenty years before, she had allegedly suf- fered ^ead^oisoning- by inhaling fumes or dust from painting. This was manifested by the loss of hair and easy bruising, poor healing, and bleed- ing from minor wounds, which she had allegedly had for 20 years. She had been on Diamox and Diuril. Physical Examination: She was obese, pale, and not jaundiced. Blood pressure was 90/55. The abdomen was obese, with no mass or tenderness. There were edema and stasis changes of both legs. The femoral pulses were palpable, but no pulses were palpable distally. Clinical Course: She was found to be markedly anemic, and was studied very intensively for the cause of the anemia. The only thing that could be proved was an abnormality of thromboplastin generation. On her llth day in the hospital, she suddenly developed severe pain, numbness, and coldness and mottling of both lower extremities, was found to have no femoral pulses, and was thought to have thrombosis of the aorta. Accordingly, she underwent an emergency operation in which she was found to have thrombosis of the abdominal aorta, iliac arteries, and left femoral artery; for this she had a Teflon bypass graft from the ab- dominal aorta to the right common femoral artery. She was incidentally found to have acute cholecystitis with gangrene, and a cholecystostomy was done. After this, the right leg was warm tempo- rarily, but within 1 day both legs were cold, the pulses had again disappeared, and her urine volume fell to less than 300 cc/day. She never became jaundiced. Details of blood pressure terminally are not known. She died 3 days after surgery, and 14 days after admission to the hos- pital. Necropsy Findings: 1. Thrombosis of the abdominal aorta from below the superior mesenteric artery distally, with thrombosis of common iliac and femoral arteries and thrombosis of the right femoral vein and right surgical aorticofemoral prosthesis. 2. Ischemic nephrosis. (There was marked narrowing of both renal artery orifices.) 3. Central zone and confluent necrosis of liver with hepatitis. 4. Thrombosis of the splenic artery with multiple splenic infarcts. 5. Infarction of the gallbladder. 6. Thrombi in pulmonary arteries. 7. Hyperemia and atelectasis of the lungs. 8. Acute and chronic cholecystitis with re- cent cholecystostomy. 9. Pancreatitis, with fat necrosis. 10. Esophageal hiatus hernia, with gastric hemorrhages. 11. Bilateral adrenal cortical adenomata. 12. Obesity. 13. Multiple cysts of liver. SUMMARY OF CASE 234 History: This 26-year-old man entered the hos- pital for elective surgery on the aortic valve and ascending aorta. He had been known to have Marfan's syn- drome for a number of years. Three months be- fore the final hospital admission, he underwent right heart catheterization, and special x-ray studies under local anesthesia showed dilatation of the aortic ring. He had no history of conges- tive heart failure. He had been on digitalis for 4 months before the final hospital admission. Physical Examination: He was tall, well de- veloped, and well nourished, with long thin fin- gers, ectopic lenses, and pectus excavatum. He had the findings of aortic insufficiency and left ventricular hypertrophy. He was not jaundiced and there was no adbominal mass or tenderness. Blood pressure was 140/50 in the left arm and 60/40 in the right arm. Clinical Course: Three days after admission to the hospital, he underwent resection of the as- cending, aorta with plastic repair of the aortic valve am' excision of one of the three valve leaf- lets done with total cardiac bypass on a heart- lung machine with hypothermia. The operation lasted 9 hr. with bypass time of 1 hr 36 min, and with a 31 - min period of difficulty in restart- ing the heart. Postoperatively, he remained hypotensive and intermittently comatose, with changing neurologic signs and with jaundice on the 2nd day. Cyanosis with ecchymosis, edema, ascites, and decerebrate rigidity preceded his death 11 days after surgery, and 14 days after admission to the hospital. During this postoperative period, dehiscense of his chest wound occurred twice, and peritoneal dialysis was performed twice. Necropsy Findings: 1. Marfan's syndrome, with arachnodactyly, arched palate, bilaterally, subluxated lenses, pes cavus, and hammer toes. 120

2. Dissecting aneurysm, thoracic and ab- dominal aorta. 3. Aortic insufficiency. 4. Left ventricular hypertrophy, 790 g. 5. Bilateral hemothorax: left, 800 cc; right, 600 cc. 6. Pulmonary congestion, edema, and hem- orrhage, marked. 7. Acute tubular nephrosis ("shockkidneys"). 8. Uremic pericarditis, uremic pleuritis, "uremic pancreatitis," and "uremic frost." 9. Centrilobular congestion and necrosis of the liver, marked. 10. Hemorrhagic gastritis. 11. Cerebral hemorrhages, multiple, terminal. SUMMARY OF CASE 255 History: This 49-year-old woman entered the hospital for elective surgery of lymphosarcoma of the intestines, diagnosed elsewhere. She had been transiently jaundiced at the age of 9. No other information was available about this episode. She had never been jaundiced at any other time. Three years before the final hospital ad- mission, she developd abdominal pain and was thought, on the basis of x-rays, to have ulcerative colitis; she improved on medical treatment. Two months before the final hospital ad- mission she was found, on a routine examination, to have an enlarged uterus. She had an explora- tory laparotomy in another hospital, and a bilat- eral salpingo-oophorectomy and total hysterec- tomy. The uterus showed myomata and adenosis. During the operation, three "sacculations" were found on the small intestines, and two of these were resected and later found to show lympho- sarcoma involving the small intestines. After this, she did well, was discharged, and was re- admitted 6 weeks later for elective surgery. Physical Examination: She was well nourished and not jaundiced. Blood pressure was 130/80. The liver was palpable 2 cm below the right costal margin, and the spleen 2 cm below the left costal margin. Clinical Course: She was studied very carefully in a cancer research institute, and 42 days after admission had her second operation. This was an exploratory laparotomy and biopsy of a mes- enteric lymph node, which showed lymphosarcoma. There was involvement of the left lobe of the liver, enlargement of the spleen, and extensive involvement of the mesenteric lymph nodes and the mesentery. No definitive resection was car- ried out. Her course after this was - ".eventful. Nine- teen days after surgery, she had chemotherapy with nitrogen mustard, 0.4 mg/kg, for a total dose of 20 mg. She did reasonably well after this, but 4 weeks after surgery gradually devel- oped back pain, jaundice, and confusion, pro- gressing to coma with a liver flap, fever as high as 102 F, gastrointestinal bleeding, hypo- tension, and death, 35 days after operation, 77 days after admission to the hospital, and 138 days after the original operation and diagnosis of lymphosarcoma. Necropsy Findings: 1. Malignant lymphoma (lymphosarcoma) with infiltration of stomach, intestines, submaxillary salivary gland, mesenteric lymph nodes, liver, and spleen. 2. Acute massive necrosis of the liver. 3. Cerebral edema. 4. Regurgitation and aspiration of gastric contents. 5. Acute tracheobronchitis. 6. Focal pulmonary edema and hemorrhage. 7. Bile nephrosis. SUMMARY OF CASE 328 History: This 27-year-old woman was re- admitted to the hospital 38 days postpartum because of anorexia, nausea, vomiting, fever, and malaise of 9 days' duration. During the 26th week of her pregnancy, she had been admitted to the hospital for 4 days for vaginal bleeding, which cleared with no specific measures. She was then re-admitted in the 30th week of pregnancy, i.e., 38 days before the final admission, with a large amount of sudden, pain- less third-trimester bleeding. She was hypoten- sive with a pressure of 60/40, and remained so for about 2 hr. Examination showed complete placenta previa, and within 2 hr of admis- sion, an emergency low cervical cesarean sec- tion under general anesthesia was performed, in which she was delivered of a 1700-g living child. During the cesarean delivery, which lasted about 45 min, her blood pressure returned promptly with transfusion from 100/60 to 120/80. She re- ceived a transfusion of a total of 2000 cc of blood before and during the cesarean delivery. The baby died at the age of 18 hr and autopsy showed pre- maturity and hyaline membrane disease. In her postoperative course, the mother received Er- gotrate, penicillin, streptomycin, Demerol, and 1000 cc of blood, 2 days postpartum. Her post- partum course in the hospital was otherwise un- eventful and she was discharged 9 days post- partum with a PCV of 33. She remained home for 1 month and was essentially well until 5 days before the final ad- mission, when she developed anorexia, nausea, vomiting, fever as high as 105 F, malaise, and dark urine, although she had not noted jaundice. The history was later reviewed in detail with the patient and relatives, and no history of exposure or ingestion of toxins could be uncovered. Physical Examination: She was severely ill, slightly jaundiced, vomiting, and disoriented. Temperature was 39 C, pulse 112, and blood pressure 100/70. The liver was palpable 121

two fingerbreadths below the right costal margin and was smooth and moderately or questionably tender. Clinical Course: In her 2 days in the hospital, she became more irritable, disoriented, and mor.e deeply jaundiced, anddevelopedecchymosis, first over her legs and then all of her body. She then developed decerebrate rigidity. Bleeding was seen from intravenous infusion sites, and a tracheostomy was performed under local anes- thesia, with some difficulty caused by oozing of blood at the incision. A lumbar puncture was negative. Her urine output diminished to 600 cc per 24 hr. She died 2 days after admission to the hospital, and 40 days after the cesarean section. Necropsy Findings (coroner's necropsy): 1. Massive necrosis of liver. 2. Hypostatic congestion and edema of the lungs. 3. Toxic nephrosis. 4. Multiple ecchymoses. 5. Cerebral edema. SUMMARY OF CASE 338 History: This 14-year-old white girl entered the hospital for elective cardiac surgery. She had been known to have congenital heart disease since birth, and had always had dyspnea on exertion, decreased exercise tolerance, cyanosis with exercise, and frequent upper res- piratory infections. One month before, she had been admitted for cardiac catheterization and cineangiograms, which showed interventricular septal defect and infundibular stenosis. She had never been jaundiced and was on no medications. Physical Examination: She was well developed, cyanotic, and not jaundiced. Bleod pressure was 110/60. The heart was not enlarged but had a systolic murmur. The liver was not palpable. Clinical Course: Two days after admission, she underwent a procedure for closure of an inter- ventricular septal defect, resection of infundi- bular stenosis, and tracheostomy under total cardiopulmonary bypass on a heart-lung ma- chine with hypothermia. She tolerated this procedure and was doing well until the 8th day, when she abruptly be- came febrile and hypotensive, and was thought to have pulmonary embolism or septicemia. She was treated with blood, antibiotics, and steroids, became anuric, never became jaundiced, but died 9 days after surgery, and 11 days after admis- sion to the hospital. Necropsy Findings: 1. Tetralogy of Fallot. 2. Multiple foci of acute myocardial necro- sis. 3. Severe acute and chronic passive con- gestion and edema and hemorrhage in both lungs. 4. Diffuse interstitial pneumonia. 5. Atelectasis of lower lobes. 6. Acute passive congestion of viscera. 7. Massive acute central necrosis of liver cells. 8. Ascites. 9. Bilateral pleural effusion. SUMMARY OF CASE 345 History: This 34-year-old police officer entered the hospital with a history that shortly before ad- mission he had suddenly become delirious, with marked confusion, belligerent behavior, and thrashing about, possibly moving the right upper and lower extremities more than the left. There was a history of heavy alcoholic intake, but fur- ther details were not available. Physical Examination: He was belligerent, un- cooperative, and complaining of headache, and had a stiff neck. Blood pressure was 145/80. He was not jaundiced, and there was no abdominal mass or tenderness. He had bilateral positive Babinski sign. Clinical Course: Lumbar puncture showed bloody spinal fluid under increased pressure. A right carotid arteriogram performed under local an- esthesia showed an aneurysm at the bifurcation of the right internal carotid artery into the an- terior and middle cerebral arteries. Two days after admission, he had a right frontotemporal craniotomy, under hypothermia, with clipping of the aneurysm. This involved 28 min of clamping temporarily of the internal carotid artery. After this operation he did well, except for slight weakness on the left side. Nine days after surgery he became confused, with left homonymous hemianopsia, with increasing weakness on the left. A second right carotid arteriogram showed a shift in the right anterior and middle cerebral artery, and pneumoenceph- alogram showed a mass, or swelling, in the left posterior temporal region. Accordingly, 11 days after operation 1, he underwent operation 2, which was a repeat craniotomy in which swelling, but no other spe- cific finding, was found. After the second opera- tion, he was confused and still weak on the left side, and developed seizures on the left; 6 days after operation 2, he became hypotensive, to the level of 80/60, and jaundiced. The jaundice was thought to be on the basis of hemolysis. He was given blood and hydrocortisone, but died 1 day after the onset of jaundice, 7 days after operation 2, 18 days after operation 1, and 19 days after admission to the hospital. Necropsy Findings: 1. Encephalomalacia at the base of the right temporal lobe, 4x6 cm. 122

2. Pulmonary edema and congestion, acute. 3. Fatty infiltration and necrosis of the liver. 4. Extradural hematoma in the right fronto- temporal area, 10 or. 5. Recent hemorrhage in atheromatous plaque of the wall of the right middle cerebral artery. SUMMARY OF CASE 352 History: This 75-year-old white man, who was an active working farmer, was admitted with a small bowel obstruction, as a transfer from another hospital. Twenty-four years before, he had had an operation elsewhere for a small bowel obstruc- tion due to adhesions. Twenty years before, he had had another operation for a strangulated femoral hernia. Three weeks before the final hospital ad- mission, cramping abdominal pain developed and a week later, he was admitted to another hospital at which he received unknown medications and from which there is no information as to what was done, except that no surgery was performed. Four days before the final transfer, he developed vomiting and abdominal distention and was found to have bowel obstruction. He had never been jaundiced. Physical Examination: He was thin, acutely ill, and dehydrated, but not jaundiced. Blood pressure was 150/90. The abdomen was distended and ten- der, without rigidity or mass. Bowel sounds were hyperactive. Clinical Course: He was treated with a Cantor small intestinal tube for 2 days with replace- ment of fluids and electrolytes and with blood and antibiotics, but without improvement of his small bowel obstruction. Two days after admission, an exploratory laparotomy was performed, with divisions of ad- hesions and repair of an accidental perforation of the small intestine. There was considerable contamination of the peritoneal cavity with in- testinal contents. After surgery he was always hypotensive and most of the time was cyanotic with rapid respirations, poor cough, inability to clear se- cretions, and temperature as high as 105 F. He became jaundiced after surgery shortly before death. He died 1 day after surgery, 3 days after admission to the hospital. Necropsy Findings: 1. Generalized peritonitis secondary to perforation of ileum (repair of ileum in- tact at autopsy). 2. Moderately severe hepatitis (possibly in- fectious) with mild jaundiced 3. Pulmonary emphysema with bronchopneu- monia. SUMMARY OF CASE 363 History: This 51-year-old man entered the hos- pital with a 4-month history of weakness, 20-Ib weight loss, diarrhea of eight watery stools per day, anorexia, dark urine, and light stools. He had a 1-month history of progressive ab- dominal enlargement and jaundice. He had been taking unknown shots and pills in a doctor's of- fice for 4 months. He had been an alcoholic for 20 years, but allegedly had had no alcohol for 5 months. No further information is available as to the amount of alcohol. Physical Examination: He was thin and deeply jaundiced. The abdomen was markedly distended with ascites; there was vague right upper quadrant tenderness, but no mass. Blood pressure was 120/70. Clinical Course: X-rays showed complete pyloric obstruction. In his first few days in the hospital, he did poorly, continued to vomit, had slight blood tinging of the vomitus, and had paracentesis of 500 cc of fluid, which showed Class III cells on cytologic examination. Five days after his admission, an exploratory laparotomy was performed and he was found to have carcinoma of the pancreas, with metastasis to the peritoneum, small intestine, diaphragm, and liver, and with obstruction of the common duct up to the cystic duct. The procedure con- sisted of a palliative gastrojejunostomy and chole- dochojejunostomy. After this operation he became confused, had marked fluid and electrolyte imbalance, gradually deteriorated, remained jaundiced, and died 4 days after surgery, and 9 days after admission to the hospital. Necropsy Findings: 1. Adenocarcinoma of the head of the pan- creas, undifferentiated, with metastasis to peritoneum, liver, diaphragm, lungs, adrenals, small intestine, and muscle. 2. Obstructive jaundice. 3. Ascending cholangitis and hepatitis. 4. Bile nephrosis. 5. Gastric dilatation, marked. (Stomach ex- tended down to the pelvis at necropsy.) 6. Pulmonary edema. 7. Pulmonary infarction, recent. 8. Bilateral pleural effusion. SUMMARY OF CASE 605 History: This 59-year-old white man, a mer- chant seaman, entered the hospital because of coughing up blood. Two years before the final hospital admis- sion he had had a gastrectomy for carcinoma of the stomach, which was said to be a "carcinoma simplex," localized to the pylorus of the stomach and adherent to the gallbladder. 123

He had been on Thorazine, 25 mg four times a day, for 2 years before the final hospital ad- mittance, for nervousness. Alcoholism was denied. Physical Examination: He was poorly nourished and appeared chronically ill. He was not jaun- diced. Blood pressure was 120/80. There was no abdominal mass or tenderness. Clinical Course: An x-ray and sputum examina- tion showed far-advanced pulmonary tuberculosis with cavitation, and for this he was treated with drugs and remained in the hospital for a total of 3 years 7 months. His sputum became negative. Two months before death he became jaun- diced for the first time, and developed epigastric tenderness, dark urine, light stools, and enlarge- ment of the liver to five to six fingerbreadths be- low the right costal margin. All of the time in the hospital he had been on Thorazine, 10 mg three times a day. The jaundice was thought to be due to the Thorazine. He was studied and observed for the jaundice for 47 days and finally underwent an exploratory laparotomy, cholecystectomy, common bile duct exploration, and liver biopsy. The common bile duct was thickened, but no stone was found. Mi- croscopic examination was interpreted as show- ing metastasis of the carcinoma from the stomach to the gallbladder. No other evidence of car- cinoma was found. The liver biopsy showed ne- crosis, acute inflammation, and biliary stasis. After the operation, he became more deeply jaundiced, vomited blood, was given blood by transfusion, was hypotensive the last 3 days of life, and died 9 days after surgery, 2 months after the onset of jaundice, and 3 years 7 months after admission to the hospital. Necropsy Findings: 1. Carcinoma of the stomach, 5 years after subtotal gastrectomy, infiltrating and un- differentiated (by history). 2. Periportal metastases (by surgical speci- men). 3. Obstructive jaundice. 4. Bile nephrosis. 5. Acute necrosis of the liver. 6. Generalized peritonitis. 7. Chronic gastritis with ulceration and gas- trointestinal bleeding. SUMMARY OF CASE 609 History: This 13-year-old white girl entered the hospital for elective surgery for interatrial septal defect. She had been known to have a heart murmur since the age of 5 months. She had had cardiac catheterization at the age of 3 years, and had been found to have a septal defect. She had never had symptoms of cardiac disease and had never been jaundiced. Two months before the final hospitalization, she had been admitted for 2 days for cardiac catheterization, which had shown findings of an interatrial septal defect. She had received peni- cillin and other injections at that time. Physical Examination: She was well nourished and not jaundiced. Blood pressure was 130/80. There were diastolic and systolic murmurs along the left sternal border. There was no abdominal mass or tenderness. Clinical Course: Two days after her admission to the hospital she had repair of the interatrial septal defect under hypothermia, with total car- diopulmonary bypass on a heart-lung machine. During this procedure, she had ventricular fibrillation during most of the repair. On the 1st day she was transiently hypotensive to 60/40. On the 2nd day she started to have convulsions, originating in the left upper extremity. After 1.5 hr of this, she had cardiac arrest from which she could not be resuscitated. Details of urine volume are not clear. She was never jaundiced. She died 2 days after surgery and 4 days after admission to the hospital. Necropsy Findings: 1. Interatrial septal defect, repaired. 2. Pulmonary edema. 3. Hemorrhagic centrilobular necrosis of the liver. 4. Acute tubular necrosis of the kidneys. Comment by Pathologist: "Death in this patient cannot be adequately explained on the basis of the anatomic findings." SUMMARY OF CASE 616 History: This 81-year-old white man entered the hospital shortly after a fall because of a fractured hip. Only a vague history was available that he had been markedly short of breath for at least 5 years. Physical Examination: He was confused, cyanotic, dyspneic, and unable to give a history. He was judged to be in critical condition. He was not jaundiced. Blood pressure was 70/40, pulse was 120, and respiration was 42. He appeared to be in marked respiratory distress and insufficiency, with diffuse wheezes, rales, and rhonchi. There were signs of cardiac enlargement. The abdo- men was distended, but there was no abdominal mass. Clinical Course: He was treated very intensively on a medical ward for 10 days before the surgery for his fractured hip. He had ileus, which was treated with a nasogastric tube that returned ma- terial with traces of blood in it. He had severe chronic bronchitis with obstructive emphysema, 124

and for this he was treated with a respirator for 10 hr and then numerous medical measures. He had urinary retention, treated with a catheter. He had hypotension, treated with a Neo-syn- ephrine drip. Ten days after admission, he had placement of a prosthesis in his left hip. Following this, he gradually improved and by the 9th day was ready to be discharged, when he suddenly began vomit- ing blood. He was hypotensive and bleeding failed to be stopped with conservative measures. Ten days after the first operation and 20 days after admission, he underwent a second procedure, which included esophagoscopy, 50 percent subtotal gastrectomy, vagotomy, gas- troduodenostomy, liver biopsy, and tracheostomy. After this procedure, he never did well. From the 1st day onward he was hypotensive and de- pendent on a vasopressor. He bled from around his tracheostomy, passed dark bloody material by rectum, became oliguric, gradually deteri- orated, was never jaundiced, and died 3 days after operation 2, 13 days after operation 1, and 23 days after admission to the hospital. Necropsy Findings: 1. Final necropsy summary and microscopic reports not available. 2. Pulmonary emphysema, bilateral, marked, with extensive bleb formation. 3. Pulmonary congestion and edema, bi- lateral, marked. 4. Acute tracheobronchitis. SUMMARY OF CASE 618 History: This 5-year-old girl entered the hos- pital 3 hr after a massive abdominal injury. She had been climbing on a 100-gal weed-spraying tank with her brother and the tank fell on the two of them. She was hospitalized elsewhere and received 1000 cc of blood. No other information is available as to what happened in the other hos- pital. She arrived at the final hospital 3 hr after the injury. Physical Examination: She was well nourished and not jaundiced. Blood pressure was 110. She was in severe abdominal pain. There was diffuse abdominal tenderness and guarding. Clinical Course: Two hours after admission, she was taken to surgery and underwent an explora- tory laparotomy through an abdominal incision. She was found to have multiple extensive lacera- tions of the liver, and the procedures included an attempted repair of the lacerations and suturing of omentum into the largest of the lacerations. Abdominal drains and a chest tube were placed. After surgery she was variably hypotensive from 0 to 80, but was doing reasonably well with blood and vasopressors. She was never jaundiced. She died unexpectedly. 2 days after surgery and admission to the hospital. Necropsy Findings: 1. Fracture of the right lobe of the liver. 2. Extensive necrosis (Grade 3) of the liver, with insufficiency central necrosis. 3. Collapse of the lower and middle lobes of the right lung with- alveolar hemorrhage. 4. Cerebral edema. SUMMARY OF CASE 619 History: This 13-year-old girl entered the hos- pital for elective cardiac surgery. A heart murmur had first been discovered when the patient was 7 years old. For 2 years, the patient had had gradually increasing easy fatigue, dyspnea on exertion, and cyanosis with exertion. She had been studied at another hospital ap- proximately 1 year before and the diagnoses es- tablished had been: ventricular septal defect with left-to-right shunt, and pulmonary hypertension, but there was some uncertainty about this. Physical Examination: The child was well nour- ished, not cyanotic, and not jaundiced. Blood pres- sure was 114/50. There was a systolic murmur. There was no abdominal mass or tenderness. Clinical Course: She was thought to have ven- tricular septal defect with left-to-right shunt and pulmonary hypertension. One day after admission, she underwent a complex cardiac operation with total cardiopulmonary bypass on a heart-lung machine, and was found to have a very unusual condition involving a patent ductus arteriosus, a congenital deformity of the mitral valve, an ex- tremely large interventricular septal defect, anomalous tricuspid valves, and severe pulmo- nary hypertension. The procedures included liga- tion of the patent ductus arteriosus, partial repair of the ventricular septal defect with a Teflon pros- thesis, and attempted correction of the mitral valve deformity. It was felt that identification of the structures was not accurate and that the re- pair was unsatisfactory. After surgery, the patient was hypotensive, gradually deteriorated, was thought to have mitral and tricuspid insufficiency, and became oliguric but never jaundiced. She died 19 hr after surgery, and 2 days after admission to the hospital. Necropsy Findings: 1. Anomalous position of atrial septum with communication of right atrium with both ventricles and communication of left atrium with left ventricle through acces- sory mitral orifice. 2. Pulmonary edema. 3. Central necrosis of the liver. SUMMARY OF CASE 620 History: This 6-year-old girl entered the hos- pital for elective cardiac surgery for known tetral- ogy of Fallot. 125

She had been known to have congenital heart disease since the age of 5 months, when she be- came cyanotic with a respiratory infection. She had had gradually increasing cyanosis over the years, especially with crying and exertion. She had progressive fatigue and dyspnea with exertion, and limited physical activity and physical and mental development. She had been on oral peni- cillin. It is not known whether she had had cardiac catheterization. It is likely that this was per- formed elsewhere. Physical Examination: She was well nourished, small, moderately cyanotic, and not jaundiced. Blood pressure was 100/60. There was a systolic murmur and clubbing of the extremities. Clinical Course: One day after admission she underwent open-heart surgery, consisting of re- pair of the ventricular and atrial septal defect with reconstruction of a right ventricular outflow tract with a Teflon prosthesis. This was done with total cardiopulmonary bypass and a heart- lung machine with intentional hypothermia. She was in poor condition from the end of the opera- tion onward, with severe hypotension in spite of large doses of vasopressors. She also had cyano- sis and atrioventricular dissociation. Her urine volume fell to 175 cc/day. Terminally she de- veloped congestive heart failure with enlarge- ment of the liver. She was never jaundiced, but died 4 days after surgery, and 5 days after ad- mission to the hospital. Necropsy Findings: 1. Congestion and edema of the lung with hemorrhages. 2. Congestion and hemorrhage of Peyer's patches of the small intestine. 3. Right aortic arch. 4. Peripheral congestion of liver with cen- tral lobular necrosis. 5. Terminal aspiration of gastric contents. 6. Tetralogy of Fallot, repaired. SUMMARY OF CASE 628 History: This 6-year-old white boy entered the hospital for elective cardiac surgery for known congenital heart disease. He had been known to have heart disease since the age of 1 month, and had been cyanotic with eating and playing. At the age of 3 years, cardiac catheterization and cardiac surgery were performed elsewhere. That was 3 years before the final hospital admis- sion. At this procedure, he underwent dilatation of congenital pulmonic stenosis, and after this was less cyanotic but still had dyspnea on exer- tion. Physical Examination: He was well nourished and not jaundiced, but moderately cyanotic. Blood pressure was 90. There was a loud systolic mur- mur. No abdominal mass or tenderness was noted. There was clubbing of the extremities. Clinical Course: Cardiac catheterization under local anesthesia was performed, showing tetral- ogy of Fallot with infundibular and valvular ste- nosis, ventricular septal defect, and hypoplasia of the pulmonary artery. Seventeen days after admission, he under- went open-heart surgery, consisting of repair of the ventricular septal defect and reconstruction of the right ventricular outflow tract under total cardiopulmonary bypass on a heart-lung ma- chine with hypothermia. After surgery, his temperature rose to 104 F, his blood pressure fell to 0, and his pulse rate increased. He remained cyanotic, had a satis- factory urinary output, and never became jaun- diced, but died 19 hr after surgery, and 18 days after admission to the hospital. Necropsy Findings: 1. Tetralogy of Fallot, operated. 2. Mediastinal hematoma, 200 cc. 3. Right-sided aortic arch. 4. Acute central necrosis of the liver. SUMMARY OF CASE 632 History: This 10-year-old girl entered the hos- pital for elective cardiac surgery. She had been known to have a heart mur- mur since the age of 3 years. Nineteen months before final hospitalization, cardiac catheterization was performed else- where, and she was found to have a ventricular septal defect, patent ductus arteriosus, patent foramen ovale, and pulmonary hypertension with bidirectional shunt. A procedure for closure of the patent ductus arteriosus was performed under general anes- thesia 1 year before the final hospital admission. Two weeks later, she again had cardiac catheter- ization, showing a pulmonary-to-systemic flow ratio of 1.3 and persisting severe pulmonary hypertension. She was rarely cyanotic. Physical Examination: She was tall, thin, and not jaundiced, but slightly cyanotic. Blood pressure was 95/70. There were systolic and diastolic murmurs. There was no abdominal mass or ten- derness. Clinical Course: She again underwent cardiac catheterization, which showed a ventricular septal defect with a bidirectional shunt and pulmonary hypertension. Three days after admission she underwent repair of the ventricular septal defect on a heart- lung machine. This operation was done with con- siderable difficulty; afterward, her condition re- mained unsatisfactory, with cyanosis, respiratory stress, and unstable blood pressure. A trache- ostomy was performed under local anesthesia, but she died 2 days after surgery, and 5 days 126

after admission to the hospital. She was never jaundiced. Necropsy Findings: 1. Plexiform change (endothelial prolifera- tion) of pulmonary arteries, severe. 2. Edema of lower lobes of both lungs. 3. Residual (4 mm) ventricular septal de- fect. 4. Atrial septal defect. 5. Pulmonary arteriosclerosis. 6. Central necrosis of liver, lobular. SUMMARY OF CASE 636 History: This 55-year-old man entered the hos- pital for elective cardiac surgery. At the age of 12 years, he had had rheumatic fever, and had been known to have a heart mur- mur since the age of 34. For 12 years, he had been known to have aortic stenosis, but this had not produced symp- toms. In recent years, a gradual increase in fa- tigue and dyspnea on exertion was noted, and he developed left ventricular hypertrophy on his electrocardiogram and cardiac enlargement on his chest x-ray. Physical Examination: He was well nourished and not jaundiced. Blood pressure was 90/70. There was a characteristic murmur of aortic stenosis, but no abdominal mass or tenderness. Clinical Course: Measurement of left ventri- cular and aortic pressure under local anes- thesia showed a marked gradient across the aortic valve. Two days after admission open-heart sur- gery was performed, consisting of resection of the heavily calcified aortic valve on a heart- lung machine. This was complicated by a frac- ture of the aortic wall with massive hemorrhage but eventual repair. After surgery there was considerable bleed- ing, and he was suspected of having cardiac tam- ponade. He was returned to surgery 7 hr after the first operation for reopening of the thoraco- tomy with attempted control of hemorrhage. No distinct bleeding point was found, only diffuse bleeding. After the second operation, he remained hypotensive in spite of Adrenalin drip, became oliguric to 70 cc/day, and had a tracheostomy. He was never jaundiced, but died 3 days after operations 1 and 2, and 5 days after admission to the hospital. Necropsy Findings: 1. Residual diffuse mediastinal hemorrhage. 2. Acute anterior myocardial infarction. 3. Acute dissecting aneurysm, origin left iliac artery, extending to the root of the aorta. 4. Bilateral hemorrhagic pulmonary edema with atelectasis. 5. Acute lower nephron nephrosis, with renal insufficiency. 6. Cerebral edema. 7. Infarct of the liver. 8. Acute central passive congestion of the liver with central necrosis. SUMMARY OF CASE 645 History: This 44-year-old white man entered the hospital for the seventh time because of increas- ing shortness of breath and debility. He had been followed for 2 years with chronic congestive heart failure, the etiology of which had never been clear. He had been thought possibly to have hypertensive cardiovas- cular disease, because of some mild hyperten- sion in the past, or, more recently and more likely, idiopathic myocarditis, and had been treated with sodium restriction and multiple drugs. Multiple pulmonary emboli were also noted, with the source not definitely known, and he was hospitalized for 1 week (and discharged 1 week before the final hospitalization) for another episode of probable pulmonary embolism. Digitalis, Coumadin, iron, and morphine with Mercuhydrin by injection were the medications used. He had never been jaundiced. Physical Examination: He was thin, chronically ill, and not jaundiced. His respiration was ir- regular and he had a temperature of 39 C, pulse of 140, and blood pressure of 88. He was thought to be questionably jaundiced by only one observer. There was venous distention in the neck. The heart was enlarged to the midaxillary line and had a systolic murmur. The liver was palpable five fingerbreadths below the right costal margin and was tender. There was edema of the feet and ankles, and a questionably tender palpable vein in the right thigh. Clinical Course: He was treated medically for his chronic congestive heart failure, but con- tinued to have chest pain, hemoptysis, and dyspnea even at rest, and developed friction rubs over both lungs. He gradually deteriorated. On the 14th day icteric serum was noted, although the patient was never again described as jaundiced. He was thought to have congestive heart failure on an unknown basis with recurrent pulmonary emboli from an unknown souce. Nineteen days after admission he underwent ligation of the inferior vena cava and after this he remained agitated, drowsy, and confused and was thought to have cerebral anoxia. One more time the serum was described as jaundiced, although the patient was not. In spite of intensive medical management, he continued to do poorly, was never definitely jaundiced, and died 8 days after sur- gery, and 27 days after admission to the hospital. 127

Necropsy Findings: 1. Diffuse myocarditis of unknown cause. 2. Extreme cardiac hypertrophy (800 g) with dilatation. 3. Thrombosis of right leg. 4. Pulmonary infarction. 5. Pulmonary congestion, emphysema, ate- lectasis, and hemosiderosis. 6. Chronic gastric ulcer. 7. Congestion of the liver and other organs. SUMMARY OF CASE 649 History: This 65-year-old white man entered the hospital for evaluation of an aneurysm of the ab- dominal aorta and hypertensive cardiovascular disease. For 4 years before, he had been known to be hypertensive, and had been treated with diet. Dur- ing this time he had been known to have widening of the abdominal aorta. He had had intermittent claudication for 2 years and this had increased in severity recently, so that he had claudication with one block of walking. He admitted using a half-pint of whiskey per day for an unknown period. He was not and had never been jaundiced. Physical Examination: He was obese and not jaundiced. Blood pressure was 180/90. The liver was palpable two fingerbreadths below the right costal margin. There was a pulsating 8-cm aneu- rysm of the abdominal aorta. Femoral pulses were palpable, but the pulses in the feet were decreased. Clinical Course: He was studied in the hospital for 7 days before surgery. Seven days after ad- mission, he underwent resection of an aneurysm of the abdominal aorta with placement of a Dacron Y-graft from the aorta to the iliac arteries and additional placement of two separate Dacron grafts from the Y-graft to the femoral arteries below. The procedure included bilateral lumbar sympathectomy. Immediately after this operation, his left leg was cold, so he was returned to surgery 2 hr later and underwent a left popliteal thromboendar- terectomy. After the second operation, his condition was satisfactory until the 2nd day, when he became hypotensive to unknown levels. He became oligu- ric and cyanotic, and his feet became cool and blue. He never became jaundiced, but died 3 days after operations 1 and 2, and 10 days after ad- mission to the hospital. Necropsy Findings: 1. Bronchopneumonia, early, lower lobe. 2. Infarcts of ileum, colon, kidney, prostate. 3. Pulmonary embolus. 4. Tracheobronchitis. 5. Central congestion with focal liver cell necrosis. SUMMARY OF CASE 650 History: This 56-year-old white man entered the hospital for the fifth time with the complaint of trouble in swallowing for 3 weeks. Two years before the final admission, he had had carcinoma of the mouth, treated by a left rad- ical neck dissection, with resection of the left half of the mandible, left half of the floor of the mouth, and a hemiglossectomy. Some 18 months before the final admission, he underwent a right radical neck dissection in which one lymph node was found to be positive. (All lymph nodes were negative in the first operation.) Some 14 months before the final admission, he developed a left pneumothorax and was found to have malignant cells in his pleural fluid. Six weeks before final hospital admission, a retrocardiac mass was found on x-ray. At this time he refused surgery and was started on radi- ation therapy. He was readmitted finally because of increas- ing trouble in swallowing. He had never been jaundiced. Physical Examination: He was thin and not jaundiced. Blood pressure was 130/80. There was evidence of a hemimandibulectomy and bilateral radical neck dissection. One firm lymph node was palpable in the right side of the neck. There was no abdominal mass or tenderness. Clinical Course: Chest x-ray and esophogram confirmed the presence of a large retrocardiac mass, presumably a metastatic tumor. Six days after admission, an esophagoscopy under local anesthesia was unsuccessful. From the 10th day onward, he had fever to 40 C. On the 13th day a gastrostomy was done under local anesthesia, but later leakage developed around the gastrostomy with continued fever. He produced copious amounts of sputum. X-ray showed leakage of dye from the esophagus into the mediastinal cavity and right middle lobe pneumonia. A tracheostomy was per- formed under local anesthesia and he remained on intravenous fluid, but deteriorated. Thirty- seven days after admission, he underwent an ex- ploratory thoracotomy, and was found to have a tumor mass in the posterior mediastinum with a fistula involving the esophagus and bronchus. A biopsy was taken and the operable fields were drained. After this he gradually deteriorated, became pale, weak, increasingly jaundiced, and comatose. He died 19 days after surgery, and 56 days after admission to the hospital. Necropsy Findings: 1. Metastatic epidermoid carcinoma involv- ing the left posterior mediastinum, the posterior pericardium, myocardium, left atrium, and esophagus. 2. Left posterior mediastinal tumor abscess cavity with openings into esophagus. 128

3. Acute mediastinitis. 4. Acute bronchopneumonia. 5. Empyema, right and left. 6. Acute suppurative pericarditis with ex- tension into wall of left atrium. SUMMARY OF CASE 651 History: This 72-year-old white woman entered the hospital for the second time because of jaun- dice of 6 days' duration. Some 21 months before, at another hospital, she had been found to have carcinoma of the cervix, Stage m, and had external radiation and then radium implantation twice, for a total dose of 7500 mg-hr. After this, the cervix appeared to heal but the pelvic mass became no smaller. Fifteen months before final hospitalization, she developed low back pain and constipation. Because of a pelvic mass developing 12 months before final hospitalization, she was ad- mitted into the hospital and was found to have a PCV of 33, hemoglobin of 10.9, bilirubin of 0.3, and BSP retention of 27 percent. She was treated with three units of blood, then injection of 15 cc of Coxsackie B-3 virus directly into the tumor, with no improvement. After this, an anterior pelvic exenteration with creation of ileal bladder was done, and a large pyometra was found, but no tumor. During this operation, a large amount of bleeding occurred, necessitating 18 units of blood. The liver was described as "firm, shrunken, cirrhotic" during this surgery. On the day of surgery, she became jaundiced for the first time. (It is not clearly stated whether the jaundice was noted before or after surgery.) Bilirubin rose to 4.5 total, with a direct of 4.0 and indirect of 0.5. Her jaundice decreased gradually over a period of 3 weeks. On develop- ment of an anti-P factor, this was thought to be evidence of a possible incompatible transfusion. She was discharged after 3 months with liver chemistries still abnormal. At discharge, the alkaline phosphatase was 17.7, bilirubin was 3.0 direct and 1.5 indirect, thymol turbidity was "slowly rising," and serum protein was "in- verted." She was followed in a clinic for 9 months and had progressive worsening of the liver chemistries, with increases in the transaminase, cephalin flocculation, thymol turbidity, and alka- line phosphatase. The BSP retention rose to 52 percent, "chemical, but not clinical jaundice" appeared, and she continued to have a poor ap- petite, poor food intake, and nausea. She was admitted finally with weakness, as always, but with 6 days of jaundice without itch- ing. There was no history of alcoholism, malaria, previous episodes of jaundice, hepatitis, ex- posure to hepatitis, exposure to hepatotoxin, or use of chlorpromazine or other drugs. She was a Seventh-Day Adventist, used no meat, and was considered to have a very low protein intake. Physical Examination: The patient was well nourished, weak, drowsy, dehydrated, and very deeply jaundiced. Blood pressure was 110/60. There were no scratch marks, no telangiectases, and no other stigmata of cirrhosis. The liver was "questionably palpable at the right costal margin" and was not tender. The spleen was not palpable. There was a functioning ileal bladder. Clinical Course: She was studied for several days in the hospital and showed increased drows- iness and increasing jaundice. Laennec's cir- rhosis plus acute diffuse hepatic necrosis of un- known etiology was a preoperative diagnosis, but she was considered also possibly to have obstructive jaundice due to metastatic nodes or carcinoma of the head of the pancreas. Nine days after admission, surgery was done, consisting of an exploratory laparotomy, common bile duct exploration, and cholecystos- tomy. No biliary tract obstruction was found. The liver was described as "cirrhotic." A T-tube was left in the common bile duct. Nothing defi- nitive was done. After this operation, she remained deeply jaundiced and comatose, gradually deteriorated, and died 11 days after admission to the hospital, and 2 days after surgery. Necropsy Findings: 1. Portal cirrhosis, liver. 2. Focal necrosis, liver. 3. Acute and chronic inflammation, portal area, liver. 4. Subacute cholecystitis with cholelithiasis (single small stone found in the gall- bladder). 5. Focal acute interstitial pancreatitis. 6. Focal encephalomyelitis. 7. Acute and chronic pyelonephritis, right. 8. Generalized congestion. Comments by Pathologist: "At necropsy, the findings in the liver were consistent with an acute viral hepatitis, rather than toxic hepatitis, with hepatic necrosis. Mild encephalitis has been re- ported in instances of viral hepatitis." SUMMARY OF CASE 653 History: This 24-year-old woman entered the hospital for elective cardiac surgery. She had been known to be cyanotic and have a heart murmur since birth. No symptoms of congestive heart failure, easy fatigue, or other heart symptoms were known. Six years before the final admission, she underwent cardiac catheterization elsewhere, showing a ventricular septal defect with a left- to-right shunt and pulmonary hypertension. One month before the final hospital admis- sion, cardiac catheterization under local anes- thesia was performed. This demonstrated a left- to-right shunt, with the right ventricle as the 129

common recipient chamber and with an anomalous coronary arterial circulation and marked pul- monary hypertension. She had never been jaun- diced. Physical Examination: She was well nourished and not jaundiced. Blood pressure was 120/80. There were signs of cardiac enlargement, sys- tolic and diastolic heart murmurs, and a thrill. There was no abdominal mass or tenderness. Clinical Course: Three days after admission she underwent closure of two interventricular septal defects on total cardiopulmonary bypass with a heart-lung machine. The first defect was repaired with a patch. After she was taken off bypass, a residual shunt was found and she was again placed on bypass for repair of the second shunt. After this she was in complete heart block, required an internal and then an external pace- maker, became hypotensive, comatose, and oligu- ric, developed increasing respiratory distress, had a tracheostomy, required increasing doses of vasopressors, was replaced on partial by- pass, was never jaundiced, but died 54 hr after surgery and 5 days after admission to the hos- pital. Necropsy Findings: 1. Congenital heart disease with two ven- tricular septal defects, origin of both great vessels from the right ventricle, subaortic stenosis, stenosis of the right pulmonary artery, patent foramen ovale, cardiac hypertrophy. 2. Pulmonary congestion, acute and chronic. 3. Pulmonary edema, moderate. 4. Passive congestion of the liver, acute and chronic with central necrosis (lobular). 5. Petechial hemorrhages in brain with focal hemorrhages in lungs, liver, adrenal, bladder, and rectum. 6. Hemorrhage, acute, anterior mediastinum and right pleural space, 160 g. 7. Pulmonary arterial sclerosis, severe. SUMMARY OF CASE 657 History: This 10-year-old girl entered the hos- pital for elective cardiac surgery. She had been cyanotic since the age of 7 months, and had had cardiac catheterization then, giving a diagnosis of tetralogy of Fallot. For 2 years before the final hospitalization, she had increasing cyanosis and fatigue with ex- ertion. She had had cardiac catheterization with angiocardiography 2 weeks before under local anesthesia, confirming the diagnosis of tetralogy of Fallot. Physical Examination: The patient was small, cyanotic, and not jaundiced. Blood pressure was 90/65. A systolic murmur was heard. No abdom- inal mass or tenderness was found. Clinical Course: One day after admission, she underwent repair of the interventricular septal defect and plastic enlargement of the right ven- tricular outflow tract under total cardiopul- monary bypass on the heart-lung machine. The surgery was inadequate, in that the right ventri- cular outflow tract could not be enlarged. At the end of the operation, she was dependent on a pacemaker because of complete heart block. After surgery, she was always hypotensive, was never jaundiced, and died 1 day after surgery, and 2 days after admission to the hospital. Necropsy Findings: 1. Congenital heart disease (tetralogy of Fallot) with intravascular web formation, with relative stenosis, right and left pul- monary arteries, immediately distal to bifurcation. 2. Hemorrhage, anterior mediastinum, lungs, ovaries, small and large intestines, thymus gland, and bone marrow. 3. Fibrinous pericarditis and epicarditis. 4. Pulmonary congestion, marked. 5. Acute massive congestion with central lobular degeneration of the liver. SUMMARY OF CASE 658 History: This 34-year-old man entered the hos- pital for evaluation for possible cardiac surgery. He had rheumatic fever at the age of 9 and subacute bacterial endocarditis at the age of 18. He was admitted to the same institution 11 months before, was studied, and was found to have marked cardiac enlargement with enlarge- ment of the left atrium and right ventricle and calcification of the mitral valve. Cardiac cathe- terizaton showed "gross mitral insufficiency." Laboratory findings at that time included: trans- aminase, 57; BSP, 22 percent; alkaline phospha- tase, 13; and bilirubin, 2.3. A diagnosis of mitral insufficiency and right-sided cardiac failure was made. In the year before the final admission, hos- pitalization was necessary for several episodes of severe congestive heart failure. He had pro- gressive dyspnea on exertion, orthopnea, periph- eral edema, and persistent right upper quadrant pain, thought to be related to the enlarged liver. Treatment including the following drugs: Aldactone, digitalis, Diamox, and Mercuhydrin intramus- cularly twice a week. Intermittent jaundice for the preceding 10 years was thought to be related to right-sided cardiac failure. Physical Examination: He was chronically ill, thin, and jaundiced. Blood pressure was 106/68, with atrial fibrillation, marked venous distention, edema, and cardiac enlargement. Systolic and diastolic heart murmurs were heard. The liver was enlarged, firm, pulsatile, and moderately tender, extending 11 to 15 cm below the right costal margin. The spleen was palpable two finger- breadths below the left costal margin. 130

Clinical Course: Intensive medical treatment for 54 days had a poor response, with marked fluid and electrolyte problems. The diagnosis was mitral insufficiency, slight mitral stenosis, func- tional tricuspid insufficiency, and marked pul- monary hypertension. Fifty-four days after admission, a total re- placement of the mitral and tricuspid valves was performed in an open-heart operation lasting 12 hr, with total cardiopulmonary bypass on a heart- lung machine. After this operation, he became hypotensive, required a respirator, developed ischemic changes in the right arm, had a marked deepening of his jaundice, gradually deteriorated, and became anuric. He died 3 days after surgery and 57 days after admission to the hospital. Necropsy Findings: 1. Aortic valvulitis, chronic, with insuffi- ciency. 2. Cardiac dilatation and hypertrophy, marked, all chambers. 3. Chronic pulmonary disease with pulmo- nary arteriosclerosis, severe. 4. Dry gangrene, right forearm and hand, probably related to ischemia from brachial artery catheterizations. 5. Acute necrosis with hemorrhage, stom- ach and bowel. 6. Cardiac cirrhosis. 7. Focal hemorrhagic infarction, liver. 8. Mitral and tricuspid valves not examined; they had been excised at surgery. SUMMARY OF CASE 660 History: This 64-year-old white man was brought to the hospital by the police shortly after having collapsed on the street. The only history available was that he had had several episodes of coughing, chest and abdominal pain, sweating, and dizziness. The timing of these episodes is unknown. Physical Examination: He was obese, semi- comatose, in acute, severe respiratory distress, and not jaundiced. He was cyanotic and dyspneic with distended neck veins. Pulse was 140. Blood pressure was 70/0. There was abdominal dis- tention, but no mass. All the peripheral arterial pulses were palpable. Clinical Course: Transferred directly to an in- tensive-care unit, he remained hypotensive and dependent on Levophed. An electrocardiogram showed no specific pattern, and a dissecting aneurysm of the thoracic aorta was the preop- erative diagnosis. Twelve hours after admission, an emer- gency left thoracotomy with a De Bakey "re- entry" was performed. It consisted of transec- tion and resuturing of the thoracic aorta, done for a completely circumferential dissecting an- eurysm of the thoracic aorta, extending from the heart to the diaphragm with hemopericardium. After surgery he was still hypotensive and comatose, and dependent on Levophed and a respirator. He had a total urine volume of 100 cc in 33 hr. He never regained consciousness, re- mained hypotensive, gradually deteriorated, was never jaundiced, and died 33 hr after surgery, and 2 days after admission to the hospital. Necropsy Findings: 1. Aortic arteriosclerosis with dissecting hematoma circumscribing the thoracic aorta, with dissection posteriorly and laterally on the right of the descending aorta to include the right renal artery. 2. Arteriosclerotic fusiform aneurysm of the left common iliac artery. 3. Arteriosclerosis of the coronary vessels with left myocardial hypertrophy, severe, and right myocardial hypertrophy, moderate. 4. Acute toxic nephrosis. 5. Severe pulmonary congestion and edema with atelectasis, diffuse, of lower lobes, bronchopneumonia, and apical emphysema. 6. Serosanguineous pleural effusion: right, 200 cc; left, 200 cc. 7. Fatty change of the liver, mild. SUMMARY OF CASE 664 History: This 27-year-old white woman entered the hospital for elective cardiac surgery. At the age of 10, she had had rheumatic fever. She was in good health until her second preg- nancy at 24, when she had a pulmonary embolism. No further details are available about this epi- sode. Some 15 months before the final admission, tachycardia developed and atrial fibrillation was found. Some 12 months before the final hospital admission, she had open-heart surgery at another hospital, where she allegedly had an "open and shut" operation. Mitral stenosis was diagnosed preoperatively, but she was found to have mitral insufficiency at surgery. No further details are available about that hospitalization. Some 9 months before the final admission, she had "hepatitis" or "possible homologous serum hepatitis," with "slight jaundice." No other details are available about this episode. Some 6 months before the final admission she went into acute pulmonary edema and was hospitalized elsewhere. Since that time, her condition deteriorated with dyspnea, orthopnea, ascites, paroxysmal nocturnal dyspnea, edema, venous congestion, and constant vague abdominal discomfort. One month before the final admission, she had been hospitalized elsewhere for another episode of pulmonary embolism, for which she was treated with anticoagulants until the time of the final admission. 131

She was taking digitalis, Dicumarol, Diuril, potassium chloride, penicillin, and a mercurial diuretic. Physical Examination: She was thin, chronically ill, and not jaundiced. Pulse was 88 and abso- lutely irregular. Blood pressure was 100/75. There were prominent pulsating distended veins in the neck and evidence of cardiac enlargement, with systolic and diastolic murmurs and thrills over the apex and over the lower sternum. The liver was palpable 3 to 4 cm below the right costal margin and was slightly tender. Clinical Course: She was thought to have rheu- matic heart disease with congestive heart failure and mitral insufficiency, tricuspid stenosis, tricuspid insufficiency, aortic stenosis, and cardiac cirrhosis, or chronic hepatitis. Five days after admission, plastic recon- struction of the tricuspid and mitral valves was performed, with total cardiopulmonary bypass on a heart-lung machine with intentional hypo- thermia. The valves were repaired by suturing. The operation proceeded with moderate dif- ficulty, and, after surgery, unresponsiveness and insufficient respiration were noticed. A tracheostomy was done under local anesthesia. Supported with a mechanical respirator, she continued to be unresponsive and hypotensive, was treated with hypothermia, gradually deteri- orated, was never jaundiced, and died 16 hr after surgery and 6 days after admission to the hos- pital. Necropsy Findings: 1. Hemopericardium and hemothorax, bi- lateral (hemopericardium, 150 cc; right hemothorax, 400 cc; left hemothorax, amount not stated). 2. Fibrinous pericarditis. 3. Rheumatic valvulitis, involving mitral and aortic valves with pseudovalve form- ation; diffuse pulmonary atelectasis, bilateral (cause of death). 4. Passive congestion of liver, spleen, and kidneys. 5. Anoxic encephalopathy. SUMMARY OF CASE 665 History: This 53-year-old white man was ad- mitted as a transfer from another hospital with acute onset of abdominal and chest pain, and with a provisional diagnosis of dissecting aneurysm of the thoracic aorta. With a past history of rheumatic fever at the age of 15, he was found at 21 to have the mur- mur of aortic stenosis. No congestive heart fail- ure or heart symptoms had been reported. He was in good health until 1 day before the final admission, when a sudden onset of severe upper abdominal pain, chest pain, and vomiting developed. He was admitted to another hospital, where he was hypotensive. A pericardial tap re- turned blood, with x-rays showing questionable widening of the mediastinum, and he was thought to have a dissecting aneurysm of the thoracic aorta. Aramine was given for the hypotension, and Demerol, with transferral to the final hos- pital. Physical Examination: He was well nourished, sweating, and in pain, but not jaundiced. Pulse was 92 and regular. Blood pressure was 170/? with Aramine running. There was a rough aortic, systolic murmur, and right upper quadrant ten- derness, and the liver was tender and palpable 2 cm below the right costal margin. Clinical Course: An electrocardiogram showed no specific change. He remained hypotensive and dependent on Aramine with increasing right upper quadrant tenderness, rising temperature, and rising WBC, from 15,000 to 40,000. Rheumatic heart disease with aortic stenosis and perforated ulcer, acute cholecystitis, or mesenteric in- farction was diagnosed. Fourteen hours after admission, an explora- tory laparotomy was done in which he was found to have thrombosis of the hepatic artery. The procedure included a periarterial sympathec- tomy of the hepatic artery, cholecystostomy, and liver biopsy, for which no report is available. As the abdominal incision was being closed, he had cardiac arrest, which failed to respond to open-chest cardiac massage with an attempted transventricular aortic valvulotomy. He died in the operating room 2 hr after the start of the operation and 16 hr after admission to the hos- pital. He was never jaundiced. Necropsy Findings: 1. Fibrofibrinous pericarditis. 2. Rheumatic carditis with extensive cal- cific aortic stenosis and marked cardi- omegaly, 770 g. 3. Bilateral pulmonary congestion and edema, marked, with pulmonary atelec- tasis, marked. 4. Passive congestion of the liver and spleen. 5. Toxic nephrosis. 6. Hepatic artery patent. SUMMARY OF CASE 666 History: This 31-year-old white woman entered the hospital for cardiac surgery. Since the age of 10, she had been known to have a heart murmur, and from age 17, she had episodes of dyspnea on exertion and paroxysmal nocturnal dyspnea. Her first known episode of rheumatic fever had been at the age of 28. All three pregnancies had been complicated by con- gestive heart failure and terminated in miscar- riages. A tubal ligation was performed, and there were numerous hospitalizations for pneumonia and urinary tract infections. 132

Some 9 months before the final admission, she was hospitalized elsewhere for 2 weeks with jaundice, nausea, and vomiting, and was thought to have "infectious hepatitis." Further details of this hospitalization are not available. This con- finement came less than 6 months after a hos- pitalization for pneumonia. Attacks similar to this episode of alleged hepatitis did not recur. She was hospitalized for 1 month, was dis- missed, and returned 1 month later for final hos- pitalization. Right and left cardiac catheteriza- tion under local anesthesia were performed, with findings of mitral stenosis and aortic insufficiency. Congestive heart failure with enlargement of the liver to one fingerbreadth below the right costal margin and enlargement of the spleen occurred. Laboratory findings included: hemoglobin, 13.5; PCV, 41; WBC, 7300; prothrombin time, 60 per- cent; BUN, 11; blood sugar, 98; SGOT, 34; BSP retention, 0 on two occasions; bilirubin, total 0.9 and 3.0 (direct 0.2 and 0.7, indirect 0.7 and 2.3); cephalin flocculation, 3-t-; thymol turbidity, 10.2; cholesterol, 175; cholesterol esters, 100; C-re- active protein, negative; antistreptolysin 0 titer, 125; sodium, 137; potassium, 5.0; chloride, 107.5; CO2, 29.5; calcium, 5.5; phosphorus, 3.3; and alkaline phosphatase, 0.6. On several occasions, a history of "severe alcoholism" was elicited. The only detail available is that she consumed one to two bottles of an un- known alcoholic beverage per week until 3 years before the final admission, when she allegedly stopped using alcohol. Before the final admission, she had been suf- fering with increased orthopnea and dyspnea and had been taking digitalis. Physical Examination: She was thin, chronically ill, and not jaundiced. Blood pressure was 110/60. There were signs of cardiac enlargement, atrial fibrillation, systolic and diastolic heart murmurs, and an opening snap. The liver was palpable two fingerbreadths below the right costal margin and was tender. There was no peripheral edema or venous distention. Clinical Course: Rheumatic heart disease was diagnosed, with mitral stenosis, aortic insuffi- ciency, atrial fibrillation, and congestive heart failure, compensated. Six days after admission, she underwent surgery for a mitral valvulotomy and then suturing of the mitral valve, with total cardiopulmonary bypass on a heart-lung machine with hypothermia, and a tracheostomy. From the 1st postoperative day onward she was hypotensive and dependent on Aramine. The left forearm became cool and pulseless, but eventually the pulse returned. From the 2nd day onward, she had high fever and jaundice, and was thought to have possible gram-negative septicemia. Remaining dependent on Aramine, she developed gastric dilatation and passed dark bloody material through the nasogastric tube, but maintained a satisfactory urine volume. The liver became smaller on the 2nd day, but then enlarged on the 3rd day. Signs of pulmonary congestion developed, but no peripheral edema or venous distention. She remained jaundiced and hypotensive, grad- ually deteriorated, and died 4 days after surgery, and 10 days after admission to the hospital. Necropsy Findings: 1. Occlusion of the circumflex branch of the left coronary artery due to a suture. 2. Acute myocardial infarction. 3. Pulmonary congestion and edema, severe, with bilateral pleural effusion and mod- erate ascites. 4. Acute passive congestion of the liver, marked, with marked jaundice. 5. Congestion of the spleen, moderate. 6. Healed rheumatic aortic valvulitis with minimal aortic stenosis. SUMMARY OF CASE 667 History: This 84-year-old white man entered the hospital because of abdominal pain and dis- tention and vomiting of 1 day's duration. Five years before the final admission, re- section for carcinoma of the sigmoid colon was performed. There was never evidence of recur- rence of this tumor. One and one-half years before the final admission, a small bowel obstruction was diag- nosed, and laparotomy with lysis of adhesion was performed under general anesthesia. Postop- eratively, he did well until 1 day before the final admission, when abdominal pain and distention and vomiting developed. Medications taken were digitalis and an un- known medicine for hypertension. He also suf- fered from Parkinson's disease. Physical Examination: He was thin and dehy- drated, but not jaundiced. Temperature was 97 F, pulse was 60 and irregular, and blood pressure was 150/100. Marked abdominal distention and marked abdominal tenderness, maximum in the left lower quadrant, were evident. The liver was not enlarged or tender. Clinical Course: X-rays confirmed the impres- sion of small bowel obstruction. One day after admission, exploratory laparotomy was per- formed with lysis of adhesions, plus a Noble plication of the small intestine (apparently a limited plication). Before and during surgery, the pulse was irregular, and his electrocardiogram showed a number of disturbances of the cardiac rhythm. After surgery, his temperature spiked to 105 F, with hypotension as low as 0 and abdom- inal distention with severe pain. He developed rebound tenderness, other evidences of perito- nitis, and evidence of pneumonia. He became oliguric and jaundiced, either by the 1st or def- initely by the 2nd day. Treated with antibiotics, 334-5530-69-10 133

vasopressors, and blood, he gradually deteri- orated, and died 3 days after surgery, and 4 days after admission to the hospital. Necropsy Findings: 1. Infarction of terminal ileum, cecum, as- cending and transverse colon, with severe congestion of descending colon. 2. Perforation of the terminal ileum. 3. Serosanguineous fluid in the peritoneal cavity, 200 cc. 4. Severe congestion of the peritoneum. 5. Chronic calculous cholecystitis. 6. Fatty infiltration of the pancreas. 7. Fatty change of the liver. 8. Acute toxic nephrosis. SUMMARY OF CASE 669 History: This 40-year-old white man entered the hospital as a transfer from another hospital because of weakness, fever, and enlarged lymph nodes of 1 month's duration. Three months before, he allegedly had "virus pneumonia" and was treated with antibiotics. It is not known whether the antibiotics were by injection or mouth. No further information is available about this illness. For 1 month, enlarged nontender inguinal lymph nodes were noticed; although no diagnosis had been made, he underwent examinations and numerous blood tests on an out-patient basis. Some 2 weeks before the final admission, he developed fever to 103 F, abdominal pain and distention, loss of appetite, and a 15-lb weight loss, and was hospitalized elsewhere, found to have ascites, and had paracentesis at least once, producing 4 liters of fluid. A lymph node biopsy showed only "reactive hyperplasia." Laboratory findings at that time included: hemoglobin, 13; RBC, 4.49; WBC, 8100; BSP retention, 30.5 per- cent; BUN, 20; blood sugar, 104; sodium, 124; potassium, 6; bilirubin, 0.8; total protein, 5.4; albumin, 3.9; globulin, 1.5; alkaline phosphatase, 2.5; SGOT, 23; and Paul-Bunnell test, negative. Physical Examination: He was acutely ill, pale, weak, and "sallow," but not definitely jaundiced. Blood pressure was 100/60 and pulse was 120. He had enlarged lymph nodes in the neck, axillas, and groins. There was abdominal distention with questionable ascites. The liver and spleen were not palpable. Clinical Course: He was thought to have probably a lymphoma, generalized infection, or both. With- in a few hours of admission, he suddenly had massive lower gastrointestinal bleeding. He had a fall in PCV from 27 to 20 and a fall in blood pressure from 110 to 85, and had a transfusion, but continued to bleed. A nasogastric tube was passed and produced dark blood. The decision to operate was made" while he was deteriorating. One day after admission he underwent ex- ploratory laparotomy with gastrotomy and gas- trostomy, pyloroplasty, and vagotomy. No spe- cific bleeding point was found. He was found to have enlarged lymph nodes throughout the ab- domen and the omentum, and the lymph nodes were biopsied, showing malignant lymphoma. After this, he continued to bleed by rectum, never had purpura or bleeding from the incision, and was treated with a Blakemore-Sengstaken tube and irrigation of his stomach with iced saline. He was never jaundiced. His urine out- put ceased. He had cardiac arrest and died 1 day after surgery, and 2 days after admission to the hospital. Necropsy Findings: 1. Lymphosarcoma, lymphoblastic type, with involvement of mediastinum, retro- peritoneal, peritoneal, para-aortic, cer- vical, axillary, and inguinal lymph nodes, liver, and spleen. 2. Ulcers, acute, multiple, stomach with massive gastrointestinal hemorrhage. 3. Atelectasis, marked, of lower lobes of both lungs. 4. Necrosis, focal, multiple, liver. SUMMARY OF CASE 670 History: This 50-year-old white man was ad- mitted to the hospital because of cough and short- ness of breath. He had been known to have hypertension for 4 years. Three years before, he underwent surgery for left nephrectomy, because of a nonfunctioning left kidney, and left lumbar sympathectomy. For 4 months, he was known to have a blood pressure of 190/100, cardiac enlargement, ab- sence of the right femoral pulse, and a bruit over the aorta, and had been taking digitalis, chlorothiazide, Peritrate, and Ismelin. Because of a 1-month history of cough and shortness of breath, increasing in severity for 1 week, he entered the hospital. X-ray had shown a right pleural effusion, and he was treated with tetracycline and aminophylline. Physical Examination: He was thin, dyspneic, orthopneic, and coughing, but not jaundiced. Blood pressure was 180/120. There were signs of bilateral pulmonary congestion, a right pleural effusion, and emphysema. There was right upper quadrant tenderness and slight clubbing and cyanosis of the extremities, but the liver was not definitely palpable. The right femoral pulse was absent and the left femoral pulse was weak. There was a bruit over the aorta and the left femoral artery. 134

Clinical Course: The day after admission, an episode of chest pain, nausea, and vomiting en- sued, and an electrocardiogram showed an acute myocardial infarction that was later confirmed by the elevations in the SGOT and LDH. This was medically treated, including anticoagulants. Three weeks later, a second episode of epigastric dis- tress and nausea occurred, with another increase in SCOT and LDH, and he was thought to have a second myocardial infarction. Blood in his stools continued, and on about the 30th day, he was given 1500 cc of blood. Enlargement of the liver, pul- monary congestion, and edema followed. On the 33rd day, 3 days after the anticoagulants were stopped, severe pain in his legs, absent femoral pulses, and cold feet developed. An emergency exploratory laparotomy was performed, with thromboendarterectomy and em- bolectomy of the aortic bifurcation and the proxi- mal portions of the arteries, and thrombosis of these vessels was found. He died as the incision was being closed, 90 min after the induction of anesthesia, and 33 days after admission to the hospital. He was never jaundiced. Necropsy Findings: 1. Arteriosclerosis, severe, of the coronary arteries, with old healing and recent myo- cardial infarctions. 2. Arteriosclerosis, severe, of the aorta, with fusiform aneurysm of the abdominal aorta, and underlying mural thrombus. 3. Arteriosclerosis, severe, of iliac arteries, with thrombotic occlusion of right common and internal iliac arteries. 4. Arteriosclerosis, severe, of renal ar- teries, with marked narrowing of the ostium of the right renal artery. 5. Nephrosclerosis, arterial and arteriolar, advanced. 6. Emphysema, severe, pulmonary. 7. Pulmonary congestion, chronic, passive, slight. 8. "There was a beautiful nutmeg change in the liver." (No other description of the liver available.) SUMMARY OF CASE 673 History: This 68-year-old white woman entered the hospital for the eighth time because of weight loss, loss of appetite, and abdominal pain. Five years before the final admission, a right radical axillary lymph node dissection was done for adenocarcinoma originating in the axillary sweat glands. She had been followed in a tumor clinic with no sign of recurrence. The liver was not enlarged at that time. She had a history of arteriosclerotic cardio- vascular disease with congestive heart failure for many years, and had been on digitalis and diuretics with symptoms including dyspnea on exertion and orthopnea, but paroxysmal nocturnal dyspnea or edema was not included. A corneal transplant was done. Liver function tests were described as "normal" at that time. Her entrance into the hospital was necessi- tated because of a 4-month history of a 37-lb weight loss with anorexia and vomiting for 3 weeks, and epigastric pain for 2 or 3 days. Physical Examination: She was obese and not jaundiced. Blood pressure was 90/60. There were signs of pulmonary congestion. The liver was en- larged to five fingerbreadths below the right cos- tal margin and was slightly tender, with a "golf ball sized" nodule palpable in the left lobe. There was evidence of a previous right axillary lymph node dissection without evidence of recurrence, and edema of both lower extremities. Clinical Course: Preoperative diagnoses were thought to be congestive heart failure and metas- tases to the liver, although it was not clear whether these came from the lesions seen in the cecum on x-ray or from the previous carcinoma in the axilla. Seven days after admission, a needle liver biopsy was done, which showed "fatty change, portal fibrosis, and focal necrosis." This was unsatisfactory, so on the llth day she had a second needle liver biopsy, which showed "liver with fatty change and metastatic adenocarcinoma." Twenty-one days after admission, a right colectomy procedure was done in which she was found to have a large carcinoma of the cecum with involvement of the mesentery and numerous lymph nodes and the liver, by numerous metas- tases. After this, she did reasonably well, except for low-grade fever, poor cough, and poor coop- eration. On the 14th day she suddenly became hypotensive and died. She was never jaundiced. She died 14 days after surgery, and 45 days after admission to the hospital. Necropsy Findings: 1. Focal pneumonitis. 2. Metastases to the liver. 3. Thrombosis of the inferior vena cava and portal veins. 4. Abscess in peritoneal cavity beneath the surgical incision. SUMMARY OF CASE 675 History: This 80-year-old woman entered the hospital directly following a fall in which she sustained a fracture of the left hip. She was known to have arteriosclerosis, with cardiac enlargement, left bundle branch block, emphysema, and diabetes, controlled by diet without insulin. She had been having an in- creasing number of falls recently. Physical Examination: The patient was obese, alert, and not jaundiced. Blood pressure was 220 130. There was no abdominal mass or tender- ness but pain occurred with motion of the left hip. 135

Clinical Course: On the day after her admission she became dehydrated and confused. Three days after admission she underwent open reduction and internal fixation of the extremely comminuted intertrochanteric fracture of the left hip with a Massey nail. After this, she did well until the 17th day, when the x-rays showed that the nail had slipped out of the head of the femur and into the acetabulum. A number of transfusions in preparation for a second operation were given, because she was found to be anemic. Twenty-six days after the first operation, a second operation was performed, consisting of removal of the nail with insertion of a Steinmann pin in the left tibia, and she was placed in trac- tion. Nine days later, a wound infection was found and she continued with fever and increasing purulent drainage, and developed a urinary tract infection and bed sores. Twenty-one days after the second operation, she had a third operation under general anes- thesia, in which she was placed in "well-leg traction," as an alternative to the usual type of traction. She continued with dehydration and fever, had a positive blood culture, developed marked generalized edema, oliguria, marked fluid and electrolyte problems, pulmonary con- gestion, and increasing bed sores, gradually deteriorated, was not hypotensive, and was never jaundiced. She died 21 days after operation 3, 48 days after operation 2, 74 days after operation 1, and 77 days after admission to the hospital. Necropsy Findings: 1. Transverse fracture of the surgical neck of the left femur. 2. Osteomyelitis of the left femur with ab- scess. 3. Thrombosis of the left femoral vein. 4. Septicemia. 5. Multiple decubiti. 6. Myocardial infarction. 7. Recent, acute infarct of cerebral cortex. 8. Hemorrhagic dissection of the arch of the aorta. 9. Pulmonary congestion and edema. 10. Multiple, organizing pulmonary emboli. 11. Chronic passive congestion of the liver. SUMMARY OF CASE 680 History: This 50-year-old woman entered the hospital with a history of swelling of both sides of the neck for 3 weeks. She had a long history of smoking and chronic cough, and for 3 months had had an increasing amount of coughing with fever. Diagnosis of bron- chitis was made and treatment with antibiotics produced no improvement. It is not known whether the antibiotics were given by mouth or injection. Physical Examination: She was well nourished and not jaundiced. Blood pressure was 140/80. There were bilateral cervical and right supra- clavicular lymph nodes that were enlarged and palpable, with no abdominal mass or tenderness. Clinical Course: X-rays showed a probable car- cinoma of the left lung. Bronchoscopy under local anesthesia showed widening of the carina and ex- trinsic compression of the left main stem bron- chus. Four days after admission, a biopsy of the right cervical lymph nodes under general anesthesia showed carcinoma metastatic to the lymph nodes and muscles of the neck. Radiation therapy followed. From the llth day onward, she was weak, aphasic, confused, and paralyzed on the right side. She gradually deteriorated, had increasing respiratory dis- tress, was never hypotensive and never jaun- diced, and died 17 days after surgery, and 21 days after admission to the hospital. Necropsy Findings: 1. Thromboembolism with thrombi in he- patic, splenic, and left middle cerebral arteries. 2. Carcinoma of the lung, with widespread metastases to lung, hilar, peritracheal, esophageal, cervical, aortic, and mesen- teric lymph nodes, subcutaneous tissues of the neck, adrenals, spleen, and liver. 3. Ischemic infarct of the brain. 4. Infarct of the kidneys. 5. Tumor in the pericardium with fibrinous pericarditis and pericardial effusion. 6. Pulmonary edema and bilateral pleural effusion. 7. Central lobular necrosis and passive hyperemia of the liver. SUMMARY OF CASE 681 History: This 53-year-old white man entered the hospital for evaluation for possible cardiac sur- gery. For 18 months, he had been having typical angina pectoris. One year before admission, he underwent bi- lateral ligation of the internal mammary arteries and showed no improvement. Severity in the symptoms increased, neces- sitating his taking 50 nitroglycerin tablets per day. No history of congestive heart failure or jaundice was given. Physical Examination: He was well nourished and not jaundiced. Blood pressure was 180/105. There were signs of cardiac enlargement. There were no abdominal masses or tenderness. Clinical Course: A left stellate ganglion block was performed, with marked relief of his angina. An electrocardiogram showed the chronic changes of coronary artery disease and also of a questionable recent evolving myocardial infarc- tion, but possibly this was not appreciated at the time. 136

Five days after admission, a left dorsal sympathectomy with pericardial poudrage was done. At this operation, a hemorrhagic area in the left ventricle was found and considered to be evidence of a recent myocardial infarction. After surgery, the electrocardiogram showed further evidence of the myocardial infarction. Remaining hypotensive and cyanotic, he required increasing doses of vasopressors, became con- fused, had continuing chest pain, was never jaun- diced, and died 2 days after surgery, and 7 days after admission to the hospital. Necropsy Findings: 1. Arteriosclerotic cardiovascular disease with recent coronary occlusion due to hemorrhage in the atherosclerotic plaque with myocardial infarction. 2. Pericarditis. 3. Hyperemia of the liver with central lobu- lar necrosis. SUMMARY OF CASE 685 History: This 70-year-old white man entered the hospital because of an upper abdominal mass that had been present for 3 or 4 months. A gradually increasing mass in the upper ab- domen for 3 or 4 months was apparent, but no pain was felt. There had been a 25-lb weight loss and, because of general weakness, he was bedridden for 6 weeks before the final hospital admission. There had been no hospitalization or specific treatment before admission, and no jaundice had been noted. Physical Examination: He was emaciated, dehy- drated, and chronically ill, but not jaundiced. Blood pressure was 170/100. There was a hard, midline, epigastric mass. The liver was not pal- pable. Clinical Course: X-rays showed a probable car- cinoma of the stomach with complete gastric out- let obstruction. He was found to be anemic and was treated with intravenous fluids, nasogastric suction, and blood. He accidentally received 20 to 25 cc of blood intended for a different patient, without detectable reaction. Six days after admission, he underwent ex- ploratory laparotomy and palliative gastrojeju- nostomy, with a feeding jejunostomy and a gas- trostomy for suction. A large carcinoma of the stomach involving the greater omentum and transverse mesocolon was found. He was hypotensive on the 1st day, then nor- motensive for several days. He developed evi- dence of left lower lobe pneumonia, was treated with antibiotics, and was fed through his jeju- nostomy, but on the 5th day developed evidence of increasing respiratory distress and became comatose and hypotensive. He remained hypo- tensive the last 2 days of life, gradually deteri- orating, was never jaundiced, and died 7 days after surgery, and 13 days after admission to the hospital. Necropsy Findings: 1. Carcinoma of the stomach, poorly differ- entiated, invading gastrocolic and gas- trohepatic ligaments, with lymph node metastases. 2. Bronchopneumonia and pulmonary hem- orrhage, focal pulmonary collapse, and patch necrosis, left lower lobe. 3. Pulmonary emphysema, moderately severe. 4. Tracheobronchitis, moderately severe, with partial bronchial mucous obstruction. 5. Generalized peritonitis. 6. Coronary arteriosclerosis, severe. 7. Cirrhosis of the liver, Laennec type, early, mild, and patchy necrosis (micro- scopic diagnosis). SUMMARY OF CASE 686 History: This 71-year-old man entered the hos- pital shortly after falling 10 ft through a hole in the floor into a basement, landing on a saw horse, and suffering immediate pain in the back and in- ability to move his legs. Physical Examination: He was well nourished and not jaundiced. Blood pressure was 120/70. There was a gibbous deformity in the upper lum- bar spine, and no abdominal mass or tenderness. There were decreased breath sounds over the left side of the chest. The right lower extremity was paralyzed, but the left was not. He had de- creased sensation over the right lower extremity and over the left foot. Clinical Course: X-rays showed fractures of multiple ribs and of the 12th thoracic and first lumbar vertebral bodies. Conservative treat- ments were given and he was observed for pos- sible other injuries. He did well until the 4th day, when he suddenly became hypotensive, with rapid pulse and respiration, and was thought by physical findings and x-ray to have a left hemothorax. On the 4th day, he underwent emergency left thoracotomy, with evacuation of 2000 cc hemo- thorax, which was coming from the fractured vertebral bodies. The diaphragm was found to be intact, but the upper abdomen was explored through the diaphragm, and a ruptured spleen re- moved. During this operation, his estimated blood loss was 4000 cc, and blood replacement was 6000 cc. The possibility of over-transfusion was discussed. Postoperatively, his condition was poor. He was plethoric and showed cyanosis of the upper half of his body and hypotensiveness. He showed an elevated venous pressure, and had multiple tourniquets applied and phlebotomy, but deteri- orated and died 7 hr after surgery, and 5 days after admission to the hospital. He was never jaundiced. 137

Necropsy Findings: 1. Extensive pulmonary collapse, severe pulmonary congestion, and intra-alveolar hemorrhage, moderately severe pulmo- nary edema, mild pulmonary emphysema. 2. Fracture of vertebral spine T12, L1; and compression injury to spinal cord. 3. Central lobular necrosis and hepatic congestion and edema. 4. Left ventricular myocardial hypertrophy. Comments by Pathologist: "In the presence of rather severe left ventricular hypertrophy, it appears that the mechanism which led to death was an acute left ventricular cardiac failure with the increased blood volume and the consequent congestion and hemorrhage in the pulmonary cir- culation. As to what extent possible over-trans- fusion has contributed to this event cannot be stated, but it is likely to be of some significance in view of the increased hemoglobin and hemato- crit values obtained shortly before death." SUMMARY OF CASE 687 History: This 48-year-old white man entered the hospital as a transfer from another hospital with the problem of duodenal ulcer. For 20 years he had had duodenal ulcer symptoms, and he had been hospitalized 15 and 13 years before the final hospitalization for duo- denal ulcer. Six months before the final hospital admis- sion, he had been hospitalized elsewhere for duo- denal ulcer, and was treated medically. His ulcer symptoms had been very severe for 2 weeks before the final hospital admission; he had vomited blood once and had lost 20 Ib. He had been hospitalized elsewhere 10 days before the final admission. Laboratory findings then were: hemoglobin, 13.0; RBC, 4.17 million; WBC, 9500; amylase, 70; and icteric index, 4.3. He was treated with Pro-banthine, Oxaine, Donnatal, Riopan, morphine, and Thorazine. No history of jaundice or gastrointestinal bleeding was given. Physical Examination: He was well nourished and not jaundiced. Blood pressure was 140/100. There was no abdominal mass or tenderness. Clinical Course: X-rays showed pyloric obstruc- tion. He was treated medically, with nothing by mouth, nasogastric suction, and intravenous fluids, without improvement. Six days after admission, he had operation 1, which was a 60 percent subtotal gastric resec- tion, with a gastrojejunostomy, a feeding jeju- nostomy, and a drainage jejunostomy. After this, his temperature spiked to 103 F, with cough and signs of pulmonary congestion. He responded to antibiotics and endotracheal suction. On the 4th day he developed first right chest pain and then generalized abdominal pain with abdominal tenderness and rebound tender- ness. On the 5th day, the left leg was numb, cold, and mottled, and the left femoral and other pulses on the left leg had disappeared. Accordingly, he was returned to surgery 5 days after operation 1 for operation 2, a throm- bectomy of the left common iliac artery, with an exploratory laparotomy, in which he was found to have generalized purulent peritonitis. The bowel was described as hemorrhagic but not necrotic. He also had drainage of bilateral subphrenic ab- scesses at this time. After operation 2, he was treated with he- parin and antibiotics. He became oliguric and on the 1st day became jaundiced for the first time and confused. He became hypotensive and more deeply jaundiced, gradually deteriorated, and died 3 days after operation 2, 8 days after opera- tion 1, and 14 days after admission to the hospital. Necropsy Findings: 1. Generalized purulent peritonitis. 2. Congestion and necrosis, small and large intestine (infarction of the intestine). 3. Atherosclerosis with ulceration and thrombosis of the abdominal aorta to 4 cm above the celiac artery. 4. Central lobular necrosis of the liver. 5. Focal pneumonia and collapse of lungs. 6. Early tubular necrosis, kidneys. SUMMARY OF CASE 688 History: This 77-year-old white woman entered the hospital because of constipation, weakness, weight loss, and the finding of an abdominal mass. Four years before she had been admitted to the same hospital for a radical mastectomy for carcinoma of the right breast. At that time she was found to have a calcified pelvic mass, about which nothing specific was done. She entered finally with a 1-year history of constipation, with increasing need for laxatives and decreasing caliber of her stools. She had a 1-month history of right lower quadrant pain, worse with standing, a poor appetite, and a 20-lb weight loss. A barium enema showed a constrict- ing lesion in the sigmoid colon. Physical Examination: She was well nourished and not jaundiced. Blood pressure was 130/60. The abdomen showed moderate right upper quad- rant tenderness on a single examination only, but no mass. Pelvic examination showed a rock- hard, fixed, tender mass on the left side of the pelvis. There was no sign of recurrent carcinoma of the breast. Clinical Course: She was studied in the hospital for 12 days before surgery, and found to have the calcified pelvic mass, as shown before, and a constricting lesion in the sigmoid colon with an enterocolic fistula. Preoperative diagnosis was thought to be a calcified uterine fibr9id or der- moici with pelvic inflammatory disease and/or diverticulitis with complications. 138

Twelve days after admission, an exploratory laparotomy was performed. She was found to have an inflammatory mass involving the sigmoid colon and bladder, thought to be the basis of divertic- ulitis, and a cystic mass of the right ovary, thought to be carcinoma but later shown to be inflamma- tory. A 12-in. segment of small bowel involving two areas of obstruction and a fistula was re- sected. A transverse colostomy and a suprapubic cystostomy were done for an accidental perfora- tion of the bladder. It was noted at surgery that there was poor blood supply to the small intes- tine. After surgery, she was hypotensive, cyanotic, and oliguric, gradually deteriorated, was never jaundiced, and died 2 days after surgery and 14 days after admission to the hospital. Necropsy Findings: 1. Infarction, large and small bowel, exten- sive, early. 2. Hemoperitoneum, 400 cc. 3. Collapse, pulmonary, right and left lower lobes. 4. Dermoid cyst, right ovary, so situated as to cause constricting angulation of the sigmoid colon (size not stated). 5. Bronchopneumonia, left. 6. Central lobular necrosis, liver. 7. Acute tubular necrosis, early. 8. "No evidence of thrombosis seen in mes- enteric vessels." No comment, otherwise, as to the condition of the abdominal ves- sels. SUMMARY OF CASE 689 History: This 68-year-old white man was re- admitted for elective thoracic surgery for bron- chiectasis. He had a 1-year history of spells of dizzi- ness, nausea, and vomiting, and had been found unconscious 2 months before the final hospital admission. One month before the final admission, he had been admitted for evaluation for 7 days. During this time, he was found to have a chronic cough, producing 2 to 3 oz of purulent sputum per day. Bronchoscopy showed blood in the left main stem bronchus, and bronchograms showed non- filling of a superior segmental bronchus of the left lower lobe. A gallbladder series was nega- tive and a number of other studies were done per- taining to the dizziness but no specific diagnosis was made. Surgery for the presumed bronchi- ectasis was advised. Physical Examination: He was confused and obese, but not jaundiced. Blood pressure was 140/40. There were decreased breath sounds and rales over the left lower lobe. The liver was pal- pable two fingerbreadths below the right costal margin, but was not tender. Clinical Course: One day after admission a left lower lobectomy was done for what proved to be bronchiectasis. Postoperatively, he did well until the 5th day, when a rash and bronchospasm developed, which were thought to be a reaction to penicillin. He was treated medically for this, but later developed dyspnea, increasing difficulty in clearing res- piratory tract secretions, increasing cough, tem- perature to 103 F, cyanosis, blood-streaked spu- tum, and, finally, pulmonary edema. He did not have enlargement of the liver or peripheral edema. Vigorous medical treatment followed. He was never jaundiced and was hypotensive only on the last day of life. He died 8 days after surgery, and 9 days after admission to the hospital. Necropsy Findings: 1. Bronchopneumonia, necrotizing, hemo- lytic Staphylococcus aureus. 2. Empyema, hemolytic Staphylococcus aureus. 3. Postthoracotomy wound infection with hemolytic Staphylococcus aureus. 4. Septicemia. 5. Septic splenitis. 6. Central lobular necrosis and acute in- flammation of the liver. 7. Visceral congestion. 8. Cystic degeneration, old, focal, left frontal lobe of brain. SUMMARY OF CASE 691 History: This 64-year-old white man entered the hospital because of difficulty and hesitancy in urinating for 4 months. For 2 years before, he had been known to have an aneurysm of the abdominal aorta. No treat- ment had been given and no change was shown. TACE, a synthetic estrogen, was the medi- cation used for 1 year, for reasons unknown. Physical Examination: He was well nourished and not jaundiced, with signs of emphysema and gynecomastia. The liver was not palpable. Blood pressure was 140/80. There was a pulsating an- eurysm of the abdominal aorta. The bladder was palpable to the umbilicus. The prostate was en- larged and very hard. Clinical Course: X-rays showed possible me- tastases to the spine. He was catheterized and found to have a residual urine volume of 850 cc. Seven days after admission, a bilateral or- chiectomy under caudal plus general anesthesia was performed. Postoperatively, he had nausea and pain in his low back, hip, and knee. In addi- tion, he had some vomiting and abdominal pain. Five days after the first procedure, he had a second operation, a transurethral resection of the prostate under general anesthesia. He con- tinued to have pain in the back and left leg post- operatively. On the 5th day, he complained of 139

dizziness and vomiting, and passed gross blood in the urine. On the 6th day, he became dyspneic and hypotensive, had increasing back pain, and remained hypotensive. He died 6 days after op- eration 2, 11 days after operation 1, and 18 days after admission to the hospital. He was never jaundiced. Necropsy Findings: 1. Carcinoma of the prostate with metas- tases to the vertebral column, T8-9, and lungs. 2. Emphysema, chronic, bilateral, with thickening of pulmonary arterial and arteriolar walls, calcification in arterial walls, and occlusion of some arterioles, and with minimal thickening of the right ventricular wall. 3. Chronic passive congestion of the liver, with central lobular necrosis, acute. 4. Generalized atherosclerosis, moderate, with narrowing of the coronary arteries, diffuse interstitial myocardial fibrosis, and mild calcific changes of aortic and mitral valves. 5. Saccular abdominal aneurysm, originat- ing below the renal arteries, with mild extravasation retroperitoneally, with no free blood in the peritoneal cavity and no rupture. 6. Superficial ulceration of the stomach with gastrointestinal hemorrhage, 800 cc. 7. No sign of myocardial infarction. Comments by Pathologist: "Blood loss was in- sufficient to explain the shock, and we are left with only speculation as to its etiology. These include a gram-negative sepsis or a cerebral disorder, since no examination of the brain was permitted." SUMMARY OF CASE 692 History: This 63-year-old white man was ad- mitted to the hospital because of vomiting of blood for 5 hr. He had suffered from a myocardial infarc- tion 10 years before the final admission, and since then had had angina and was taking nitro- glycerin and Peritrate. On admission 21 months before, he had undergone excision of an aneurysm of the abdo- minal aorta, extending from below the renal ar- teries to the iliac arteries, and replacement with a Dacron Y-graft. This operation involved trans- fusion of 4500 cc of blood. There was no mention of enlargement of the liver in this hospitalization, and the operative report did not mention the liver. At this time, hemoglobin was 11.0; RBC, 3.95 million; WBC, 8000; blood sugar, 105; and BUN, 35. There were no liver function tests. Because of left chest pain, he had been ad- mitted to another hospital approximately 1 year before the final admission. Thoracentesis pro- duced 5 quarts of whitish fluid and the diagnosis of chylothorax was made. The underlying cause of this was never determined and the condition cleared with a tube thoracostomy. Seventeen years before the final admission, he had been known to have a duodenal ulcer mani- fested by abdominal pain. This was treated medi- cally with relief, and ulcer symptoms did not return. Having vomited bright red blood, he was ad- mitted, finally, to the hospital. Five hours later, he developed sharp stabbing pain in the upper abdomen, radiating to the back. Physical Examination: He was obese and not jaundiced. Blood pressure was 140/80. The ab- domen showed midline epigastric tenderness. The liver was not palpable. Clinical Course: He was treated conservatively medically and appeared to be stable initially. On the 2nd day, he again vomited blood, became hypotensive to 80/50, and showed a fall in PCV from 34 to 26. He was thought to have duodenal ulcer, or recurrent aneurysm of the abdominal aorta, or weakening of the suture line of the previous graft with erosion into the duodenum. Two days after admission, an emergency ex- ploratory laparotomy was performed in which he was found to have a 10 x 12-cm bulging re- current aneurysm of the abdominal aorta, with the transverse portion of the duodenum wrapped around it, containing a bleeding ulcer. The aneu- rysm was resected and replaced by a graft. All of the duodenum except the upper half of the first portion was resected, and a duodenojejunostomy done. The aorta was clamped above the renal ar- tery for an unknown period, but the resection and graft were from below the renal artery to the distal portion of the previous graft. During this operation, he received a large amount of blood and a Neo-synephrine drip to support blood pres- sure. Immediately after surgery, his pressure was in the normal range, but from the 1st day onward, he was hypotensive and dependent on vasopres- sors. He was also oliguric and was treated with fluid restriction. He continued this way until the 3rd day, when he had cardiac arrest. He was re- suscitated with closed-chest cardiac massage, had a tracheostomy, remained unresponsive, anuric, and dependent on a respirator, and became increasingly hypotensive. He died 3 days after surgery, and 5 days after admission to the hos- pital. He never was jaundiced. Necropsy Findings: 1. Atherosclerosis, generalized, severe. 2. Acute tubular necrosis of the kidneys. 3. Acute, extensive centrilobular hepatic necrosis. 4. Hemoperitoneum, 1500 cc. 5. Hemorrhage into adrenal medulla, bi- lateral. 140

6. Infarction of the descending colon. 7. Thrombosis of the splenic vein. 8. Pulmonary edema and congestion, mod- erate. 9. Acute peptic ulceration of the fundus of the stomach. SUMMARY OF CASE 707 History: This 21-year-old white man was ad- mitted for elective cardiac surgery. He had always been known to have a heart murmur, and had always suffered from dyspnea on exertion, fatigue on exertion, and mild cyanosis with exertion. These symptoms had been gradually increasing in severity. Six months before the final hospitalization, he was admitted for cardiac catheterization, which yielded the diagnosis of interventricular septal defect with infundibular pulmonary ste- nosis. Physical Examination: He was well nourished, not jaundiced, and not cyanotic. Blood pressure was 120/80. There was systolic murmur and thrill. Clinical Course: Seven days after admission, he underwent an infundibular resection and repair of an interventricular septal defect, with total cardiopulmonary bypass on a heart-lung machine and hypothermia. This operation was unusual, in that it lasted 10 hr and there was more difficulty with bleeding than usual. After this operation, bleeding continued and x-ray showed evidence of widening of the medi- astinum. Thirty-six hours after the first operation, a second operation was performed: reopening of the thoracotomy with attempted control of mul- tiple bleeding points in the thymus, pleura, and sternum. Following this procedure, he was oliguric, as he had been before the second operation, re- mained hypotensive, and continued to bleed through the chest tubes and from the incision. Dialysis on an artificial kidney was considered but not done because of his bleeding tendency. Bleeding continued, he remained dependent on vasopressors, and he had cardiac arrest, which failed to respond to external cardiac massage. Never jaundiced, he died 2 days after operation 2, 3 days after operation 1, and 10 days after ad- mission to the hospital. Necropsy Findings: 1. Tetralogy of Fallot, postoperative. 2. Shock kidney (renal tubular hydropic change). 3. Pneumonia. 4. Mediastinal hemorrhage. 5. Pleural hemorrhage. 6. Passive congestion of the liver. SUMMARY OF CASE 709 History: This 37-year-old white woman entered the hospital for evaluation for possible cardiac surgery. She had been well until 21 months before the final hospital admission, when she developed chest pain and a left pleural effusion. Fourteen months before the final admission, she had two episodes of paroxysmal nocturnal dyspnea, dyspnea on exertion, and fatigue on ex- ertion, was started on digitalis and Diuril, and, following this, did well. Nine months before the final admission, she began to have numerous respiratory infections. Before the final hospitalization, she was ad- mitted elsewhere for a 1-month stay, with pneu- monia. At that time, she had her first cardiac catheterization, which showed pulmonary hyper- tension, no evidence of a shunt, and suggestion of a patent ductus arteriosus. She had been at home for 1 month before the final admission, during which time she had another episode of pneumonia, with fever and dyspnea. Her final admission was due to dyspnea, edema, fatigue, and a 25-Ib weight loss in 14 months. She had no history of rheumatic fever and had never been known to have a heart mur- mur before. Digitalis, Hydrodiuril, potassium chloride, Cafergot for migraine, aspirin, Darvon, codeine, and Compazine were the medications she had been taking. Compazine in unknown dosages was taken for an unknown period. Physical Examination: She was thin and not jaundiced with a regular pulse of 72, tempera- ture of 99 F, and blood pressure of 100/70. There were systolic and diastolic murmurs. The liver was palpable 8 cm below the right costal margin and was not tender. Clinical Course: On the day of admission, she developed fever to 102.8 F and had thoracentesis of 420 cc of clear fluid, which was negative on culture and on examination for malignant cells. Under local anesthesia she had a tube thoracos- tomy, which remained in place for 3 days. Four days after admission, a second cardiac catheterization, which was a left-heart catheteri- zation, was performed under local anesthesia and showed acute rupture of the chordae tendinae, for which she was treated conservatively. She was also thought to have possible pulmonary em- boli, for which she was treated with anticoagu- lants. Thirty-six days after admission, operation 1, a third catheterization, being a right-heart cath- eterization, was performed under general anes- thesia, and showed pulmonary hypertension and signs of mitral stenosis and insufficiency. One day following the first procedure, she had operation 2, excision of the mitral valve and 141

replacement with a ball-valve prosthesis, per- formed with total cardiopulmonary bypass on a heart-lung machine with hypothermia to 29 C. During this procedure, cannulation of the femoral artery was attempted twice with difficulty and finally abandoned. The subelavian artery was eventually cannulated and eventually ligated. One day later, she bled from the femoral artery, necessitating operation 3, exploration of the groin with evacuation of a 1000-cc hematoma and ligation of a small arterial branch of the femoral artery. After operation 3, she continued with mod- erate hypotension, severe pain in the right lower quadrant, and tachycardia. She continued to bleed from the right groin, which was opened under no anesthesia and evacuated of a hematoma. A car- diac arrest followed, which responded to external cardiac massage. Terminally, she had gastroin- testinal bleeding, gradually deteriorated, and was never jaundiced. She died 1 day after operation 3, 2 days after operation 2, 3 days after operation 1, and 39 days after admission to the hospital. Necropsy Findings: 1. Mitral valve excised and replaced with a total prosthesis. 2. Retroperitoneal hematoma. 3. Hemoperitoneum. 4. Ischemic necrosis of the liver. 5. Severe chronic passive congestion of the lungs. 6. Old, small pulmonary infarcts. 7. Hemorrhagic gastroenteritis. 8. Subarachnoid hemorrhage. 9. Hydropic degeneration of the proximal tubules of the kidneys. 10. Inactive rheumatic heart disease with previous mitral insufficiency. SUMMARY OF CASE 711 History: This 33-year-old man entered the hos- pital as a transfer from another hospital 3 days after the closure of a perforated duodenal ulcer. Ulcer symptoms had been noticeable for 9 years. Three days before transfer to the final hos- pital, he entered the first hospital with perfo- rated duodenal ulcer, for which he underwent sur- gery quite promptly, under an unknown type of anesthesia, and consisting of closure of the ulcer. After surgery, he became oliguric, with urine volumes of 250, 250, and 100 cc per 24 hr. He was treated with fluids and electrolyte solutions, but not plasma or blood, became dehydrated, and showed signs of generalized peritonitis with dis- tention, ileus, and pain. Physical Examination: He was obese and not jaundiced. Blood pressure on arrival was 0. The extremities were cold and mottled. The abdomen was distended and silent, with a fluid wave. The liver was not palpable. Clinical Course: He was treated with 1500 cc of plasma in 2 hr with restoration of his blood pressure. Paracentesis produced 3 liters of brown fluid with an amylase of 146. X-rays showed free air, free fluid, and a suggestion of an abscess in the right upper quadrant. The day after transfer to the final hospital, and 4 days after the first operation, a second op- eration was performed for reclosure of the per- forated duodenal ulcer, with a pyloroplasty and cholecystectomy. He was found to have an open ulcer in the duodenum, with a perforated gall- bladder, which apparently had been adherent to the perforation in the duodenum. After operation 2, he did reasonably well until the 8th day, when gastrointestinal bleeding started, which was treated conservatively with- out improvement. Therefore, 8 days after opera- tion 2, operation 3 was performed: a transtho- racic, bilateral, truncal vagotomy. Postoperatively, he had massive lower gas- trointestinal bleeding and became hypotensive. Two days after operation 3, he underwent opera- tion 4, a 50 percent subtotal gastrectomy and a splenectomy, done for several bleeding gastric ulcers. He was hypotensive, maintained a good urine volume, required vasopressors, was never jaundiced, had cardiac arrest, and died 1 day after operation 4, 3 days after operation 3, 11 days after operation 2, 12 days after transfer to the final hospital, and 15 days after operation 1. Necropsy Findings: 1. Staphylococcal bacteremia. 2. Massive pulmonary atelectasis and bron- chopneumonia. 3. Acute purulent tracheitis. 4. Scattered areas of hepatic infarction. 5. Small areas of peripancreatic fat necrosis. 6. Peritonitis. 7. Esophageal erosion. SUMMARY OF CASE 712 History: This 19-year-old white girl entered the hospital for elective cardiac surgery. She had been known to have heart disease since infancy, which was manifested by cyanosis and dyspnea on exertion. Eighteen months before the final hospitali- zation, she had been admitted for cardiac cath- eterization. At that time, she had cyanosis and a systolic murmur, but no enlargement of the liver. Cardiac catheterization and angiocardiog- raphy showed valvular and infundibular pulmonic stenosis with no septal defect. It was thought that the cyanosis was due to a small atrial septal defect or a patent foramen ovale with two-way flow due to the high pressure on the right side of the heart. On her final admission for elective cardiac surgery, she had had no progression of symptoms, nor any history of congestive heart failure. 142

Medications included monthly prophylactic injections of penicillin. Physical Examination: She was well nourished (weight, 112 Ib), cyanotic, and not jaundiced. Blood pressure was 100/60. There was a systolic murmur. There was no abdominal mass or ten- derness. Clinical Course: Eight days after admission, she underwent closure of an interatrial septal defect, infundibular resection, and pulmonary valvulot- omy, with plastic reconstruction of the right ven- tricular outflow tract, with a patch, performed with total cardiopulmonary bypass on a heart- lung machine with hypothermia. Postoperatively, she continued to bleed a large amount through the chest tubes, developed a large hematoma on the anterior chest wall, and was given large volumes of blood by transfusion. On the 2nd day, she became jaundiced and oligu- ric and was treated intensively medically, but the jaundice increased and the oliguria persisted. Studies for a possible transfusion reaction were negative. Blood culture was negative. Remaining deeply jaundiced and oliguric, she gradually de- teriorated, terminally had cardiac arrest, and died 4 days after surgery, and 12 days after ad- mission to the hospital. Necropsy Findings: 1. Pulmonary stenosis, infundibular and valvular types, operated. Atrial septal defect at fossa ovalis, op- erated. Hemothorax: left, 700 cc; right, 200 cc. Organizing pericarditis. Myocardial necrosis. Fat embolization to kidneys. Extreme acute passive congestion of the liver. Atelectasis of left lung. Passive congestion of right lung. Hematoma of anterior chest wall, exten- sive. Hydropic degeneration of renal tubes. Acute hemorrhagic focal necrosis of the frontal, occipital, and temporal lobes of the right side of the brain. Fat embolization to white matter of brain. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. SUMMARY OF CASE 713 History: This 13-year-old Hawaiian-Japanese boy entered the hospital for elective cardiac surgery. Since the age of 5, he had been known to have a heart murmur, and had occasional episodes of dyspnea and cyanosis with squatting. At the age of 11, 2 years before the final hospital admission, cardiac catheterizaton was done elsewhere, showing an interventricular septal defect, patent ductus arteriosus, pulmo- nary hypertension, and a bidirectional shunt. Physical Examination: He was well nourished and not jaundiced. Weight was 103 Ib and blood pressure was 130/80. There was a harsh systolic murmur and mild cyanosis of the extremities. There was no abdominal mass or tenderness. Clinical Course: Cardiac catheterization with angiocardiography was done under local anes- thesia, giving the findings of interventricular septal defect, bidirectional shunt, valvular and infundibular pulmonic stenosis, anomalous right upper pulmonary venous drainage into the su- perior vena cava, and a patent foramen ovale or an interatrial septal defect. A patent ductus arte- riosus was not demonstrated. Nine days after admission, he underwent surgery consisting of total cardiopulmonary by- pass on a heart-lung machine with hypothermia, including repair of an interventricular septal defect, infundibular resection, pulmonary val- vulotomy, and plastic reconstruction of the right ventricular outflow tract with an Ivalon patch, with implantation of a cardiac pacemaker. He was found to have tetralogy of Fallot with in- fundibular and valvular pulmonary stenosis, anomalous right upper pulmonary venous drain- age, and a patent foramen ovale. Postoperatively, on the 1st day, he was in complete heart block, had fever, and was treated with the cooling blanket. On the 2nd day, he sud- denly and unexpectedly had cardiac arrest, which failed to respond to external cardiac massage. He was never jaundiced, and died 2 days after surgery, and 11 days after admission to the hos- pital. Necropsy Findings: 1. Tetralogy of Fallot (surgically treated). 2. Patent ductus arteriosus. 3. Partial anomalous connection, right upper pulmonary vein to superior vena cava. 4. Atrial septal defect. 5. Atelectasis, lower lobes. 6. Hydropic change in the proximal convo- luted tubules of the kidney. 7. Silicone emboli in the kidneys. 8. Hemothorax, right, 200 cc. SUMMARY OF CASE 716 History: This 58-year-old white man entered the hospital for an elective Whipple operation. During the year preceding the final admis- sion, he had a 20- Ib weight loss. Some 6 months before the final admission, painless jaundice gradually developed. Three months before the final admission, a laparotomy was performed elsewhere, and adeno- carcinoma involving the ampulla of Vater, with extension to the pancreas, was found. A cholecy- stoduodenostomy was done and the jaundice cleared. He was eventually admitted for elective surgery. Physical Examination: He was thin and not jaun- diced. Blood pressure was 150/90. There was no abdominal mass or tenderness. 143

Clinical Course: Three days after admission, a very extensive operation lasting 11 hr was per- formed, including a modified Whipple, resection of the transverse colon, vagotomy, cecostomy, and ligation of the splenic artery without splen- ectomy. Carcinoma involving the ampulla of Vater, the local lymph nodes, the omentum, the head of the pancreas, and the cholecystoduodenal anastomosis was diagnosed. On the night of surgery he had a satisfactory urine volume, but on the morning of the 1st day, he was found to be anuric and to have marked hemolysis, with a fall in PCV as low as 2, a fall in total hemoglobin as low as 6.4, a fall in RBC hemoglobin as low as 6.0 g percent, and a rise in plasma hemoglobin to 5.8 g percent. A trans- fusion reaction was diagnosed initially, but not proved. He was thought to have septicemia, prob- ably clostridial. He had fever from 103.8 down to 96 F, became jaundiced (an orange-red hue), and was treated with an exchange transfusion, antibiotics, steroids, and gas gangrene antitoxin. He remained anuric and died 2 days after sur- gery, and 5 days after admission to the hospital. Necropsy Findings: 1. Massive hemolysis due to Clostridium perfringens. 2. Massive infarction of the spleen due to interruption of the splenic artery. 3. Infarcts of the liver. 4. Abscess, peripancreatic, due to Clostrid- ium perfringens. 5. Pulmonary edema. 6. Acute renal tubular degeneration. 7. Hemorrhagic effusions of all serous cavities: right pleura, 800 to 1000 cc; left pleura, 800 to 1000 cc; peritoneum, 1500 cc; and pericardium, 20 cc. 8. Degeneration of heart muscle. 9. Mild cholestasis and portal fibrosis. 10. Congenital cysts of the liver. 11. Culture of the purulent material about the pancreas at necropsy grew Clostrid- ium perfringens, a Klebsiella species. and intermediate coliform organism, alpha-hemolytic streptococci, and an Alcaligenes species. 12. Culture of the free peritoneal fluid at necropsy grew Clostridium perfringens, E. coli, and alpha-hemolytic strepto- cocci. SUMMARY OF CASE 717 History: This 66-year-old white man entered the hospital for evaluation of arterial insuffi- ciency in his legs. Arteriosclerotic heart disease was preva- lent for 5 years. Five years before the final ad- mission, he had had a myocardial infarction, and he had been on digitalis since then. For 2 years, he had had intermittent claudi- cation in the left leg, with pain in the gluteal area, thigh, and calf, but particularly the gluteal area, coming on with walking one block. Two months before the final admission, he was hospitalized elsewhere with pneumonia, and was found to have a right pleural effusion. Physical Examination: He was well nourished and not jaundiced. Blood pressure was 130/70. He had signs of a right pleural effusion. There was no abdominal mass or tenderness. The left femoral, popliteal, posterior tibial, and dorsal pedal pulses were absent, whereas the pulses on the right were strong. Clinical Course: Chest x-rays showed a right pleural effusion. Thoracentesis produced 750 cc of fluid, which was negative for malignant cells. An aortogram showed complete obstruction of the left iliac artery, and a left femoral arterio- gram showed that the common, superficial, and deep femoral arteries were patent. Nine days after admission he was to have surgery, but an attempted epidural anesthesia became subdural, so no procedure was done. Fourteen days after admission, or 5 days after the original attempted anesthesia, he under- went placement of a Teflon graft from the aorta to the left common femoral artery. During this procedure, there was some difficulty with clotting and with establishment of flow. After this, the pulses became weaker and disappeared, and the left leg became cool and pale. Five hours after the first operation, he had a second operation, which was re-exploration of the graft, with removal of clot and retrograde flushing through an incision in the posterior tibial artery. Immediately after this operation, the pulses were good, but within 4 hr the left leg was cold and pale. He was then treated with caudal anesthesia and heparin. Over the next 2 weeks, pain and gangrene developed in the left lower extremity and 23 days after operations 1 and 2, operation 3 was done: a left above-the-knee am- putation. One day postoperatively, he developed marked chest pain, a pulmonary embolism was diagnosed, and he was treated with heparin. On the 2nd day, he again had severe chest pain, his liver was enlarged to 6 cm below the costal mar- gin, and he showed signs of pulmonary conges- tion. He was never jaundiced and was not hypo- tensive terminally. He died 2 days after operation 3, 25 days after operations 1 and 2, and 39 days after admission to the hospital. Necropsy Findings: 1. Arteriosclerotic heart disease. 2. Acute coronary thrombosis due to arteri- osclerosis. 3. Generalized arteriosclerosis obliterans. 4. Arteriosclerotic heart disease with old and recent myocardial infarction. 5. Congestive heart failure secondary to arteriosclerotic heart disease. 6. Cerebral arteriosclerosis. 7. Aneurysm of the left common iliac artery. 144

SUMMARY OF CASE 718 History: This 47-year-old white man entered the hospital because of trouble in swallowing for 6 weeks. He gave a history of food sticking low in his chest for 6 weeks before the final admission. He had been able to take only fluids and had lost 60 to 70 Ib. X-rays had shown "cardiospasm." There was no history suggestive of an ulcer. An attempt to pass a tube into the stomach had been unsuc- cessful. Six months before the final admission, he had been hospitalized for 4 days with an alleged myocardial infarction, and had been taking digi- talis since then. Diabetes was known for 4 years, and he was taking 50 units of NPH insulin per day. Physical Examination: He was thin and not jaun- diced. Weight was 127 Ib. Blood pressure was 150/80. There was no abdominal mass or ten- derness. Clinical Course: X-rays showed a large carci- noma involving almost all of the stomach and the lower 3 to 4 cm of the esophagus. Nine days after admission, after preparation with antibiotics, an extensive 9-hr operation was performed, in- cluding a total gastrectomy, splenectomy, resec- tion of the tail of the pancreas, resection of 5 to 6 cm of the esophagus, with esophagojejunostomy, jejunojejunostomy, and a feeding jejunostomy. Postoperatively, he had fever, pneumonia, and suspected pulmonary embolism or myocar- dial infarction, developed a fluid collection in the right chest, was shown by administration of Congo red to have leakage from the anastomosis, had placement of several tubes in the abdomen and in the chest under local anesthesia, and was demonstrated by x-ray to have leakage from the anastomosis. He was hypotensive for the last 3 days of life, requiring vasopressors and blood. He was never jaundiced, gradually deteriorated, and died 11 days after surgery, and 20 days after admission to the hospital. Necropsy Findings: 1. Extensive infarcts, parenchymal necro- sis, lobular atrophy, metastatic adeno- carcinoma, and passive congestion of the liver. 2. Pleural scarring, atelectasis, multiple lung abscesses, and scattered pneumonia. 3. Breakdown of the esophagojejunal anasto- mosis, with resulting leak and loculation of mucopurulent material at the site of the anastomosis and with about 700 cc of serosanguineous fluid in the left pleural cavity. 4. Pericarditis. 5. Peritonitis. 6. Metastatic carcinoma to omentum and para-aortic lymph nodes. 7. Generalized arteriosclerosis. 8. Acute mucosal ulcerations of the esoph- agus. 9. Submucosal necrosis and hemorrhage of the colon. SUMMARY OF CASE 719 History: This 62-year-old white woman entered the hospital for the seventh time for the treatment of her ulcerative colitis. She had been followed in the same clinic for 4 years with preoperative diagnoses thought to be rheumatoid arthritis, Alzheimer's disease (cen- tral-nervous-system disease), chronic constipa- tion, hemorrhoids, and chronic anemia. Four years before the final admission, a hemorrhoidectomy was performed under general anesthesia. The tissue removed at this time showed nonspecific granuloma. She was allegedly incontinent of feces from this time onward. At that hospitalization, the total protein was 6.8; albumin, 3.9; and globulin, 2.9. Review of all the records reveals no other tests pertaining to the liver. Two and one-half years before the final ad- mission, she was admitted for "anal stenosis" and underwent a posterior anotomy and a limited hemorrhoidectomy. This second operation was also performed under general anesthesia. One year before the final admission, she was admitted for evaluation of her diarrhea, rectal bleeding, and alleged incontinence of feces. Barium enema at this time was negative. She was thought to have subacute ulcerative colitis and was started on medical treatment, the details of which are unknown. During this time she had had several other hospitalizations for psychosis and Alzheimer's disease, but there was never complete agree- ment as to the nature of the central-nervous- system disease. She was admitted finally with a history of 15 to 20 bowel movements a day, with rectal bleed- ing and passage of mucus by rectum for 2.5 years. Recent barium enema and proctoscopy had shown the changes of ulcerative colitis. During this time her muscle weakness, ataxia, sensory loss, and memory loss had waxed and waned. Physical Examination: She was poorly nourished (weight, 90 Ib), appeared chronically ill, and was not jaundiced. Blood pressure was 120/70. The liver was palpable three fingerbreadths below the right costal margin and was tender. There was poorly localized right lower quadrant tenderness. There was decreased sensation over both lower extremities. Clinical Course: X-rays again confirmed ulcera- tive colitis. She was thought this time to have polyneuropathy, rather than Alzheimer's disease. Eight days after admission, a total colectomy, including abdominal-perineal resection of the rectum, with an ileostomy was performed. The 145

specimen showed ulcerative colitis with pseudo- polyposis and an ulcer completely surrounding the ileocecal valve. Postoperatively, she did well and her ileostomy was functioning until the 7th day, when she developed abdominal cramps and distention. Eight days after the first operation, opera- tion 2 was performed: a laparotomy for a small bowel obstruction. She was found to have volvulus of the small intestine around the ileostomy in the gutter, which had not been closed. The volvulus was reduced and the gutter closed, and no resec- tion was necessary. From the time of operation 2, marked right upper quadrant tenderness developed, and a closed-loop obstruction or a loop of gangrenous intestine was diagnosed. Accordingly, 3 days after operation 2, she underwent operation 3, ex- ploration of the right upper quadrant under local anesthesia, in which serosanguineous fluid was found, but no abscess or obstructed or gangrenous loop. After operation 3, she remained oliguric and hypotensive and developed twitching, and then gross bleeding through the nasogastric tube and from the right lower quadrant drain. She developed convulsions, gradually deteriorated, was never jaundiced, and died 5 days after operation 3, 8 days after operation 2, 16 days after operation 1, and 24 days after admission to the hospital. Necropsy Findings: 1. Pseudomembranous colitis. 2. Fibrinopurulent peritonitis. 3. Infarction of the liver (no comment in necropsy report about hepatic artery). 4. Atelectasis of both lungs. 5. Bronchopneumonia. 6. Renal tubular necrosis. 7. "Alzheimer II changes" described in the brain (no other diagnosis made concern- ing brain). SUMMARY OF CASE 723 History: This 62-year-old white man entered the hospital because of gradual deterioration for 1 year, with pain in both legs and hips. He had been admitted 5 years before the final admission with symptoms of urinary obstruction and pain in his back. Cystoscopy and biopsy of the prostate showed carcinoma of the prostate. X-rays showed metastases to the pelvis. There was no abdominal mass or tenderness. He under- went bilateral orchiectomy and was started on stilbestrol. Laboratory findings at that time were: hemoglobin, 11.7; RBC, 3.89 million; WBC, 7200; platelets, 139,000; sedimentation rate, 115; blood sugar, 101; acid phosphatase, 2.8; alkaline phos- piuita.se. 4.9; total protein, 6.9; albumin, 4.2; globulin, 2.7; and NPN, 43. Two years before final hospitalization, he was admitted for 3 days with the complaint of pain in his hip. At that time, he was still taking stilbestrol, 50 mg three times a day, and Meti- corten, 5 mg three times a day. He had no abdom- inal mass or tenderness. X-rays showed very extensive metastases. Cystoscopy showed no change, and he was advised to continue his medi- cations. Laboratory findings that time were: hemoglobin, 12.2; RBC, 3.89million; WBC, 10,800; sedimentation rate, 16; alkaline phosphatase, 6.3; and acid phosphatase, 0.80. Because of gradual deterioration, pain in his hips and legs, and a 30-Ib weight loss, he was admitted finally. He had become anemic and had had multiple blood transfusions, the number and timing of which are not known. It is known, how- ever, that he received 1000 cc of blood 2 months before the final admission. Physical Examination: He was emaciated (weight, 116 Ib), appeared chronically ill, and was not jaundiced. Blood pressure was 100/70. There was bilateral gynecomastia. The liver was enlarged to percussion, although the size was never ac- curately determined. The liver was also described as "palpable and tender." He had numerous ec- chymoses, and enlarged lymph nodes in both inguinal regions. The prostate was markedly en- larged and hard and was almost totally obstruct- ing the rectum. Clinical Course: X-rays showed numerous bony metastases. He was studied and prepared with drugs and then, 13 days after admission, under- went hypophysectomy by the trans-antral trans- sphenoidal route. Postoperatively, he never improved re- markably, but continued to have thrombocytopenic purpura, gradually became weaker, and was treated with steroids, stilbestrol, thyroid, blood, and antibiotics. On the 23rd day, his temperature rose to 104 F, he developed jaundice and dark urine, and the liver became tender and enlarged to five fingerbreadths below the right costal mar- gin. Remaining jaundiced, he became confused and disoriented and was thought to be in hepatic coma, but did not show liver flap. At this time, it was determined that he had had transfusion 3 months previously and he was thought to have serum hepatitis or liver metastases. A lumbar puncture was negative. He remained jaundiced, gradually deteriorated, and died 42 days after surgery, and 55 days after admission to the hospital. Necropsy Findings: 1. Adenocarcinoma of the prostate with local extension to the seminal vesicles, involve- ment of supraclavicular, hilar, lumbar, para-aortic, iliac, femoral, and inguinal lymph nodes, and subpleural lymphatics; metastases to liver, both adrenals, and cranial dura mater; extensive bony me- tastases and replacement of vertebral, sternal, and costal bone marrow with secondary anemia, thrombocytopenia, and cutaneous purpura. 146

2. Bilateral hydrothorax, marked, 1500 cc. 3. Partial atelectasis of lower lobes of lungs. 4. Ascites, 500 cc. 5. Chronic passive congestion of the liver and central hemorrhagic necrosis, marked. 6. Organizing pneumonitis, left lower lobe. 7. Extramedullary hematopoiesis in spleen and liver. 8. Metastatic carcinoma in cerebral dura, left cavernous sinus, mucous membrane of the sphenoid sinus, and sphenoid bone. 9. Acute and chronic sphenoid sinusitis, left. 10. Acute and chronic osteomyelitis, mild, localized, in bony septum of sphenoid sinus. 11. No residual pituitary tissue found in the sella turcica post mortem. Comments by Pathologist: "Necropsy disclosed widespread malignancy and a constellation of ana- tomical lesions which indicated congestive heart failure. One component of the latter condition, that is, central hemorrhagic necrosis of the liver, is considered to be the cause of jaundice in this case." SUMMARY OF CASE 724 History: This 33-year-old white woman re- entered the hospital for repeat elective cardiac surgery. She had no definite history of rheumatic fever, but had had scarlet fever and many sore throats as a child. Two heart murmurs had been known since her first pregnancy, 11 years before the final admission. Nine months before the final admission, angi- ocardiography showed mitral stenosis, mitral insufficiency, and pulmonary hypertension. At that time, she had had a closed mitral valvulotomy under general anesthesia and was found to have severe disease of the mitral valve with consid- erable mitral insufficiency. It was felt that little -was accomplished and that she needed later sur- gery with opening of the heart with use of a heart- lung machine. Three months before final hospitalization, she was admitted for 3 days for evaluation. Nothing specific was done at that time. The liver was not palpable at that admission. In the interim preceding the final admission, no improvement was noted. She had pneumonia treated with an unknown antibiotic, and an increas- ing dyspnea on exertion. Digitalis, potassium chloride, Diuril, and sulfadiazine were the medi- cations taken. The liver was described as pal- pable four to five fingerbreadths below the right costal margin, but not tender, on two examina- tions in the clinic. This is the only time the liver had been noted to be enlarged. Physical Examination: She was thin, not cyanotic, and not jaundiced. Pulse was 100 and absolutely irregular. Blood pressure was 110/70. There were systolic and diastolic heart murmurs and signs of cardiac enlargement and atrial fibrilla- tion; there was no abdominal mass or tender- ness, and no sign of congestive heart failure. Clinical Course: Seven days after admission, she underwent a procedure for valvulotomy and plastic correction of the insufficiency of the mitral valve with a Teflon patch, including total cardiopulmonary bypass on a heart-lung machine. It was felt that the repair was completely un- satisfactory and that increased mitral insuffi- ciency had been produced. The operation was terminated because of a tear in the atrium, with bleeding that was never completely controlled. Postoperatively, she continued to bleed through her chest tube and developed cyanosis, signs of pulmonary edema, and a left hemothorax. She became oliguric and hypotensive, gradually deteriorated, was never jaundiced, and died 4 days after surgery, and 11 days after admission to the hospital. Necropsy Findings: 1. Rheumatic mitral valvulitis with mitral stenosis and insufficiency. 2. Cardiac hypertrophy. 3. Congestive heart failure. 4. Hemothorax, left, 900 cc. 5. Infarction of left and right ventricles, massive, acute. 6. Cardiac dilatation. 7. Embolization of glomerular capillaries, cause undetermined (? silicone from antifoam chamber of the pump oxygen- ator). SUMMARY OF CASE 802 History: This 65-year-old white man was ad- mitted to the hospital because of vomiting of blood. The patient was not able to give an accu- rate history, but the history was obtained from a friend that he had had vague abdominal pain for 3 weeks. There was no history of gastroin- testinal bleeding or abdominal pain previously. He was admitted because of 1-day vomiting of dark blood, followed by vomiting of bright red blood, and then passage of dark blood by rectum. He "used to drink fairly heavily," but ad- mitted to less than a half-pint of whiskey per day. It appears likely that he used more alcohol than this, because he had alcohol on his breath when he was admitted and because the hospital records show that he had been brought to the hos- pital twice in the hands of the police for minor injuries. One month before the final hospital admis- sion, he had had an injection of cortisone for arthritis. Physical Examination: He was obese, acutely ill, drowsy, and confused, and had alcohol on his breath. He was not jaundiced. Pulse was 80 and 147

blood pressure was 150/60. There was no ab- dominal mass or tenderness and no spider angi- omata. Clinical Course: He was given blood and stopped bleeding, but then restarted. He was then treated with a very large amount of blood with a Blake- more-Sengstaken tube. Continuing to bleed in spite of intensive drug and massive blood admin- istration, he was taken to surgery for an emer- gency operation 1 day after admission. This operation was an exploratory laparotomy with two gastrotomies, ligation of a single large bleeding gastric varix, and a side-to-side porta- caval shunt, with good reduction in the portal pressure. Postoperatively, he was hypotensive and confused, and continued to bleed both through the nasogastric tube and by rectum. He was given large amounts of blood and again treated with the Blakemore-Sengstaken tube. He was never described as jaundiced, but probably was jaundiced for the last 2 days of life, as indicated by the bilirubin (up to 6.6). Gradually deteri- orating, he died 2 days after surgery, and 3 days after admission to the hospital. Necropsy Findings: 1. Arteriosclerotic heart disease. 2. Postnecrotic cirrhosis, with superim- posed hepatoma. 3. Esophageal, gastroduodenal, and gastric varices with multiple bleeding points. 4. Portacaval anastomosis intact and ap- parently functioning as seen at necropsy. SUMMARY OF CASE 807 History: This 57-year-old white man, a farmer, entered the hospital because of a 1-month history of steadily increasing chest pain and loss of ap- petite. There was a history of a "high alcoholic in- take," but no further details were available on this point. Physical Examination: He was thin, appeared chronically ill, and was not jaundiced. Blood pressure was 125/80. There were decreased motion and decreased breath sounds over the left lung. There was no abdominal mass or ten- derness. Clinical Course: Chest films showed a lesion in the left lung, which was probably a carcinoma. A single sputum was positive for acid-fast bacilli, but numerous other sputums were negative. Bron- choscopy under local anesthesia showed a lesion in the left lower lobe, which was biopsied and shown to be a squamous cell carcinoma. Fourteen days after admission, he underwent a left pneumonectomy for what was shown to be a squamous cell carcinoma of the left lower lobe, adherent to the chest wall, with central abscess formation. Postoperatively, he did well until the 3rd day, when he was transiently hypotensive but re- sponded to 500 cc of blood. After this, he did well until the 12th day, when he suddenly became cya- notic and hypotensive; but he improved when his left chest was tapped and a small amount of air was released. A bronchogram done then showed no leakage from the bronchial stump. He died suddenly 13 days after surgery, and 27 days after admission to the hospital. He was never jaun- diced. Necropsy Findings: 1. Bilateral hemothorax (1800 cc clotted blood, left pleural cavity; 300 cc clotted blood, right pleural cavity). 2. Acute and partially organized sanguino- fibrinous pericarditis (80 cc, E. coli cul- tured at necropsy). 3. Congestion and edema of the right lung, moderate, 920 g. 4. Acute tracheobronchitis. 5. Acute congestion of the liver, advanced, with central lobular necrosis. 6. Acute congestion of the spleen and kid- neys, moderate. SUMMARY OF CASE 812 History: This 65-year-old white man, an itin- erant unemployed handyman and chronic alco- holic, entered the hospital for the fourth time, 5 days after his most recent discharge from this hospital, because of fever. Three years before the final admission, he was hospitalized for 25 days with pneumonia of the right lower lobe. At that time he was not jaundiced and the liver was not enlarged. Bronch- oscopy under local anesthesia showed narrowing of the left lower lobe orifice. He was treated with penicillin and Achromycin, and was also diagnosed as having "probable Laennec's cirrhosis," based on laboratory findings. Laboratory findings were: hemoglobin, 10; PCV, 35; WBC, 23, 300; prothrom- bin time, 35 percent; NPN; 36; blood sugar, 89; total protein, 6.5; albumin, 3.0; globulin, 3.5; thymol turbidity, 6.5, 10; cephalin flocculation, 2-3+ in 24 hr, 4+ in 48 hr; alkaline phosphatase, 4.1; bilirubin, total 0.8, direct 0. 5, indirect 0.3; and BSP retention, less than 5 percent. One year before the final admission, he was admitted for the second time for 21 days with severe pneumonia of the left lower lobe and left upper lobe, plus congestive heart failure. Bronch- oscopy under local anesthesia showed narrowing of the right upper lobe orifice. The liver was en- larged to five fingerbreadths below the right costal margin and was slightly tender. He was not jaun- diced and was treated with digitalis, penicillin, Chloromycetin, and streptomycin. Representative laboratory findings at that time were: hemoglobin, 13; PCV, 37; WBC, 23,000; BUN, 82, later 26; creatinine, 2.2; blood sugar, 124; total protein, 6.3; albumin, 3.9; globulin, 2.4; bilirubin, total0.5. 148

direct 0.3, indirect 0.2; and BSP retention, less than 5 percent. Forty days before the final hospital admis- sion, he was admitted for a third time for 45 days. At that time, he entered with a 2.5-week history of chills, fever to 102 F, anorexia, and polydipsia, and was found to have signs of emphy- sema and enlarged lymph nodes in the neck, axilla, and inguinal region. The liver was found 5 fingerbreadths below the right costal margin. A right axillary and supraclavicular lymph node biopsy, which was done under local anesthesia, gave the diagnosis of Hodgkin's lymphoma. He was treated with nitrogen mustard, 0.1 mg/kg twice and 0.2 mg/kg once. This was followed by a fall in the WBC and PCV, but no improvement. He was then treated with prednisone, 15 and later 10 mg four times a day, with improvement. Rep- resentative laboratory findings at that time were: hemoglobin, 13, later 9.5; PCV, 42, later 30; WBC, 5300, later 420, later 11,500; platelets, 407,000; BUN, 16; blood sugar, 87; total protein, 8.0; albumin, 5.0; globulin, 3.0; thymol turbidity, 4.1; alkaline phosphatase, 3.5; bilirubin, total 0.5, direct 0.3, indirect 0.2; and uric acid, 2.9. After his most recent discharge, he had been home for 5 days, and for 3 days had no fever, but had had fever and sweating for 2 days. He had been taking prednisone, 10 mg three times a day. Physical Examination: He was obese (weight, 180 Ib), chronically ill, and sweating, but not jaundiced. Temperature was 103 F and blood pressure was 130/70. There were enlarged lymph nodes in the neck and inguinal regions. The liver was two fingerbreadths below the right costal margin and was not described as tender. The spleen was not palpable. Clinical Course: He was treated with steroids and then Vincaleukoblastine, but continued to have fever. His bone marrow became depressed and he was treated with antibiotics. On the 36th day, he was found to be hypoten- sive to 70/40, to be passing blood by rectum, and to return bright red blood from his nasogastric tube. He continued to bleed in spite of transfusion. Accordingly, on the 36th day, he underwent an exploratory laparotomy, in which he was found to have bleeding from multiple superficial ulcers throughout the stomach. The procedure included a sixty percent subtotal gastrectomy, with gastro- jejunostomy, and suture-ligature of ulcers re- maining in the retained portion of the stomach. After this operation, he was comatose with fever as high as 104 F. He went into congestive heart failure, was thought to be suffering from over-transfusion, had two phlebotomies, and was treated intensively medically. He remained coma- tose, had serosanguineous drainage from his in- cision, and was thought to have had dehiscence of the fascial portion of the incision. Continuing to bleed by rectum, he had increasing respiratory 334-553 O-69-1I distress, was thought to show signs of pneumonia, gradually deteriorated, was not hypotensive, was never jaundiced, and died 6 days after surgery, and 42 days after admission to the hospital. Necropsy Findings: 1. Hodgkin's disease, granulomatous type with lymphadenopathy, systemic, in- volving mediastinal, periaortic, cervical, and mesenteric lymph nodes, with sple- nomegaly, 490 g. 2. Bronchopneumonia, acute and organizing, massive, bilateral, with congestion and edema, massive, of lungs. 3. Ulcerations, acute, superficial, small, multiple, mucosal, of remaining portion of stomach. 4. Bleeding, massive, recent, gastrointes- tinal tract. 5. Hemoperitoneum, recent, localized to site of operation, 400 cc. 6. Valvulitis, rheumatic, healed, of mitral and aortic valve, with mitral stenosis, slight, cardiomegaly (500 g), ulcerations, superficial, multiple of the mitral valve, and vegetations, nonbacterial, small, mul- tiple, on the mitral valve. 7. Chronic passive congestion, marked, of liver, with central necrosis. 8. No gross involvement of the liver by Hodgkin's disease. SUMMARY OF CASE 824 History: This 10-year-old white girl entered the hospital for elective cardiac surgery. She had been known to have a heart murmur since birth, with no significant symptoms. Four years before the final admission, she had had cardiac catheterization, which showed interventricular septal defect and pulmonic ste- nosis. The liver was not palpable at this admis- sion. She was admitted finally for elective cardiac surgery, with a history only of slight easy fa- tigue and slight dyspnea on exertion, and no his- tory of cyanosis or congestive heart failure. Physical Examination: She was well nourished (weight, 64 Ib), not cyanotic, and not jaundiced. Blood pressure was 120/70. There was a sys- tolic murmur. There was no abdominal mass or tenderness. Clinical Course: Six days after admission she underwent an open-heart operation, consisting of attempted closure of an interventricular septal defect by suturing over it a flap consisting of a pulmonary valve leaflet, pulmonary valvulotomy, and plastic reconstruction of the right ventricular outflow tract, with a Teflon patch. This was per- formed with total cardiopulmonary bypass on a heart-lung machine. There were two attempts at the enlargement of the right ventricular outflow tract, and the pump time in two runs was a total of 82 miu. 149

Postoperatively she was slightly cyanotic, but not hypotensive, and initially oliguric. She was in and out of complete heart block and was on a pacemaker. On the 1st day, she became oliguric, with urine volumes under 100 cc per 24 hr. From the 2nd day onward, she had convulsions, first right- sided, then left-sided, and then generalized. She became unresponsive and showed hemiplegia. She remained oliguric and had bloody urine and marked fluid and electrolyte imbalance. She was hypotensive only for the last hour of life. She was never jaundiced. She died 3 days after surgery, and 9 days after admission to the hospital. Necropsy Findings: 1. Congenital heart disease with pulmonary stenosis, valvular and infundibular; in- terventricular septal defect, membranous, high, large, anterior; bicuspid pulmonary valve; right ventricular hypertrophy; operated, with significant right ventricular outflow tract obstruction, unintended, en- trapment of the chordae tendinae of the tricuspid valve in the sutures for the re- pair of the interventricular septal defect, and significant incomplete closure of the interventricular septal defect. 2. Recent encephalomalacia, multiple, small, partly hemorrhagic, in cerebral hemi- spheres and cerebellum. 3. Petechial hemorrhages, recent, diffuse, in cerebrum, cerebellum, and brainstem. 4. Pulmonary hemorrhage, focal ("pump lungs"). 5. Acute passive congestion of viscera. 6. Acute passive congestion of liver with central lobular necrosis. 7. Albuminous casts in kidney tubules, ex- tensive. 150

CHAPTER III-2. REPORT OF THE PATHOLOGY PANEL Edward A. Gall* University of Cincinnati College of Medicine and Cincinnati General Hospital Cincinnati, Ohio Massive hepatic necrosis was initially se- lected as the basis for an analysis of halothane toxicity. It seemed reasonable to assume that this condition could be related to universally ac- ceptable criteria and that, when present, it would constitute a sufficiently important lesion to find its way into a necropsy summary or a list of diag- noses. Thus, in each of the 34 participating hos- pitals a knowledgeable physician ("local selec- tor") reviewed the files of the cases necropsied at his institution during the 4-year period of the Study and selected all those thought to reflect massive hepatic necrosis that occurred within 6 weeks of the administration of a general anes- thetic. This survey yielded a total of 184 cases from all institutions; these were gathered from an over-all total of 10,171 complete necropsies. Later, abstracts of all necropsy reports were resurveyed by another person in a central institution (a nurse-medical librarian), to be cer- tain that no cases of hepatic necrosis had been missed by the local selector. To ensure the in- clusion of all possible cases, the reviewer se- lected all additional cases that were thought to represent massive or even lesser degrees of ne- crosis or whose necropsy reports mentioned hepatitis. This survey yielded 42 additional cases. The aggregate from the two surveys was therefore 226 cases. To establish the fact of massive necrosis with reasonable consistency and assurance, a Pathology Panel was convened, consisting of six members with special interest and experience in hepatic disorders. For each of the 226 cases, a complete abstract (lacking only an indication of the anesthetic used), a summary of the necropsy findings, and representative sections of liver were supplied to the Panel. METHOD OF PATHOLOGY REVIEW Initially, each member of the Pathology Panel received sections of all 226 livers stem- ming from this portion of the survey, but with no knowledge of the source or the clinical mani- festations. The Panel developed a simple tally form on which were indicated the various his- tologic features to be evaluated (Pathology Form 1). This tally had two purposes: (1) to determine the nature and extent (or absence) of necrosis, •For the Pathology Panel: Edward A. Gall (Chairman), Archie H. Baggenstoss, I. Nathan Dubln, Paul R. Glunz, Hans Popper, and Hans F. Smetana. and (2) to permit tabulation of the histologic fea- tures that, in aggregate, might constitute a com- plex with specific implications for halothane or other agents. Thus, parenchymal cellular altera- tion, autolysis, fatty change, inflammatory exu- date, cholestasis, and ductal and ductular pecu- liarities, and their degree and distribution, were listed and directed the attention of all panelists to common features. It must be emphasized that throughout this and later steps the pathologists did not know which anesthetic had been used in any patient. EXTENT OF NECROSIS In examining the liver for necrosis, each Panel member substantiated its existence (or absence) and indicated its degree. The latter was arbitrarily classified as: 1+, minor, not affecting more than 25 percent of the lobular parenchyma; 2+, affecting 25 to 50 percent of the parenchyma; 3+, destruction of approximately 75 percent of the parenchyma; or 4+, massive, affecting all or almost all the parenchyma. No effort was made to delineate the nature or cause of the necrosis during this phase of the study. In a later survey, however, cases that exhibited histologic features attributable to coincidental intrahepatic disor- ders, such as infarction, abscess, necrotic neo- plasm, and alterations related to biliary obstruc- tion, were deleted from further consideration, as were those with autolysis of a degree sufficient to preclude interpretation. On the cases retained as acceptable examples of hepatic necrosis, there was reasonably close agreement among the evaluators. Variations in scores were usually minor. But it was necessary for the members of the Panel to resolve dif- ferences in the relatively few cases at issue. That was accomplished readily, inasmuch as the discrepancies were almost wholly related to a failure, in the course of the preliminary planning, to consider the obscuring factors cited above and those related to pre-existing liver disease. When the differences had been reconciled, the scores were averaged and three categories of necrosis were established: minimal, with an average score of 1.5+or less (Fig. 1); intermediate, with a score of 1.6 to 2.5+ (Fig. 5); and massive, with a score of 2.6+or more (Fig. 6). In the course of determining the terminology to be used at the outset of the study, it was difficult to select phrases that would alert nonpathologist 151

screeners at each participating hospital to cases of hepatic necrosis that might be classified by other expressions. These selectors were there- fore urged to be lenient in their interpretation of terminology, so that borderline cases would not be missed. Undoubtedly as the result of this, the Panel found it necessary to eliminate 29 of the 226 cases initially received; of these, three were thought to exhibit no evidence of necrosis, seven to be associated with neoplasm, and 19 to be the seat of marked uninterpretable autolysis. More- over, among the 197 cases retained, 131 were judged to represent minimal necrosis, occasion- ally barely detectable. Lesions of this type are common in any necropsy population; they consti- tute a nonspecific reflection of the agonal state and are considered to have negligible significance. These cases were obviously not properly included among bona fide cases as examples of hepatic necrosis, and were therefore deleted. There re- mained, however, 66 cases: 35 with necrosis of intermediate degree and 31 with massive necro- sis (2.6+ or more). This relatively small yield (29 percent) among the cases originally selected for consideration will be discussed further. SUPPLEMENTARY SELECTION Experience with selection on the basis of necropsy abstracts suggested that some examples of massive necrosis might have been overlooked by local selectors. It seemed desirable, there- fore, to make another effort at screening cases of necrosis that might conceivably have been missed in the first search. This was accomplished by another survey of necropsy protocols. A pa- thologist* was selected by the Panel and was re- quested to gather all conceivable examples of hepatic necrosis for final study. In reviewing the 10,171 necropsy reports, it was found that the liver was mentioned in the list of final diagnoses in 5967. The pathologist was asked to consider these carefully and, as in the case of the local selectors, to cull cases whose necropsy reports contained any indication of primary hepatic in- jury, including hepatitis. Cases of necrosis in re- lation to metastatic neoplasm, in which there was fatty metamorphosis without necrosis, and in which there was an obvious independent condition (e.g., infarction, abscess, pylephlebitis, obstruc- tive jaundice, alcoholic hepatitis, or other pre- existing disease) were not to be included. On the basis of this survey, 746 additional cases were selected for more detailed evaluation. Histologic preparations were obtained from 720 of these; tissue and sections were not available from the remainder. Two pathologists** at the Armed Forces Institute of Pathology with con- siderable experience in hepatic disorders re- viewed the 720 preparations. They were familiar with the needs of the Study and selected all ex- •Charles M. Blumenfeld, Sacramento. **Kamal G. Ishak and Beatrice Ishak. amples of necrosis, regardless of degree, that were not obscured by autolysis or readily attrib- utable to obvious extrahepatic or intrahepatic cause. An additional 146 cases of hepatic necrosis were brought to light. Representative sections of these were circulated among members of the Pathology Panel for review, as in the original group of cases submitted. The Panel agreed on the existence of necrosis in all instances. As in the initial survey, the scores rendered were averaged; in 80 there was intermediate ne- crosis, and in 51 massive necrosis. Most of the remainder represented minimal necrosis and were therefore excluded. The final tally, there- fore, combining both the initial screening and the supplementary selection, was 82 cases of mas- sive hepatic necrosis and 115 cases of interme- diate hepatic necrosis. CAUSES OF HEPATIC NECROSIS At this stage another method of study was carried out with the 226 cases submitted orig- inally by local selectors. Members of the Pathol- ogy Panel, who had already reviewed and evalu- ated the histologic sections, now received abstracts of the clinical course with details of the operative procedure (s), laboratory tests, postoperative course, and findings at necropsy. Again, knowledge of the anesthetic (s) was with- held. From this information and with the knowl- edge of the histologic features in the liver, another form was completed (Pathology Form 2). This permitted the panelists to indicate their impressions of the causative basis for the hepatic necrosis (i.e., halothane, any hepatotoxin, any drug sensitization, or hepatitis virus; shock, anoxia, or sepsis; any other factor; autolysis; etc.). Unfortunately, in this phase of the study, opinions were greatly individualized and thus showed little uniformity. No pertinent criteria for designating the various etiologic categories had been agreed on in advance by members of the Panel. Each pathologist, therefore, used his own criteria and often found it necessary to designate more than one possible cause. Indeed, it is well recognized that a number of different agents may cause identical hepatic alterations (3,8,13). In one category, nonetheless, there was a remark- able degree of conformity: in the group attributed to "shock, anoxia, or sepsis." This group did not, of course, constitute a pathologic entity, but in- cluded many overlapping patterns. Moreover, the clinical record made it fairly obvious that one or more of these conditions had prevailed and un- doubtedly influenced the pathologist in his con- clusion. PATHOLOGIC FEATURES Hepatic necrosis has no consistent pattern; all forms and variations may be observed (14). These range from minor focal lesions with either random or regular zonal distribution to total 152

parenchymal destruction. Thus, among the cases excluded were those with small collections of neutrophils intermingled with clusters of necrotic liver cells, scattered irregularly, and with no uniform lobular orientation. These occurred fre- quently, affected considerably less than 25 per- cent of parenchymal substance, and were deemed of minor import (Fig. 1). They represented the hepatic counterpart of terminal infection or the disintegrative effects of the agonal state. Another reflection of the metabolic derange- ments of terminal illnesses and of the postopera- tive state was the occurrence of fatty vacuoliza- tion, which in various degrees might accompany any form of necrosis or indeed appear in marked degree without any necrosis at all (Fig. 2). Such cases were weeded out and excluded because in most instances they represented coincidental con- comitants and, although they may have attained considerable prominence, in themselves appeared to have no bearing on the maintenance of hepatic integrity. In a few instances, however, the lesion constituted a significant widespread alteration reflecting severe parenchymal injury (Fig. 3). In these the appearance of the lipid differed some- what from that unaccompanied by recognizable hepatic cell injury. It exhibited a microvacuolar form causing marked enlargement and irregu- larity of cells and much architectural disarrange- ment. Nuclei variously exhibited swelling and pyknosis. Cells underwent cytoplasmic coagula- tion and necrosis, usually focal; in some there was rather widespread distribution. Paralleling these changes were canalicular bile stasis, neu- trophil aggregation, pigment deposit in and undue prominence of Kupffer's cells, and occasionally inflammatory exudate in portal areas. In two cases this pattern had the added feature of "alcoholic hyalin" formation (Fig. 4); both patients were flagrant overusers of alcohol. In most instances the necrosis was oriented about the centrilobular vein with the extent vary- ing from minimal, or less than 25 percent of the lobule (Fig. 1), to maximal, or more than 75 per- cent of the lobule (Figs. 5, 6). Total loss of pa- renchyma (Fig. 7) was rare; the lesions of major degree often showed a thin periportal row of dis- turbed but viable parenchymal epithelium (Fig. 8). In this group two basic patterns were recognized, but on occasion they appeared to overlap, partic- ularly if of some duration or obscured by post- mortem changes. In one pattern, constituting the result of vas- cular disturbance and thus characterized by pas- sive congestion, there was dilatation and engorge- ment of centrilobular veins and the central reaches of hepatic sinusoids (Fig. 9). Seepage of red cells or plasma into the spaces of Disse resulted in attenuation of parenchymal cell plates and ultimately in their necrosis. Cells underwent di- rect disintegration or exhibited cytoplasmic eo- sinophilia and nuclear pyknosis. It is probable that these cytologic features merely represented variations of the same process. In those with terminal accentuation of congestion or the later superimposition of another clinical complication (e.g., hemorrhage, shock, or sepsis), cytoplasmic coagulation resulted; in the others, parenchymal attenuation or frank necrosis followed a longer and perhaps more gradual process. Inflammatory cells appeared in moderate numbers, neutrophils predominating in the acute lesion and macrophages in those of longer standing. In cases with sudden and fatal shock, a seeming central pooling of blood and loss of parenchyma were manifest. In this circumstance the linear division between viable and nonviable parenchyma was usually ir- regular and ill-defined, with contiguous viable cells containing small amounts of lipid. Occa- sional cells were swollen but exhibited few fea- tures of regeneration. The portal areas in these cases were essentially normal. The other pattern lacked significant evidence of congestion. Here also, however, various com- ponents of the lesion exhibited features that ap- peared to depend in large part on duration. In its most striking form, acute coagulation necrosis of part of or all the lobular parenchyma appeared (Fig. 10). All cells were in an identical state of recent death, characterized by a granular, coagu- lative shrinkage of cytoplasm with loss or pyk- nosis of nuclei. A sharp line of separation existed at the juncture with viable elements. Neutrophils were intermingled with the necrotic cells and were aggregated at the zonal margins; various numbers, usually few, were evident in the periph- eral viable zone. A rare necrotic cell, seques- tered from its neighbors, assumed a hyaline ap- pearance reminiscent of the acidophilic body observed in viral hepatitis (6,11,15). Little fatty change accompanied this lesion and the portal areas were unaffected, except in cases of total parenchymal destruction. In the instances of total or subtotal destruction, the peripheral residuum of parenchyma was the seat of some regenerative activity with swelling and multinuclearity of the parenchymal cells. This was often accompanied by early ductular proliferation. In still other examples, presumably repre- senting the same lesions but probably with more prolonged courses (or perhaps with long post- mortem intervals), cytoplasmic disintegration had occurred, with "fallout" of cells (Fig. 11). The zone of necrosis in these was characterized by a content of granular detritus, fewer or no neutrophils, and an intermingling of macrophages (or Kupffer's cells) filled with bile and hemosid- erin pigment. The line of juncture here was not sharp. The residual viable cells now exhibited ir- regularity, loss of polarity, multinuclearity, and even mitotic activity. At this stage few neutro- phils remained. In the more extreme lesions in which the periphery of the lobule was affected, periportal ductular proliferation was striking (Fig. 12). In some of these the portal areas were edematous and contained moderate lymphocytic infiltration. In a few, in both acute coagulative and "fallout" lesions, a very heavy lymphocytic exudate prevailed in the portal areas and was, on occasion, universal in its distribution (Fig. 13). 153

Figure 1.—Minimal centrilobular necrosis (Case 7). Ne- crosis affects less than 25 percent of the lobular paren- chyma. Cells bordering on the centrilobular vein have undergone disintegration and there is dilatation of re- lated sinusoids with a scant intermixture of neutrophils. The remainder of the lobule is intact. Postmortem change affects sharpness of detail. Hematoxylin and eosin. X 150 Figure 4.—Alcoholic hepatitis (Case 33). Liver cells are markedly swollen and Irregularly disposed and exhibit foci of individual cell necrosis surrounded by a narrow halo of inflammatory cells. Some of the swollen cells appear vacuolated, and others exhibit condensation of cytoplasm to form a refractile eosinophilic coagulum (alcoholic hyalin). Hematoxylin and eosin. X 250 Figure 2.—Fatty liver (Case 105). Liver cells are the seat of severe coarse vacuolization. There is, however, no disarrangement of parenchymal plates and no evidence of accompanying necrosis. A portal area included is quies- cent, exhibiting no inflammation. Hematoxylin and eosin. X150 Figure 5.—intermediate necrosis (Case 200). The central portion of all lobules has undergone necrosis and disin- tegration. Hematoxylin and eosin. X 100 Figure 3.~Toxic hepatitis (Case 206). Severe fatty vacuoli- zation is here characterized by a prevalence of fine foamy cytoplasmlc vacuolization with irregularly swollen epi- thelium. Liver plates are two or more cells thick and elsewhere in this lobule are minute areas of acute ne- crosis with neutrophil reaction. The portal area included also exhibits a significant inflammatory (lymphocytlc) exudate. Hematoxylin and eosin. X200 (See Fig. 6.) Figure 6.—Massive necrosis (Case 206). Most of the pa- renchyma has undergone necrosis, with only a few small islands of viable cells remaining. In the main, the necro- sis centers about central veins, one of which may be seen in the center of the photograph. Hematoxylin and eosin. X 100 (See Fig. 3.) 154

Figure 7.—Massive necrosis (Case 46). Massive necrosis is characterized by complete loss of parenchyma with re- placement by detritus, Kupffer's cells, and a mixed in- flammatory exudate. At the right is the remnant of a portal area containing interlobular bile ducts and inflam- matory cells. Hematoxylin and eosin. X 200 Figure 8.—Massive necrosis, periportal area (Case 36). Almost all the lobular parenchyma has undergone coagu- lation necrosis and disintegration. A thin rim of viable but abnormal and irregular cells remains, fringing the portal tract. Hematoxylin and eosin. X 150 (See Fig. 18.) Figure 9.—intermediate necrosis with centrilobular con- gestion (Case 82). Centering about the central vein, sinu- soids are widely distended by packed red cells, which, because of destruction of approximately one-third of the parenchyma, appear to be pooled. A scant inflammatory reaction appears in the area of destruction. Hematoxylin and eosin. XI50 Figure 10.~Centrilobular necrosis (Case 98). Parenchymal cells in the central half of this lobule have undergone coagulation necrosis. Shadowy outlines of the affected cells persist but the cytoplasm has become granular, refrac- tile, and eosinophilic. A few pyknodc nuclei remain but nuclear staining is generally absent. Only a mild early inflammatory reaction is evident at the margin of the necrotic zone. The more peripheral viable parenchyma exhibits cytoplasmic swelling and fatty vacuollzation. Hematoxylin and eosin. X 150 .•V**v»VC T - ,srfMr Figure 11.—Intermediate centrilobular necrosis with "fall- out," probably reflecting duration and, perhaps, post- mortem interval (Case 86). Necrotic cells have disap- peared, leaving behind only an amorphous stromal matrix in which are fragments of nuclear debris and pigment- laden phagocytes. The radial pattern of residual viable cells is undisturbed. Hematoxylin and eosin. XI50 ^Xlf-r.i&^ CT-..--«•"• f i^y^P^T, ^^^ •• .:•; c- Figure 12. — Massive necrosis (Case 93). Coagulated ne- crotic cells border on an inflamed portal tract. The few remaining viable elements are swollen, their nuclei are vesicular and bizarre, and there is a ductule-like pro- liferation. This is thought to represent an abortive effort at regeneration. Hematoxylin and eosin. X 200 155

Figure 13.—Massive necrosis (Case 44). Only a few small Islands of viable parenchyma remain; the bulk of the liver Is necrotlc. Each portal area stands out as darkly stained, because of heavy lymphocytlc infiltration. There is little inflammation in the parenchymal region. Hematoxylin and eosin. X 100 (See Fig. 19.) DISCUSSION The incidence of postoperative hepatic ne- crosis was relatively modest. The massive lesion appeared in approximately 0.7 percent of necropsy cases, and intermediate necrosis in 1 percent. The minimal lesion was ignored because, as in- dicated, it is considered to be commonplace in the process of dying and is universally accepted as such. For this reason, its existence might or might not be listed among anatomic diagnoses and its selection by the screener would be unpredict- able. This minor degree of alteration, moreover, would not be expected to have significant clinical manifestations or to bear on the outcome of a case. Intermediate necrosis, however, could well contribute to a lethal outcome. Although the Study was not designed to collect cases of this nature, some actually appeared in the first group gathered by local selectors, and others came under con- sideration in the later collections. Such cases would not, however, be expected to cause death unless associated with another potentially fatal disorder. But massive hepatic necrosis, as de- fined by the Panel (Figs. 6, 7, 8, and 12), is with very rare exceptions incompatible with life; it is in itself a fatal condition (2,10). It seems most unlikely that instances of truly massive hepatic necrosis would escape the screen- ing methods used among the necropsy cases. It would have been unusual, indeed, for massive lesions to fail to come to the attention of the local selector, the nurse-medical librarian, and the pathologist examining the necropsy abstracts. It was with this in mind that wide latitude was given the case finders in determining those cases to be subjected to pathologic scrutiny. Such categories as "hep- atitis" and "liver degeneration," for example, were therefore included initially, inasmuch as it was intended from the outset to submit sections from all cases to scrutiny by the Pathology Panel. Although some of these did prove to be hepatic necrosis, many were of necessity excluded, and only 31 of the originally collected cases found their way into the final group with massive ne- crosis. Nonetheless, in the face of the obvious dif- ficulties in case finding, one may well raise the question of how many examples of hepatic ne- crosis observed pathologically may have failed to emerge in the diagnostic listings and thus may never have come to the attention of the various screeners. As an additional precaution, the ne- cropsy cases were sampled to detect hepatic abnormality that was not recorded in the final diagnosis. No instances of massive necrosis had failed to be included in the lists of diagnoses in the necropsy protocols examined, although several cases of intermediate necrosis had been missed. It is reasonable to conclude that almost all examples of massive necrosis in the necropsy population were recognized and examined by the Panel. There is no doubt that there were ad- ditional fatal cases with similar lesions among those not necropsied. There is no feasible way of detecting these at present. Reliability of Coded Diagnosis A more disturbing matter, however, was the apparent lack of uniformity among pathologists at large in recognizing or designating hepatic ne- crosis in such a way that it could be appreciated by nonpathologist readers of the pathology re- ports. The need of the Pathology Panel to reject out of hand 29 of the original 226 cases and to consider 131 others to have only negligible ne- crosis may in some measure be attributed to typographic errors, the submission of poor or improper sections for review, the manner of per- formance of necropsies, or the coding of diag- noses by inadequately trained personnel, as well as to the policy adopted of encouraging the local selector to submit questionable cases for evalua- tion. A review of the abstracts, unfortunately, also indicated a distressing variation in nomenclature and a significant range of pathologic criteria for the diagnosis of necrosis. Among the 226 cases submitted initially, 108 were stated by the local pathologists to have some form of hepatic necro- sis and 66 were classified as hepatitis. The sub- mission of the remaining 52 may have repre- sented bias or error, but in most cases un- doubtedly reflected an arbitrary choice by the local selector in an effort to avoid missing pos- sible cases of necrosis. They had been listed as fatty infiltration, biliary obstruction, hepatic neo- plasm, putrefaction (? autolysis), or pre-existing cirrhosis. However, even among the 108 in which the pathologist's opinion clearly stated that ne- crosis or hepatitis existed, the Panel found that the lesion could be established as massive ne- crosis in only 31 cases, and as intermediate ne- crosis in 35. There was no necrosis in two, ne- crotic neoplasm in five, and sufficient autolysis to preclude interpretation in 10; in the remaining 25 cases, the necrosis was minimal. 156

Interpretation of Autolysis Because it was known that the existence of autolysis would neither exclude nor substantiate the existence of necrosis, the sections and clinical abstracts in 19 cases were evaluated more crit- ically (the 10 originally listed as necrosis by the submitting pathologist and nine considered to rep- resent autolysis but with other features contrib- uting to the selection). So that it could be deter- mined whether necrosis might have been masked by autolysis, the appraisal consisted of a corre- lation of clinical phenomena and detectable evi- dence of hepatic necrosis in the poorly stained section (Fig. 14). It appeared reasonable to make this distinction, and in three of the 19 cases he- patic necrosis undoubtedly existed before death. One of these was a patient with choledocholithiasis and biliary obstruction, and another was con- sidered to have had homologous serum hepatitis. The third case, however, could not be explained by the clinical data. The remaining livers, 10 of which had been claimed by the local pathologist to show necrosis, were considered to have been un- damaged in life. Pathologic Alterations Mistaken for Necrosis A number of cases were listed in necropsy reports as examples of hepatic necrosis but were not so considered by the Panel. The reasons for their exclusion are given below. In instances of sudden death in healthy per- sons whose livers were unaffected by degradation before death, the preservation of hepatic paren- chymal glycogen, the clarity of cytoplasmic stain- ing, and the sharpness of cell outline all contrast with the usual somewhat blurred "normal" post- mortem appearance (Fig. 15). This was, in at Figure 15.~Normal liver (Case 288). Radiating from the central vein are clearly outlined liver cells with uniform nuclear content. The preservation of the sharp cell mem- brane is a feature of the liver in sudden death. Hematoxylin and eosin. X200 least one case, misinterpreted as an abnormality and bears comment only because it was taken as an indication of intrinsic hepatic injury. The accumulation of parenchymal fat was also considered by some as evidence of hepatic damage. Actually, it is common during a terminal period of illness with restricted caloric and pro- tein intake, and common in the postoperative state as well. Such fatty "degeneration," reflecting re- duced protein synthesis (Fig. 2), may be mistaken for toxic hepatitis, which is also characterized by lipid accumulation (Fig. 3) (1,16). Examples of the former complicated by minor evidences of agonal hepatic cellular necrosis, passive conges- tion, or postmortem parenchymal cell "fallout" seemingly had been misinterpreted as hepatic necrosis, particularly when the fat accumulation was considerable. A distinction between this form of fatty degen- eration and that more commonly associated with toxic injury to the liver, whether following the * i -. r•- V ' •fi!'*'- -/^w" -"C T - V' .- x.^^Vtf! >,- •?•» :-i Figure 14.--Autolysis (Case 27). Staining capacity is lost, cytologic detail is obscured, and inflammatory cells cannot be identified. It is still possible, however, to distinguish the centrilobular zone of necrosis from the peripheral fringe of quasi-preservation. Hema- toxylin and eosin. X150 157

ingestion of noxious agents (as in carbon tetra- chloride toxicity) or in the case of acute alcohol- ism, should be possible in most instances (5). The latter condition was occasionally encountered among the cases with intermediate necrosis. The fuzzy microvacuolar appearance of the lipid (Fig. 3) and its accompanying focal necrosis, bile stasis, neutrophil exudate, and (in the patients with alcoholism) alcoholic hyalin (Fig. 4) con- stituted clearly distinguishing features. No ex- ample of sudden death with simple fatty metamor- phosis was encountered. In a few cases, pre-existing hepatic disorders were improperly related to the postoperative state. Although in some there was evidence of terminal necrosis, this fell into the pattern of chronic hepatitis with portal area inflammation and ductular proliferation but little current paren- chymal alteration. Obviously, these had been vul- nerable livers and could have been unduly suscep- tible to vasomotor disturbances. As examples of necrosis induced by anesthetics, however, such cases would have little validity. Extrahepatic biliary obstruction appeared with the usual manifestations of cholestasis (6) but were often overlain by suppurative complica- tions as well. Whether for this reason or other causes, autolysis was a frequent concomitant, leading in some instances to inclusion in the he- patic necrosis group. In like manner, cases with inflammatory reaction reflecting systemic in- fection, some with abscess formation (Fig. 16) or advanced autolysis (as with gas bacillus infection), were unjustifiably included. Other conditions en- countered were arterial or venous vascular oc- clusions (some with pylephlebitis), infarction (Fig. 17), and metastatic carcinoma with necrosis of contiguous parenchyma. Each of these conditions exhibited distinguish- ing features, and the Pathology Panel felt justified in their exclusion from consideration. Indeed, in almost every instance the manner of death was unrelated to hepatic failure and reflected, instead, another primary disorder. Figure 16.—Hepatic abscess (Case 214). Case of obstructive jaundice with suppurative cholangitls. Hematoxylln and eosin. X100 The Panel thus accepted only those cases in which cell death in vivo was recognizable and in which none of the factors indicated above could be incriminated. This constituted the basis for the ultimate selection of the 222 cases. Hepatic Necrosis Attributable to Anesthetic Agents Any organ as susceptible to injury by such a wide variety of influences as the liver poses a problem in determining the immediate cause of its malfunction. It is relatively easy (and many have followed this course) to indict an adventitious circumstance in a given instance of hepatic ne- crosis. But experience has shown that easy as- sumptions are not particularly fruitful. All attend- ant conditions require critical evaluation before any single factor can be implicated. This was es- sentially the situation in patients receiving an an- esthetic; they suffered from ailments, serious or not, that required operation, and thereafter they were subjected to the surgical procedure and a host of adjuvant treatments. Each of these pro- vides inherent risks. Moreover, the population at -*. -*'. >,'rV«- **'*- Figure 17.—Hepatic infarct (Case 4). A sharply circumscribed zone of necrosis is brightly eosinophilic and set off from the sur- viving viable hepatic substance. in the higher-power view (right), the contrast between the cells in the infarct and the viable survivors is well shown. A narrow zone of inflammatory cells encircles the necrotic elements.i Hematoxylin and eosin. Left, X 100; right, X 150. 158

large carries adventitious illness at a certain rate, whether or not manifestations are overt (e.g., viral hepatitis) (4,12,19). Finally, potential risks exist in the anesthetics themselves. Thus, in determining the causal relationships between anesthetics and a group of cases with hepatic ne- crosis, each case requires individual probing. The results of a survey carried out by four members of the Subcommittee, representing dif- ferent medical specialties (anesthesiology, medi- cine, surgery, and pathology), are recorded in Chapter III-1. That group attempted to determine on the basis of the clinical data available whether the hepatic necrosis could be attributed to factors other than the anesthetic. The group found itself in agreement that the cause of the lesion was ap- parent in the patient's record in 90 percent of the 197 cases of massive and intermediate necrosis. It would follow that the anesthetic, whatever it proved to be, could well be exonerated in those cases. But there were 19 cases in which all or most of the group did not determine an apparent cause for the necrosis. These were considered "unexplained," as distinct from the "explained" cases in which a clinical basis for the liver de- struction was apparent. In these 19 cases, neither the clinical course, the operative procedure, nor the existence of complicating illness appeared to have had the capacity to contribute to the hepatic process. In nine of the 19 cases the lesion was mas- sive, and in 10 it was intermediate. When decoded as to the anesthetic exposure, it was found that halothane was the agent used in 14 cases (seven massive and seven intermediate), nitrous oxide- barbiturate once (intermediate), ether twice (both intermediate), cyclopropane once (massive), and Other once (ethylene, massive). The occurrence of 19 instances of "unex- plained" hepatic necrosis in a necropsy popula- tion of 10,171 persons (with abdominal necropsy examination) exposed to anesthesia may be taken to indicate that the liver is only rarely vulner- able to an anesthetic agent. The question at is- sue, however, is: "Does halothane have a greater role in this respect than other agents?" In this small group halothane appeared to be a more common offender. It is obviously possible that anesthetic- induced hepatic disorder also occurred among those cases ascribed to definable causes in the "explained" category. And it is equally plausible to argue that an undetected factor, other than an anesthetic, may have prevailed in the "unex- plained" group. If one deals only with the results of the methodology used, whatever its crudities, one may conclude that, among the 10,171 ne- cropsied persons subjected to anesthesia (and among the 197 patients with massive and inter- mediate hepatic necrosis), there were 19 in whom the hepatic process might reasonably have been attributed in some way to the anesthetic used. Of these, 14 patients had received halothane and five had received other anesthetics. Specific Lesion Caused by Halothane Once the category of "unexplained" hepatic necrosis had been established, an effort was made to distinguish a histologic pattern that might reflect the specific effects of halothane and aid in the distinction of the lesion from that ap- pearing after the administration of other agents. As indicated above, members of the Pathology Panel were unable to find a common meeting ground to derive such a conclusion. In a further effort, sections from the 19 cases were intermixed with those from 19 "explained" cases selected at random and examined by one member of the Panel* without recourse to clinical information until the analyses were completed. Of the 19 "explained" cases, 17 fell among the group ascribed to "shock, anoxia, or sepsis"; six of the 19 "unexplained" cases exhibited such lesions. As in the original survey, many variations appeared related to the duration of the lesion. Thus, a necrotic zone might exhibit cytoplasmic coagulation (Fig. 18) and disintegration in some sections, and "fallout" in others (Fig. 11); the one would reflect a recent lesion, and the other, one of longer standing. This was also the case with intralobular inflammatory reaction; cases of re- cent origin exhibited little or no exudate; those of longer duration exhibited a neutrophil reaction reaching from the margin of necrosis and ulti- mately intermingling with the nonviable cells. Cases characterized by "fallout" exhibited little neutrophil reaction; here, macrophages prevailed, but with varied prominence. Except in one in- stance (case 98, Fig. 10), parenchymal fat was purely adventitious. Regeneration was evidenced by irregular swelling of residual liver cells, multinuclearity, and, rarely, mitoses (Fig. 12). These changes were paralleled by periportal ductular proliferation, which, however, was not striking. Such bile stasis (cast formation) as oc- curred was limited to these ductules and was rarely marked. *ws* ^y. 'Tgl -A^98,Vz Figure 18.—Massive necrosis (Case 36). A residual perl- portal Island of viable parenchyma borders the necrotic lobules in which coagulated and disintegrating cells have not yet lost individuality. Contrast with Fig. 10. Hematox- ylin and eoain. X 200 (See Fig. 8) *E. A. Gall. 159

Figure 19.—Massive necrosis with portal area exudate (Case 44). Coagulation necrosis has destroyed all but two- or three-cell-layered periportal lamina. The portal area it- self is heavily infiltrated with lymphocytes; this was a feature of all portal areas in this liver. Hematoxylin and eosin. X200 (See Fig. 13.) In 15 cases (13 "unexplained" and two "ex- plained"), the portal areas exhibited enlarge- ment, edema, and inflammatory (mononuclear) reaction of rather marked degree. In 12, the dis- tribution of this process was universal, affecting all portal areas (Figs. 13 and 19) (8). Of the "un- explained" cases, 11 were patients who had re- ceived halothane; one was given nitrous oxide- barbiturate and one, cyclopropane. In neither of the two cases of "explained" necrosis was halo- thane involved. Although there was no unique or consistent lesion reflecting the effects of halothane admin- istration, the feature of severe and universal portal area inflammation occurred with signifi- cantly greater frequency in the small group of "unexplained" cases in which halothane was the agent used. None of the other histologic changes (distribution, type or degree of necrosis, type of intralobular exudate, etc.) appeared to have any pertinence. It is noteworthy that neither canalic- ular bile stasis nor a prevalence of eosinophils appeared in any of the cases. The pattern of portal area inflammation, however, is not unfamiliar to the pathologist; it has also been observed in cases of fatal hepatic disease of other causation, nota- bly in fatal viral hepatitis (18) and in some drug intoxications (7,9,17,18). SUMMARY A pathologic survey concerned with the in- cidence and nature of hepatic necrosis was car- ried out in 10,171 necropsy cases. These were all the cases in which there had been complete necropsy, including examination of the abdomen. Variations in diagnostic criteria and nomencla- ture in the different participating hospitals, in methods of classification, and in screening tech- niques interfered with proper case selection. Despite this, it is believed that all examples of massive hepatic necrosis and almost all those with intermediate necrosis among cases necrop- sied were brought to light. A scrutiny of necropsy diagnoses by varied means led to the accumulation of 972 cases of possible hepatic necrosis; microscopic sections of 946 of the livers were procured for review. A panel of six pathologists, experienced in hepatic disorders, reviewed the sections obtained independently and with no knowledge of the clin- ical history or anesthetic used. Hepatic necrosis of various degrees was found in 222 cases: 82 massive, 115 intermediate, and 25 minor and deemed negligible. The Pathology Panel next attempted to assign a cause for the hepatic necrosis, combining a knowledge of the clinical data (except the anes- thetic used) and the histologic pattern of the liver. Except for recognition of the effects of anoxia, shock, or sepsis, the Panel was not able to de- termine an etiologic basis for the lesions with any degree of uniformity or consistency. The histologic appearances of sections from 19 cases with necrosis, considered by a multi- specialty committee to be "unexplained" by fac- tors detectable in the clinical record, were criti- cally studied and compared with 19 cases in which the hepatic necrosis was deemed to be the result of overt factors. No consistent histologic pattern could be attributed to halothane. It appeared, however, that cases associated with halothane exhibited a lesion simulating that encountered in fatal viral and some drug-induced forms of hep- atitis more often than cases associated with other anesthetics. In respect to the apparent relationship, three questions may be posed: (1) Had the patient harbored a clinically in- apparent viral hepatitis that had progressed by spontaneous exacerbation to a fatal outcome? (2) Had an occult and seemingly innocuous viral hepatitis been provoked into violent pro- gression under the stress of a complicating disease, the surgical procedure required for its correction, or the anesthetic used? (3) Had the hepatic disorder been induced de novo by the anesthetic, either as a direct toxic effect or by reason of idiosyncrasy? Unfortunately, the evidence gathered does not permit unequivocal affirmation of any of the assumptions implicit in these questions. One may suspect that in a rare person exposed to halothane a special sensitization constitutes a triggering mechanism, but there is no indication that this was regularly the case or that one or the other mechanisms may not have existed equally as well. CONCLUSION The incidence of massive hepatic necrosis in a large postoperative necropsy population was exceedingly low. Moreover, in the bulk of such cases the hepatic lesions were readily attribut- able to such factors as shock, infection, anoxia, pre-existing disease, and even extensive sur- gical manipulation. Only rarely did the anesthetic appear to be involved: in 19 cases of massive 160

and intermediate necrosis among the 10,171 ne- cropsied cases investigated. Of these, 14 cases involved halothane, and five did not. No clear-cut or universally acceptable histologic lesion was regularly found in the cases attributed to halo- thane. REFERENCES 1. Ballard, H., M. Bernstein, and J. T. Farrar. Fatty liver presenting as obstructive jaun- dice. Amer. J. Med. 30:196-201, 1961. 2. Davidson, C. S. Hepatic coma; thoughts on terminology. Arch. Intern. Med. 104:515- 517, 1959. 3. Dible, J. H. Degeneration, necrosis, and fi- brosis in the liver. Brit. Med. J. 1:833-841, 1951. 4. Gal1, E. A. Posthepatitic, postnecrotic, and nutritional cirrhosis: A pathologic anal- ysis. Amer. J. Path. 36:241-271, 1960. 5. Gal1, E. A. The diagnosis of heptatitis by needle biopsy, pp. 475-498. In F. W. Hart- man, G. A. LoGrippo, J. G. Mateer, and J. Barron, Eds. Hepatitis Frontiers. Henry Ford Hospital International Symposium. Boston: Little, Brown and Co., 1957. 6. Gal1, E. A., and O. Dobrogorski. Hepatic al- terations in obstructive jaundice. Amer. J. Clin. Path. 41:126-139, 1964. 7. Herbut, P. A., and T. M. Scaricaciottoli. Diffuse hepatic necrosis caused by sul- fadiazine. Arch. Path. 40:94-98. 1945. 8. Hoffbauer, F. W., Ed. Liver Injury. Trans- actions of the Sixth Conference. May 1-2, 1947. New York: Josiah Macy, Jr. Founda- tion, 1947. 74 pp. 9. Liber, A. F., and B. Barshay. Polykaryotic hepatitis in a patient treated with para- minosalicylic acid. Arch. Path. 58:153-158, 1954. 10. Lucke', B., and T. B. Mallory. The fulminant form of epidemic hepatitis. Amer. J. Path. 22:867-945, 1946. 11. Mallory, T. B. The pathology of epidemic hepatitis. J.A.M.A. 134:655-662. 1947. 12. Neefe, J. R., R. F. Norris, J. G. Rinehold, C. B. Mitchel1, and D. S. Howell. Carriers of hepatitis virus in the blood and viral hepatitis in whole blood recipients. I. Studies on donors suspected as carriers of hepatitis virus and as sources of post- transfusion viral hepatitis. J.A.M.A. 154: 1066-1071, 1954. 13. Popper, H. Liver disease - morphologic considerations. Amer. J. Med. 16:98-117, 1954. 14. Popper, H., and F. Schaffner. Response of the liver to injury. Progr. Liver Dis. 1:86- 108, 1961. 15. Popper, H., P. B. Szanto, and M. Partha- sarathy. Florid cirrhosis; a review of 35 cases. Amer. J. Clin. Path. 25:889-901, 1955. 16. Popper, H., and P. B. Szanto. Fatty liver with hepatic failure in alcoholics. J. Mount Sinai Hosp. N.Y. 24:1121-1131, 1957. 17. Rosenblum, L. E., R. J. Korn, and H. J. Zimmerman. Hepatocellular jaundice as a complication of iproniazid therapy. Arch. Intern. Med. 105:583-593, I960. 18. Smetana, H. F., T. C. Keller, and I. N. Dubin. Histologic criteria for the differential diagnosis of liver diseases in needle biop- sies. Rev. Gastroenterol. 20:227-244, 1953. 19. Stokes, J., Jr., J. E. Berk, L. L. Malamut, M. E. Drake, J. A. Barondess, W. J. Bashe, I. J. Wolman, J. D. Farquhar, B. Bevan, R. J. Drummond, W. D. Maycock, R. B. Capps, and A. M. Bennett. The car- rier state in viral hepatitis. J.A.M.A. 154: 1059-1065, 1954. 161

CHAPTER III-3. ANALYSIS OF MASSIVE HEPATIC NECROSIS DATA John P. Gilbert Harvard Computing Center Cambridge, Massachusetts John P. Bunker Stanford University School of Medicine Palo Alto, California The National Halothane Study was initiated to determine whether the few cases of massive he- patic necrosis reported to have occurred after halothane anesthesia might reflect a much higher incidence of unreported cases. The study of he- patic necrosis, described in the preceding two chapters, failed to uncover the large number of cases feared. On the contrary, the incidence of massive hepatic necrosis after halothane was very small, and differed little if at all from that after the other anesthetic practices. The very scarcity of observed cases makes it difficult to draw conclusions about other specific, more- probing questions. Lack of necropsy material for some of the deaths, possible "volunteer bias" in the selection of the participating institutions, and prior publication of about half the so-called "un- explained" cases add to the difficulty of inter- preting the hepatic necrosis data. THE OVER-ALL INCIDENCE OF MASSIVE HEPATIC NECROSIS During the 4 years reviewed, 856,515 admin- istrations of general anesthesia were followed within 6 weeks by 16,840 deaths. Of these deaths, 10,171 had necropsies that included examination of the abdominal cavity. Among these necropsied deaths, 82 instances of massive hepatic necrosis were identified by the procedures described in Chapter m-1. To estimate the over-all incidence of massive hepatic necrosis, we must consider the nonnecropsied cases and we must also con- sider the possibility that some cases among those necropsied could have escaped detection. The possibility that massive hepatic necrosis could be overlooked at necropsy was judged to be slight by the members of the Pathology Panel. Some support for this opinion was provided by a site-visit review of six institutions conducted by William H. Forrest, Jr., and John P. Bunker. Re- view of the complete necropsy reports of all cases at those institutions uncovered no new cases that seemed likely to involve massive hepatic necrosis. Although this limited review does not preclude the loss of a few cases by clerical or diagnostic error (as discussed in greater length in Chapter m-1), the loss of cases of massive hepatic ne- crosis in the necropsied deaths can probably be regarded as of relatively minor importance. The loss of cases of massive hepatic necro- sis in deaths not examined by necropsy is clearly of greater importance, although it is difficult to estimate how great. On first thought, it seemed likely that when a patient died in clinical hepatic failure every effort would be made to obtain ne- cropsy, because of the widespread interest in disorders of the liver. However, in a review of the clinical summaries of the 6669 deaths in which there was no necropsy (or in which ne- cropsy did not include examination of the abdo- men), hepatic failure was judged to have been a major contributing cause of death in 241. Thus, a considerable number of potential cases of mas- sive hepatic necrosis were lost by failure to ob- tain a necropsy. On the other hand, the diagnosis of hepatic failure was made in only about one- third of the 82 necropsy-confirmed cases of mas- sive hepatic necrosis. Thus, suspicion of hepatic injury cannot be relied on either to identify the majority of possible cases or to ensure ne- cropsy. Some appraisal of the incidence of massive hepatic necrosis in the nonnecropsied deaths can be obtained by comparing the rate of massive he- patic necrosis per necropsy in institutions with high necropsy rates with that observed in insti- tutions with low necropsy rates. To do this, the institutions were first ranked by necropsy rates and separated into seven groups, each group hav- ing approximately the same number of deaths. In Fig. 1, the number of cases of massive hepatic necrosis per 1000 necropsies is plotted against the necropsy rate for each of these homogeneous groups. This graph suggests that the number of massive hepatic necrosis cases per 1000 necrop- sies is nearly constant at nine for those groups of institutions with necropsy rates of 55 percent or more. If it is assumed that the rate of massive hepatic necrosis per death is approximately the same for all institutions (see below), it is appar- ent that institutions with necropsy rates below 55 percent are deficient in cases of necrosis. And Fig. 1 suggests that, if all deaths had been ne- cropsied, there might have been about nine cases of massive hepatic necrosis per 1000 deaths. At this rate, the study would have produced about 153 (9 XI7) such cases, almost twice as many as the 82 actually identified at necropsy. 162

12 10 Figure 1.—The relationship between the number of massive hepatic necrosis cases per 1000 necrop- sies and the percent of deaths necropsied for seven groups of institutions. institutions with similar necropsy rates were pooled in groups of about 2000 deaths. -X- 45 50 55 60 65 70 75 PERCENT NECROPSIES IMPLICATIONS OF THE MISSING CASES AND THE POSSIBILITY OF NECROPSY BIAS The conclusion that a substantial portion of the massive hepatic necrosis cases was not iden- tified is disturbing, because some of the factors determining whether a case was necropsied are related to those being studied. For example, if hepatic failure and death occurred in a patient who had received halothane, already under some suspicion during the years studied, necropsy might have been more likely to be performed. The limited death-certificate information available on the nonnecropsied cases is consistent with such a hypothesis: of the 241 nonnecropsied cases with clinical evidence of hepatic failure, 50 (21 per- cent) received halothane; halothane accounts for 30 percent of all general anesthetics in the Study, 28 percent of all deaths, and 29 percent of ne- cropsied deaths. But because death-certificate information is notoriously unreliable, these data can be taken only as indicating the possibility of necropsy bias. INCIDENCE OF MASSIVE HEPATIC NECROSIS BY ANESTHETIC PRACTICE We now turn to the analysis of the 82 cases of massive hepatic necrosis actually observed in the Study, keeping in mind the reservations im- plied by the preceding discussion. Insofar as the occurrence of massive hepatic necrosis is related to the same factors that de- termine the patient's prognosis, such as the type of operation or the patient's age, the rate of mas- sive hepatic necrosis per death (or per necropsy) should remain fairly constant. Thus, we would predict the same number of cases of massive he- patic necrosis per 1000 deaths for patients under- going low-risk operations as for patients under- going high-risk operations. At the same time, the rate per anesthetic administration would vary 163

considerably, compared with the rate per death. This is well illustrated by the right-hand column of Table 1; although the rate per 10,000 estimated administrations (EA) varies from 0.08 to 5.18, among the three groups of operations, the rate per 1000 deaths varies only from 3.55 to 5.03. We choose to study the rate of hepatic necrosis per death because it provides better control for such factors as physical status and severity of opera- tion than does rate per administration. This choice is quite consistent with the finding that, in 73 (89 percent) of these 82 cases, the occurrence of massive hepatic necrosis could be attributed to factors not directly related to the anesthetic agent, such as shock or overwhelming infection. Examination of Table 1 shows that, except for the excess of massive hepatic necrosis cases after cyclopropane in the middle-risk group of opera- tions, there is little difference between the num- ber of cases observed and the number expected under the hypothesis of no anesthetic differences. CASES POSSIBLY RELATED TO THE ANESTHETIC USED Although the incidence of massive hepatic ne- crosis after halothane was virtually the same as that for the over-all Study (Table 1). this does not preclude the direct association of some of these cases with the use of halothane. The efforts to identify a medical syndrome and a pathologic lesion associated with the use of halothane are discussed in Chapters III-2 and m-4. In this chapter we consider the possible association of halothane and hepatic necrosis more from a statistical point of view. Table 2 presents the observed and expected incidences of massive hepatic necrosis catego- rized by previous exposure to halothane and by the possibility of explanation on the basis of clin- ical history. The categories of "explained" and "unexplained" were assigned by four physician members of the Subcommittee independently, and the cases so classified are those on which a ma- jority agreed. (The details of that review are given in Chapter m-1.) The numbers of expected cases in Table 2 are computed from the necrop- sies. By using the number of necropsies as the base, rather than the number of anesthetic ad- ministrations, we partially correct both for the possibility that one agent was used by preference in more hazardous cases and for variations in the necropsy rates. Operation Group Hal N-B Cyclo Ether Other Total Necrosis observed 2 0 1 0 0 3 Necrosis expected* 0.8 0.7 0.6 0.2 0.6 2.9 Low-death-rate Number of deaths 234 209 175 63 163 844 operations EA (in thousands) 86.7 105.3 67.5 50.1 57.4 367.0 Rates/1000 deaths 8.55 0.0 5.71 0.0 0.0 3.55 Rates/10,000 EA 0.23 0.0 0.15 0.0 0.0 0.08 Necrosis observed 13 6 17 4 7 47 Necrosis expected* 12.5 8.6 11.7 4.1 10.1 47.0 Middle-death-rate Number of deaths 2562 1757 2397 837 2073 9626 operations EA (in thousands) 146.2 101.3 68.1 44.3 67.5 427.4 Rates/1000 deaths 5.07 3.41 7.09 4.78 3.38 4.88 Rates/10,000 EA 0.89 0.59 2.50 0.90 1.04 1.10 Necrosis observed 11 9 7 1 4 32 Necrosis expected* 10.4 6.7 6.4 2.5 6.1 32.1 High-death-rate Number of deaths 2066 1323 1270 492- 1205 6356 operations EA (in thousands) 21.8 11.6 11.7 7.6 9.1 61.7 Rates/1000 deaths 5.32 6.80 5.51 2.03 3.32 5.03 Rates/10,000 EA 5.05 7.78 5.99 1.31 4.40 5.18 Necrosis observed 26 15 25 5 11 82 Necrosis expected** 23.7 16.0 18.7 6.8 16.8 82.0 Number of deaths 4863 3292 3845 1396 3444 16840 Totals EA (in thousands) 254.9 218.2 147.4 102.0 134.0 856.5 Rates/1000 deaths 5.35 4.56 6.50 3.58 3.19 4.87 Rates 10,000 EA 1.02 0.69 1.70 0.49 0.82 0.96 TABLE 1.—OBSERVED AND EXPECTED OCCURRENCE OF MASSIVE HEPATIC NECROSIS FOLLOWING HIGH-, MIDDLE-, AND LOW-DEATH-RATE OPERATIONS *Necrosis expected (H) = total necrosis X deaths (H) total deaths -3 X 234 --0 ft -- ^- **Total necrosis expected is the sum of those expected in the three categories of operations. 164

The expected numbers present a remarkably good fit with the observed numbers in categories where more than one operation was performed. In the group of patients with only one operation, halothane has six fewer cases of "explained" mas- sive hepatic necrosis than expected (these are only partially balanced by the three "unexplained" cases in this group). The fact that the high rate of "explained" massive hepatic necrosis after cyclopropane in the single-operation group (the observed number is almost twice the expected) does not appear in the group with multiple opera- tions is something of an enigma. If the over-all high rate of necrosis is due to the selective use of cyclopropane for patients with poor preopera- tive physical status and increased likelihood of shock, why does this not hold for the multiple operations as well? If the two parts of Table 2 dealing with mul- tiple operations are combined and the operations are classified with respect only to whether they involved halothane, the result is Table 3. Here we see that the few operations that involve two or more exposures to halothane have a higher rate of massive hepatic necrosis than the other groups. Because these comparisons are based on so few cases of massive hepatic necrosis, they are par- ticularly sensitive to sources of bias. Unfortu- nately, the use of existing data, rather than those generated by a randomized study, makes it im- possible to prevent such sources from operating. The small amount of information makes it im- possible to control for such factors in the anal- ysis. For example, we cannot control for the pos- sibility that institutions vary not only in their death rates and in their use of the different agents, but also in the types of cases that they tend to examine by necropsy; nor could we as- sign cases to be examined by necropsy at random to avoid such a source of bias. THE "UNEXPLAINED" CASES Seven of the nine patients with "unexplained" massive hepatic necrosis had received halothane during the final operative procedure. Five of the seven died after clinically evident hepatic failure; this was in contrast with the patients whose mas- sive necrosis was considered explained by pro- longed shock or overwhelming sepsis, and in most of whom hepatic failure was not suspected clin- ically. The microscopic pattern of hepatic injury in six of the seven "unexplained" halothane cases resembled that observed in viral or some drug- induced forms of hepatitis, again in contrast with the microscopic pattern of the "explained" group, which was in almost every case consistent with the effects of shock. It is not possible to say whether the very few cases of "unexplained" hepatic necrosis were caused by halothane or were due to other factors. For example, they may have been the result of pre-existing or unrecognized viral hepatitis, which they resembled both clinically and patho- logically. The principal considerations that bring us to question the validity of a cause-and-effect relationship in these cases are as follows. There was no certain way to determine whether a patient who died with clinical evidence of hepatic failure might have been more likely to undergo necropsy if halothane had been admin- istered, as discussed above. A small number of such cases could result in the apparent excess of "unexplained" massive hepatic necrosis among patients who received halothane, and yet not have a detectable effect on over-all necropsy rates, which were almost identical in the five anesthetic groups. The period of study, 1959-1962, was ex- plicitly chosen to antedate the widespread con- cern that began early in 1963 and to minimize necropsy bias. Massive hepatic necrosis after halothane had been reported as early as 1958 (1,2), however, and some suspicion must have been entertained during the period of the Study. Confidence in comparisons among agents in this very small group of patients is further weakened by the fact that approximately 40 per- cent of the deaths were not necropsied or were necropsied without examination of the abdomen. This 40-percent loss in necropsy represents such a high rate of nonresponse that confidence limits on rates computed from the completed ne- cropsies would be so broad as to be useless or would be based on strong assumptions that we are not in a position to verify. Reports of four of the seven "unexplained" massive hepatic necroses after halothane had been published, and another two were known to the participating institutions before the Study be- gan. The five institutions from which these six known cases came were invited or volunteered to join the Study at least in part because of those cases. Thus, the inclusion of those cases in any comparison of hepatic necrosis rates for dif- ferent anesthetics could lead to a "volunteer" bias in the over-all estimate of the rate of mas- sive hepatic necrosis after halothane. To illus- trate the possible effect: If an event has a low rate of occurrence, perhaps 0.2 per institution per observation period, and if we were to pick only institutions in which at least one event had oc- curred, then the method of selection would yield an average of 1.2 (or a bias of about five cases in our Study, inasmuch as five institutions would be affected). Thus, in the present Study, the bias would be more than enough to account for the ap- parent small excess of "unexplained" halothane cases. Because of this source of bias, we have listed the literature cases separately in Tables 2 and 3. As a final point in the consideration of the "unexplained" cases and the apparent excess of 334-553 O-69—12 165

TABLE 2.--"EXPLAINED" AND "UNEXPLAINED" MASSIVE HEPATIC NECROSIS BY EXPOSURE TO HALOTHANE AND CYCLOPROPANE Anesthetic Number of necropsies* "Explained" MHN "Unexplained" MHN Total Obs. Exp. New Literature MHN SINGLE OPERATIONS: H C Neither TWO OPERATIONS: Prev.** H H H noH noH noH Last H C Neither*** H C Neither 2595 1890 4272 262 69 143 323 414 826 10 20 23 4 0 0 2 3 5 15.7 11.4 25.9 1.8 0.5 1.0 2.2 2.8 5.7 2 0 0 1 0 0 0 0 0 13 21 23 7 0 0 2 3 6 THREE OR MORE OPERATIONS: Prev.** Last H H 43 1 0.5 0 1 2 H C 6 0 0.1 0 0 0 H Neither*** 17 0 0.2 0 0 0 Mix H 47 1 0.6 0 0 1 Mix C 25 0 0.3 0 0 0 Mix Neither*** 52 0 0.6 0 0 0 noH H 41 1 0.5 0 0 1 noH C 90 1 1.1 0 0 1 noH Neither*** 174 2 2.1 0 0 2 *The number of necropsies includes 1118 partial necropsies in which the abdominal cavity was not ex- amined. **The only datum recorded for previous operation was whether halothane was used. ***Because of the small number of cases, the anesthetic practices other than halothane and cyclopropane are pooled into one group called "neither." TABLE 3.—SUMMARY OF NECROPSIES AFTER MULTIPLE EXPOSURES Previous operation Last operation Number of necropsies "Explained" MHN "Unexplained" MHN Total MHN Obs. Exp. New Literature H H 352 6 3.0 2 2 10 H noH 3L2 0 2.7 0 0 0 noH H 364 3 2.7 0 0 3 noH noH 1504 11 11.7 1 0 12 halothane cases in this special group, it must be appreciated that separating out the "unexplained" cases leaves fewer "explained" halothane cases than expected. We have no explanation for this deficit . The data on intermediate hepatic necrosis appear to be similar to the massive necrosis data. There was an excess of halothane cases in total as well as in "unexplained" intermediate necrosis. But for this group of patients, submis- sion bias almost certainly occurred. Cases in- volving lesser degrees of necrosis were sub- mitted only as possible massive necrosis, and there was evidence that a doubtful case was more likely to be submitted if halothane had been the anesthetic agent. An example of this bias is pro- vided by the distribution of anesthetic agents among the cases of missing data. Of the 41 pieces 166

TABLE 4.--RATES OF MASSIVE HEPATIC NECROSIS PER 100 DEATHS BY INSTITUTION AND ANESTHETIC The first column under each anesthetic agent gives the rate per 100 deaths, when this is not zero; the second column, the number of deaths observed. MHN per 100 deaths MHN's/ deaths Institution H N-B 3 E 0 1 1.1 189 55 7 5 38 0.7 2/294 2 226 94 1.1 177 22 95 0.3 2/614 3 25 106 20 1 49 - 0/201 4 105 98 1.3 223 94 197 0.4 3/717 5 333 267 0.9 346 55 196 0.2 3/1197 6 90 103 23 56 1.7 60 0.4 1/332 7 152 45 98 58 189 - 0/542 8 0.4 671 0.9 115 2.0 51 0.3 299 1.9 212 0.6 8/1348 9 0.8 261 0.4 256 0.8 121 235 103 0.4 4/976 10 0.8 228 1.3 152 1.0 295 2.4 42 82 0.9 7/799 n 128 2.8 71 1.2 84 122 0.7 150 0.7 4/555 12 0.6 178 30 1.2 173 7 116 0.6 3/504 13 71 12 98 2 63 - 0/246 u 28 11 56 6 40 - 0/141 15 64 129 1.1 190 1.6 61 142 0.5 3/586 16 67 0.4 253 81 3 115 0.2 1/519 17 52 8 19 18 2.2 89 1.1 2/186 18 73 75 0.8 124 10 45 0.3 1/327 19 0.4 228 80 97 2 79 0.2 1/486 20 2.3 43 41 0.8 245 0.8 131 0.4 267 0.7 5/727 21 0.8 248 1.6 185 0.5 185 20 0.9 177 0.9 7/815 22 1.6 243 2.2 92 138 8 133 1.0 6/614 23 18 40 19 0 6 - 0/83 24 2.0 147 0.6 514 0.4 229 3.7 27 1.7 118 1.0 10/1035 25 126 50 166 23 0.5 213 0.2 1/578 26 125 131 78 10 48 - 0/392 27 98 30 113 6 49 - 0/296 28 10 5 022 - 0/19 29 2.2 89 15 35 2 30 1.3 2/171 30 2.3 130 47 7.7 26 0 20 2.2 5/223 31 59 23 79 1 18 - 0/180 32 137 1 4 68 0 57 - 0/276 33 0.5 210 140 106 63 162 0.1 1/681 34 11 5 75 5 84 - 0/180 TOTAL DEATHS 4863 3292 3845 1396 3444 167

of missing data (see Chapter II-2), only two were from patients who had received halothane. We conclude that a greater effort was made to pro- vide data for halothane cases than for others. RATES OF MASSIVE HEPATIC NECROSIS BY INSTITUTION Differences in the standardized death rates among institutions are discussed in Part IV. It is of interest here that such differences do not seem to manifest themselves in the massive hepatic necrosis rates. Table 4 shows the rate of mas- sive hepatic necrosis per 100 deaths by institu- tion and by anesthetic. Again we compute the rate per 100 deaths in order to control for the patient population being treated in the various cells. The table is remarkable for the uniformity of the rates, considering the wide variety of institutions in the Study. The highest rate in a cell with at least 150 deaths is 1.9 per 100 deaths, and it oc- curs in an institution with 212 deaths in the cell associated with the anesthetic class "Other." When the number of cells with 150 or more deaths is considered, this occurrence is not at all extreme; in fact, it is not even remarkable, except perhaps for being small. When we look at institution totals, instead of single cells, we observe that institution 30 has a rather high number of massive hepatic necroses for its deaths, 2.2 per 100 deaths. In studying the variability for institutions, we found the rates to be about two standard deviations larger than would be expected if all institutions were alike. Institution 30 made the whole difference, with five massive hepatic necroses, compared with 1.1 expected. No other institution had a notable rate. Thus, institutions do not separate into two good- sized clumps, for example. Whether there is any special reason for institution 30's record cannot be known without breaking the code. At any rate, except for this institution, further institutional studies are not warranted by these data. CONCLUSIONS It is impossible to give a precise figure for the incidence of massive hepatic necrosis in the Study, because only 60 percent of the deaths were examined by complete necropsy. An over-all rate of nine per 1000 deaths is suggested by the data, however. This is equivalent to slightly less than one per 5000 operations and includes an allow- ance for the cases that were not necropsied. The over-all rates were about the same for the dif- ferent anesthetic practices, with the possible ex- ception of cyclopropane, which was slightly higher than the others. When cases of massive hepatic necrosis that could not be explained on the basis of a clinical history of sepsis or shock were picked out, it was found that seven of the nine such cases in- volved halothane. When the cases that could be so explained were examined, cyclopropane was found to be associated with almost twice as many as would be expected on the hypothesis of no dif- ferences among the agents. Cases involving mul- tiple operations were also found to have a higher incidence of massive hepatic necrosis and, of these, cases involving multiple exposure to halo- thane were found to have the highest incidence. These results must be interpreted with cau- tion for two reasons. First, the lack of randomi- zation and the fact that only 60 percent of the deaths were necropsied completely are certain to introduce biases. Second, there are so few actual cases that the analysis could neither estimate these biases nor hope to correct for them. REFERENCES 1. Burnap, T. K., S. J. Galla, and L. D. Vandam. Anesthetic, circulatory and respiratory effects of Fluothane. Anesthesiology 19:307- 329. 1958. 2. Postoperative death after Fluothane. Anes- thesiology 19:562-563, 1958. . J 168

CHAPTER III-4. THE CLINICAL SYNDROMES ASSOCIATED WITH POSTOPERATIVE HEPATIC NECROSIS Bernard M. Babior* Thorndike Memorial Laboratory Boston City Hospital Boston, Massachusetts Charles S. Davidson Harvard Medical School and Thorndike Memorial Laboratory Boston City Hospital Boston, Massachusetts Eighty-two cases of massive hepatic necro- sis were identified and confirmed by members of the Pathology Panel during the Study. Complete hospital records were available for 80 of the 82 cases, thus affording an unusual opportunity to examine the clinical manifestations of postopera- tive hepatic necrosis. This chapter presents the findings of that review. METHOD The hospital records of 80 of the 82 cases were reviewed and categorized on the basis of clinical features. Particular attention was paid to the presence of shock and heart failure, and their relationship to any clinical evidence of he- patic disease that developed during a patient's illness. Cases were selected solely on the basis of postmortem hepatic histology, so that it was possible that a patient might have histologic mas- sive hepatic necrosis without having displayed any symptoms of hepatic disease during life; in fact, that proved to be the most common situation. The pertinent features abstracted from the hospital records are listed in Table 1. In addition, a history of hepatic disease was noted, as was any comment regarding epidemiologic factors as- sociated with toxic or viral hepatitis (e.g., occu- pational exposure to jaundiced persons, medica- tions taken before admission, and alcoholism). Blood and plasma transfusions were noted. The operative notes and anesthetic records were re- viewed, with particular attention to all the anes- thetics used, to the duration of operation, to the occurrence of hypotension during operation, and, where available, to the operative findings in the right upper quadrant of the abdomen. Shock was defined as a fall of 25 percent from admission levels in either systolic or diastolic pressure lasting 30 min or more, by the development of acute renal failure, or by the need for vasopres- sor drugs. Congestive failure was indicated by dyspnea and an enlarged heart, increased venous pressure, and the need for digitalis during hos- pitalization. Finally, the results of the necropsy were recorded. TABLE 1.—INFORMATION RECORDED FRCM THE HOSPITAL RECORDS OF PATIENTS WITH MASSIVE HEPATIC NECROSIS Signs and symptoms suggestive of hepatic disease: Gastrointestinal symptoms Jaundice Ascites Palpable liver Confusion or coma (including results of lumbar puncture) Laboratory findings suggestive of hepatic disease (actual values recorded): Bilirubin Alkaline phosphatase Transaminase (SGOT) Serum albumin and globulin Prothrombin time Measurements of cardiovascular and renal status: Pulse Blood pressure Venous pressure Serum urea nitrogen Serum creatinine Urinary output Evidence of bleeding: Presence and site of bleeding Hematocrit or hemoglobin Stool guaiac Evidence of sepsis: Temperature White-blood-cell count Cultures for bacteria RESULTS Two broad categories of clinical disturbance emerged: (1) cardiovascular, in which hepatic dis- ease was probably the result of shock or conges- tive failure; and (2) hepatitis, in which hepatic disease could not be accounted for on a cardio- vascular basis. In general, patients in the cardio- vascular category experienced an episode of hypo- tension or acute congestive heart failure before any clinical manifestation of hepatic disease, •Present address: National Heart institute, National Institutes of Health, Bethesda, Maryland. 169

TABLE 2.—ILLNESS ASSOCIATED WITH HEPATIC NECROSIS IN PATIENTS IN THE CARDIOVASCULAR CATEGORY Heart disease (25): Congenital heart disease Rheumatic heart disease Acute myocardial infarction (diagnosed at necropsy) Malignancy involving pericardium Myocarditis Diseases of blood vessels (10): Aneurysm of aorta Aneurysm of internal carotid artery Thrombosis abdominal aorta Thrombosis hepatic vasculature (l associated with malignancy) Bleeding (9): Gastrointestinal (2 associated with malignancy) Malignancy with bleeding tendency Sepsis (U): Peritonitis (2 associated with malignancy) Malignancy with abscess Miscellaneous Severe trauma Other malignancies 12 7 3 (l without hypotension) 2 (l without hypotension) 1 (without hypotension) 5 1 1 (without hypotension) 3 (l without hypotension) 8 3 (l without hypotension) 3 (l without hypotension) TABLE 3.--OPERATION ASSOCIATED WITH EVENT LEADING TO HEPATIC NECROSIS IN PATIENTS IN THE CARDIOVASCULAR CATEGORY Laparotomy (25): Exploratory Vagotomy and pyloroplasty Gastrectomy Colectomy Enteroenterostomy Gastroenterostomy and choledochojejunostomy Whipple procedure Portacaval shunt Cholecystectomy Cardiac surgery on bypass Repair of aneurysm 11 2 5 1 1 1 1 1 2 19 5 Miscellaneous (16): Clip aneurysm of internal carotid artery 1 Removal of celestin tube 1 Exploration right common iliac artery l Aortofemoral graft 1 Inferior vena cava ligation 1 Saddle embolectomy aorta 1 Sympathectomy and pericardial poudrage 1 Thoracotomy for hemostasis 1 Above-knee amputation 1 Pneumonectomy 1 Operation not directly associated with event leading to 6 hepatic necrosis (5 deaths from sepsis and 1 from cere- brovascular thrombosis): cases 44, 650, 675, 680, 689,and 691 170

whereas patients in the hepatitis category dis- played signs and symptoms of hepatic disease without antecedent cardiovascular difficulties. Cardiovascular Category Sixty-five of the 80 patients were placed in the cardiovascular category. Their diagnoses and the operations most closely related to their shock or congestive failure are classified in Tables 2 and 3. It is apparent that these patients were severely ill. All but seven were hypotensive for hours or days before death; over half the hypotensive patients showed acute renal failure. Of the seven patients who were not hypoten- sive, four had severe heart failure as judged by intractable dyspnea, venous pressures over 160 mm H2O, or acute pulmonary edema; cases 675 and 717 had overtransfusion, case 645 had longstanding myocarditis, and case 807 had heart failure associated with bilateral hemothorax and pericarditis. Of the remaining three, two had thromboses of major vessels; case 223 had thrombosis in the aorta to the level of the su- perior mesenteric artery, and case 680 had he- patic venous thrombosis. We believe that in six patients (i.e., the four with congestive failure and the two with thromboses of major vessels) the hepatic necrosis could probably be accounted for by the vascular lesions. The seventh (case 650) is discussed below. Clinical evidence of hepatic disease was not prominent in this group of patients. Jaundice was present in 18 patients; all but two of these patients had been hypotensive (Table 4). Jaundice was present on admission in three patients (cases TABLE 4.—DIAGNOSES OF PATIENTS IN THE CARDIOVASCULAR CATEGORY WHO WERE JAUNDICED BEFORE DEATH Onset o Diagnosis days bef f event, Case ore death f^^. Jaundice tnetic Shock 1 Noted to be Jaundiced on day he died 1 Hal 44 Jaundiced last day of life 1 3 Hal 74 History of hepatic disease 9 1 Cyclo 185 Jaundiced last day 1 2 Hal 222 Congestive failure due to aortic stenosis 5 5 N-B 234 Congestive failure; postoperative dissecting aneuiysm 9 10 N-B of aorta 345 Alcoholism; hemolytic crisis 3 days before death 1 2 Hal 687 Peritonitis; thrombosis iliac artery 2 1 N-B 712 Atrial septal defect; pulmonic stenosis* 2 4 N-B 716 Jaundiced 2 1 Hal 802 Cirrhosis with bleeding varices 1 2 Cyclo 352 Jaundiced before death 2 hr 1 363 Carcinoma head of pancreas with liver metastases, On admis- biliary tract obstruction, and ascending cholangitis sion 605 Carcinoma stomach; biliary tract obstruction from On admis- metastasis; bleeding gastric ulcer sion 650 Carcinoma esophagus; lung abscess 16 658 Rheumatic mitral stenosis, mitral insufficiency, and On admis- tricuspid insufficiency* sion 666 Rheumatic mitral and aortic stenosis and aortic 3 4 insufficiency* 667 Infarction of bowel with perforation of ilium, 2 3 peritonitis Cyclo Cyclo Cyclo Cyclo Hal Hal Hal *Hepatomegaly on admission. 171

363, 605, and 658); one of these had rheumatoid valvulitis and an enlarged liver, and two had biliary tract obstruction from carcinoma. In 11, the jaundice developed after a prolonged hypoten- sive episode. In the remaining four (cases 1, 74, 650, and 687), the etiology of jaundice was not clearly related to shock or congestive failure. For example, one patient (case 687), admitted with peritonitis, developed jaundice the day before a terminal hypotensive episode. The day before jaundice appeared, he had had an iliac thrombec- tomy. Classification of this patient was difficult, but he was ultimately placed in the cardiovascular category because he was severely ill with a num- ber of serious diseases before the jaundice ap- peared and because, after the appearance of jaun- dice, the course of his illness was not that of fulminant viral hepatitis (7); it is possible, how- ever, that the jaundice resulted from viral hep- atitis superimposed on his other illnesses. Case 650 was admitted with carcinoma of the esopha- gus, a bronchoesophageal fistula, and a media- stinal abscess. He had not shown hypotension, although jaundice appeared 16 days before death. He had been on prochlorperazine, however, and hepatic function tests were consistent with phe- nothiazine jaundice (SGOT, 95; alkaline phospha- tase, 26; units unspecified). At necropsy, the liver showed intrahepatic cholestasis, as well as centrilobular necrosis. (These findings were not known when the patient was classified.) Classi- fication was based on the same criteria used for case 687; the jaundice in case 650 could prob- ably be attributed to prochlorperazine. Similar difficulties were encountered in categorizing the remaining cases. Hepatitis Category The remaining 15 patients (of the 80 with massive hepatic necrosis) were placed in the "hepatitis" category. Twelve developed jaundice without pre-existing shock or congestive failure. Cases 98 and 99 never developed jaundice, but were placed in the hepatitis group because they died with normal cardiovascular systems and had hepatic necrosis at necropsy (anicteric mas- sive hepatic necrosis due to viral hepatitis has been previously reported) (7). Case 97 developed jaundice 5 days after a 4-hr bout of hypotension due to a bleeding ulcer; in the interval, however, the blood pressure was normal, urinary output was good, and the patient seemed well, so we be- lieved that jaundice was unrelated to the preced- ing hypotensive episode and placed the patient in the hepatitis category. These 15 patients were subdivided into two groups: those who had hepatitis before operation, as indicated by preoperative jaundice and in- creased transaminase levels (cases 81, 205, and 651); and those who developed hepatitis after op- eration. The three patients who had hepatitis be- fore operation will not be considered further, except to remark that surgery is known to in- crease greatly the incidence of fatal hepatic fail- ure in viral hepatitis (9). The courses of the 12 patients who developed hepatic disease after operation are shown in Table 5. The course was similar for most of the patients. It began with fever, which developed shortly after operation, usually within 2 to 3 days. In most cases, fever was soon followed by jaun- dice, which deepened progressively. At that time, a tender liver could be felt in some patients. Confusion, somnolence, and a flapping tremor developed within a week after the onset of fever. The confusion usually progressed rapidly to coma and death. Hypotension was a very late manifes- tation, usually appearing only on the last day. Ex- cept for one patient (case 723), whose course was atypical, the total duration of the illness was extremely short, the longest interval between the onset of symptoms of hepatic failure and death being 9 days. The course was similar to that described by Lucke and Mallory in patients with fulminant viral hepatitis (7). The results of laboratory examinations of the 11 patients* (Table 6) were consistent with severe hepatocellular damage, with an elevated bilirubin and transaminase (SGOT), a moderate increase in alkaline phosphatase, and a greatly prolonged prothrombin time, which was unresponsive to the parenteral administration of vitamin K. There was a tendency for the transaminase values to fall terminally. Two patients (cases 98 and 99) failed to develop jaundice. However, the remainder of their courses was typical of those of the group as a whole, with fever followed by central- nervous-system symptoms and rapid death. Ex- cept for terminal prothrombin times, liver- function studies were not obtained in either of these patients; the prothrombin time in each case was prolonged. Case 99 had fever on admission and central-nervous-system symptoms after brain surgery. The extent to which hepatic ne- crosis was responsible for his symptoms is, therefore, a matter of conjecture. In three patients, the appearance of post- operative jaundice was delayed. In cases 255 and 328, rapid deterioration and death occurred after jaundice had disappeared. Case 723, a man with carcinoma of the prostate metastatic to the liver whose jaundice developed after a hypophysectomy, showed an unusually prolonged course. Jaundice did not develop until the 4th postoperative week, and death did not ensue until 18 days later. Neverthe- less, massive hepatic necrosis was seen at necropsy, and we assume that his disease differed only in degree from the illness observed in the others. Specific causes for postoperative necrosis of the hepatitis type were difficult to assign. The difficulty is reflected in the fact that, in seven of the 12 cases, necrosis was considered to be unexplained in the "blind" clinicopathologic review of all 82 cases of massive hepatic ne- *No laboratory data were available on case 36. 172

TABLE 5. —CLINICAL FEATURES OF PATIENTS IN THE HEPATITIS CATEGORY* Onset of event, days after last operation CNS symptoms Remarks Case Operation Jaun- dice Fever Bleeding Death Pre- Coma coma 36 Many dressing changes On admission 2 and skin grafts (to- tal, 9 operations) 51 Gastrectomy 64 Cholecystectomy 2 days be- fore operation 91 Excision carcinoma 1 skin of right leg; skin graft 97 Closure of perforated 2 ulcer, gastric re- section 98 Tendon repair 7 No 99 Cranictomy 100 Resection carcinoma stomach; drainage subphrecic abscess On admission No 13 days be- fcre last operation 122 Esophagoscopy; chcle- 3 cystectomy; repair dehiscence twice 2 3 None 3 5 8 None 11 17 No None 20 3 4 None 7 8 No None 8 9 9 11 (up- 15 per 01) 1 No None 5 None 11 None Temperature rose sub- stantially (103-105 F) 4 days before onset of Jaundice Plication of ulcer 2 months before death - no transfusion then Precoma followed brain operation Laparotomy 2 months be- fore death - no trans- fusion then Transient fever following third operation 255 328 Laparotomy, biopsy Cesarean section 28 28 30 38 33 33 35 Hysterectomy 2 months before death 33 38 39 40 40 723 Hypophysectomy 1 23 29 no None 41 Enlarged liver on admis- sion — probable metastatic carcinoma *Cases 81, 205, and 651 not included because hepatitis was present before operation. 173

TABLE 6.--RESULTS OF LABORATORY EXAMINATIONS OF PATIENTS IN THE HEPATITIS CATEGORY Serum alkaline Serum bilirubic, phosphatase, mg/100 cc Bessey-Lowry SCOT, Prothrombin units/ml time Case units lst high Maximum lst hieh Maximum value value 1st high Maximum lst nieh Maximum value value 51 18 (3)* 30 (8) 4.3 (3) 4.9 (8) 720 (3) 720 (3) 39 sec (3) 44 sec (6) 64 13 (17) 19 (18) 5.9 (17) 5.9 (17) 1100 (17) 1100 (17) 10* 10* 91 11.8 (4) 18.0 (7) 10.3 (4) 10.3 (4) 740 (5) 765 (7) 40 sec (7) 40 sec (7) 97 4 (5) 10 (7) 17* (7) 98 -- 10* (12) 99 — 20 sec (5) 100 12 (5) 21.2 (9) 262 (7) 262 (7) 12* 12* 122 8 (2) — 10.3 (2) 111 (3) 7* (3) 255 25 (30) — 1.9 (30) 125 (30) — <10* (30) 328 5.8 (30) 7.4 (31) 10.5 (30) 10.5 (30) 16,740 (30) 16,740 (30) 39 sec (31) 39 sec (31) 723 7.8 (-13) — 7.5 (25) 10.1 (28) 354 (28) -- 18 sec (-13)21 sec (26) *Numbers in parentheses are numbers of days after final operations that the measurements were made. TABLE 7.—TREATMENTS RECEIVED BY THE PATIENTS IN THE HEPATITIS CATEGORY THAT MAY HAVE BEEN ETIOLOGICALLY RELATED TO MASSIVE HEPATIC NECROSIS No. of transfusions 10 or more days before Jaundice Drugs reported to cause Jaundice Principal anesthetic (last operation) Case Cholestatic Necrotic 36 81 None None Hal (6)» 51 None None None Hal 64 None — ~ Other 91 1 None Tolbutamide Hal (2) 97 None Promazine None Hal (2) 98 None Promethazine prochlorperazine Sulfadimethoxine Hal 99 None None INH Hal (2) 100 8 Promethazine Sulfisoxazole Hal (2) 122 None Prochlorperazine None Hal (2) 255 None None None Hal 328 5 None None Cyclo 723 3 Prochlorperazine Sulfisoxazole Hal "Number of exposures to halothane of patients who received it more than once. 174

crosis. (See Chapters III-1 and m-2.) Table 7 summarizes some of the possible etiologic fac- tors: the number of transfusions (blood and plasma) and the administration of drugs re- ported to be associated with jaundice, as well as the principal anesthetic agent used in the opera- tion immediately preceding hepatic failure. Two of the three patients in whom the appearance of jaundice was delayed received transfusions 10 or more days before the onset of jaundice, whereas such transfusions were given to only three of the eight patients whose illness developed shortly after operation. Five patients received drugs of the type associated in the past with hepatic injury. (2-6,8) In four cases these were sulfonamides; the fifth was isonicotinic acid hydrazide (INK). Ten of the 12 patients whose hepatic disease was noted after operation received halothane for the final opera- tion; of these 10, six had received halothane pre- viously. DISCUSSION The two clinical categories into which we have placed the 80 cases of massive hepatic ne- crosis were easily distinguished. Those in the hepatitis category progressed rapidly from rel- atively good health through fever, jaundice, and coma, with death ensuing usually within a week of the first symptoms. Hypotension ap- peared only on the last day of life, and conges- tive heart failure was not prominent in any. In contrast, the patients in the cardiovascular category were severely ill, with prolonged shock or, less frequently, severe congestive heart fail- ure. Half the hypotensive patients developed renal shutdown. Jaundice was an unusual mani- festation, appearing in only 15 patients and then usually only terminally. In most cases, hepatic disease was not suspected during life. Although cardiovascular disease was prob- ably the cause of the hepatic necrosis in pa- tients in the cardiovascular category, the etiol- ogy of the hepatic damage in patients in the hep- atitis category seemed to be unrelated to shock or congestive failure. The fulminating hepatic necrosis seen in the latter patients is usually attributed to a virus or to a drug reaction. In most of the patients in the hepatitis cate- gory, hepatic necrosis appeared within a week of operation. Three of these patients received transfusions 10 or more days before the onset of hepatic necrosis, so the disease may have been serum hepatitis. Inasmuch as the remainder had received no transfusions, their hepatic necrosis would have to be attributed either to the fortui- tous appearance of infectious hepatitis during the 1st postoperative week or to a reaction to a drug given near the time of operation. In three patients, however (cases 255, 328, and 723), as mentioned above, hepatic necrosis did not appear until several weeks after opera- tion. All received blood or plasma at the time of operation. The interval between operation and the onset of hepatitis was probably too long for the damage to be attributed to a drug adminis- tered in connection with the operation, but is consistent with the course of posttransfusion hep- atitis (1). Medications that were given in the operative period, and that had heretofore been associated with massive hepatic necrosis, were the sulfon- amides, INH, and halothane. Hepatic damage due to sulfonamides has usually been associated with other manifestations of sensitivity, such as rash, arthralgia, and eosinophilia, none of which was present in these patients; furthermore, there have been no reports of fatal hepatic damage as- sociated with any of the particular sulfonamides given to these patients. We believe, therefore, that hepatic damage in these patients was un- related to the sulfonamides. INH, however, has on rare occasions been associated with massive hepatic necrosis, and therefore remains a pos- sible, although unlikely, cause of hepatic failure in case 99. In the present series, 10 of 12 patients (83 percent) who developed postoperative massive hepatic necrosis of the hepatitis type received halothane for their final operation, whereas the over-all incidence of halothane anesthesia in the entire series of over 800,000 patients was 29.8 percent. Similarly, the percentage of patients who received multiple administrations of halothane was considerably higher among the hepatitis group (six of 15) than among the cardiovascular group (four of 65). It is not possible, however, to conclude that halothane was responsible for the excess of pa- tients in the hepatitis category. For example, the method of case selection introduced a bias that could have favored this hypothesis. The statistical difficulties encountered in attempting to assess the role of the anesthetic agent in such a small group of patients are discussed in detail in Chap- ter m-3. SUMMARY The National Halothane Study made available for investigation 82 postoperative instances of necropsied massive hepatic necrosis (listed in Table 8). By clinical analysis of the records of 80 of them, these patients were classified into two groups, representing different types of hepatic necrosis. Sixty-five were classified as necrosis after vascular insufficiency due to shock, heart failure, or both. Of these, only 25 percent were jaundiced. In the icteric patients, cardiovascular insufficiency preceded jaundice in almost every instance. Of the 15 patients whose necrosis was not explained by vascular failure, three had hepa- titis (probably viral) before operation, leaving 12 with no obvious cause for their hepatic disease. These 15 progressed rapidly from relatively good health, through fever, jaundice, and coma, to death within a week of the first symptoms. All but two were jaundiced. Hypotension appeared only terminally. 175

TABLE 8.--CASES REVIEWED Cardiovascular category Hepatitis category No chart available 1 619 685 36 647 44 620 686 51 817 55 628 687 64 68 632 688 81 72 636 689 91 74 645 691 97 93 649 692 98 127 650 707 99 135 653 709 100 156 657 711 122 185 658 712 205 222 660 713 255 223 664 716 328 234 665 717 651 338 666 718 723 345 667 719 352 669 724 363 670 802 605 673 807 609 675 812 616 680 824 618 681 Thus, postoperative hepatic necrosis is most commonly associated with vascular insult, and displays few of the clinical findings of the better known, but much less frequent, "acute yellow atrophy" of presumed drug or viral etiology. REFERENCES Allen, H. L., and D. W. Metcalf. A search for halothane liver complications. Anesth. Analg. 43:159-162, 1964. Cohen, R., M. H. Kaiser, and R. V. Thomson. Fatal hepatic necrosis secondary to isoni- azid therapy. J.A.M.A. 176:877-879, 1961. Frey, R. Halothan und Leberschaden. Anaesthesist 13:315-316, 1964. Fries, J., and R. Siragenian. Sulfonamide hepatitis. Report of a case due to sulfa- methoxazole and sulfisoxazole. New Eng. J. Med. 274:95-97, 1966. Gingrich, T. F., and R. W. Virtue. Post- operative liver damage: Is anesthesia in- volved? Surgery 57:241-243, 1965. Lindenbaum, J., and E. Leifer. Hepatic ne- crosis associated with halothane anes- thesia. New Eng. J. Med. 268:525-530, 1963. Lucke, B., and T. B. Mallory. The fulminant form of epidemic hepatitis. Amer. J. Path. 22:867-945, 1946. Tisdale, W. A. Focal hepatitis, fever and skin rash following therapy with sulfa- methoxypyridizine, a long-acting sulfona- mide. New Eng. J. Med. 258:687-690, 1958. Tygstrup, N. Halothane hepatitis. Letters to the Editor. Lancet 2:466-467, 1963. 176

CHAPTER III-5. SUMMARY OF STUDY OF HEPATIC NECROSIS: CLINICAL IMPLICATIONS" John P. Bunker Stanford University School of Medicine Palo Alto, California Leroy D. Vandam Harvard Medical School and Peter Bent Brigham Hospital Boston, Massachusetts DEGREE OF NECROSIS The Pathology Panel examined sections of the liver microscopically in 946 cases in which massive hepatic necrosis was suspected. In 222 cases, the Panel confirmed the presence of he- patic necrosis not obscured by autolysis and not explainable by tumor, infarct, or abscess. The degree of necrosis was rated by each pathologist independently on a scale of 0 (none) to 4+ (total destruction of parenchyma). These ratings were averaged and the cases were sep- arated into three categories: massive necrosis (average score, 2.6+ or above); intermediate ne- crosis (1.6+to 2.5+); and minimal necrosis (1.5+ or below). Of the 222 cases, 82 were scored as massive, 115 as intermediate, and 25 as minimal necrosis. Minimal necrosis was considered to be a common and negligible occurrence in any ne- cropsy population and these cases were thereafter disregarded. The 82 cases of massive hepatic necrosis were collected from 10,171 necropsies, or ap- proximately one in 125 necropsies. It was difficult to estimate the incidence of hepatic necrosis per administration of general anesthesia, because of the 6669 cases in which necropsy was not per- formed or the liver was not examined; but the data suggested one per 5000 administrations. If the 115 cases of intermediate hepatic ne- crosis are added to the 82 cases of massive ne- crosis, the combined incidence is one in 2000 (or five in 10,000) administrations of general anes- thesia. Any inferences drawn from the data on intermediate necrosis should be weighed with caution, however. The Study was designed to de- tect massive hepatic necrosis, and cases with less than massive necrosis were culled only to avoid missing an occasional instance of the more extensive lesion. Accordingly, principal attention was directed, as planned, to the group with mas- sive hepatic necrosis. EFFECT OF OPERATION Operations were grouped for purposes of analysis on the basis of death rates (low, middle, and high). The low-death-rate category consisted of operations on the mouth or eye, herniorrhaphy, dilatation and curettage, hysterectomy, cystos- copy, and plastic procedures. The high-death- rate group included craniotomy, open-heart op- erations, exploratory laparotomy, and large bowel procedures. All other operations were arbitrarily assigned to the middle-death-rate category. Hepatic necrosis occurred more commonly after operations associated with high death rates: there were three cases of massive necrosis after 366,992 low-death-rate operations (approximately 0.1 per 10,000), 47 after 427,355 middle-death- rate operations (1.1 per 10,000), and 32 after 61,719 high-death-rate operations (five per 10,000). Nineteen, or nearly one-fourth, of the massive necroses followed open-heart operations with cardiopulmonary bypass, although those pro- cedures accounted for only 1 percent of all op- erations in the Study. Operations on the large blood vessels (primarily the aorta), gastrectomy, and exploratory laparotomy (such as lysis of ad- hesions for relief of intestinal obstruction, confirmation of inoperable neoplasm, control of hemorrhage, and drainage of abscess) were also associated with relatively high incidences of mas- sive hepatic necrosis. Contrary to expectations, an increased in- cidence of massive hepatic necrosis did not oc- cur after biliary tract operations. An estimated 27,677 patients underwent cholecystectomy, common-duct exploration, or both, with or with- out other major surgery, and massive hepatic necrosis occurred in only six of them, for a rate somewhat lower than those for most other ab- dominal operations. One of the six patients had received halothane, whereas halothane was administered for approximately 30 percent of *The first five sections of this chapter (I.e., through "Pathology") were prepared by the entire Subcommittee as part of the Summary of the National Halothane Study. 177

the cholecystectomies and common-duct explo- rations. Massive hepatic necrosis occurred in an additional three patients who had undergone a biliary tract procedure previously within 6 weeks of death, and one of them had received halothane. EFFECT OF ANESTHETIC AGENT The highest rate of massive hepatic necrosis followed administration of cyclopropane, parti- cularly in the middle-death-rate group. Cyclo- propane was also the anesthetic with the second highest rate of hepatic necrosis in the high-death- rate group, despite the fact that it was used in only 10 percent of open-heart operations. The in- cidence of massive hepatic necrosis after admin- istration of halothane was virtually the same as that after administration of nitrous oxide- barbiturate or "Other" anesthetics, slightly more than that after ether, and considerably less than that after cyclopropane. There were 80,600 patients who had two or more operations under general anesthesia in the same or successive months. The incidence of massive hepatic necrosis was considerably higher in patients who had undergone multiple procedures (24 of 80,600, or three per 10,000) than in patients who had not (58 of 775,900, or 0.7 per 10,000), and that seemed particularly true of halothane (10 of 14,100, or 7.1 per 10,000). There usually appeared to be an adequate clinical explanation for the massive hepatic ne- crosis observed at necropsy, shock, especially with prolonged use of vasopressors; overwhelm- ing infection; severe and prolonged congestive heart failure; and pre-existing hepatic disease. In a few cases, however, the underlying reason for hepatic necrosis was not easily established; accordingly, four members of the Subcommittee independently reviewed 80 of the 82 cases of con- firmed massive hepatic necrosis. They classified each case "explained" or "unexplained" on the basis of whether the necrosis could be assigned to a recognizable clinical factor. These ratings were made from summaries of the clinical rec- ords from each of which the identity of the anes- thetic agent(s) had been deliberately omitted. Among the 80 cases of confirmed massive hepatic necrosis, nine were considered to be "un- explained" by at least three of the four members of the Subcommittee; seven patients had received halothane for the final operation, one had re- ceived cyclopropane, and one had received eth- ylene ("Other"). Of the nine patients, five had undergone one or more operations previously within 6 weeks of the final procedure. Of the five, four had received halothane on at least two occa- sions and the fifth had received ethylene for the final operation and ether for the previous one. CLINICAL SYNDROMES "Unexplained" hepatic failure was usually characterized by fever within 2 or 3 days after op- eration, soon followed by jaundice, which deepened progressively, and the development of a tender, palpable liver. Confusion, somnolence, and a flapping tremor developed within a week after the onset of fever. The confusion usually progressed rapidly to coma and death. Hypotension was a late manifestation, usually appearing only on the day of death. The total duration of the illness was short, the longest interval between the onset of symptoms of hepatic failure and death being 9 days. The course was similar to that associated with fulminant viral hepatitis and to that which may follow chloroform anesthesia or poisoning by carbon tetrachloride. In contrast, the patients in whom necrosis was considered "explained" were seriously ill, usually with shock for many hours or days or, less commonly, with severe congestive heart failure. Half the patients with hypotension became anuric. Jaundice was a less common manifestation, and usually occurred only terminally. In most of these cases, hepatic injury was apparently not suspected during life. PATHOLOGY The appearance of the liver on histologic examination in the "explained" cases of massive hepatic necrosis was, in most instances, consist- ent with that observed in shock or hypoxia, re- flecting the severe circulatory disorders that occurred in almost all these patients before death. These sections were characterized by centrilobular congestion and, ultimately, pooling of sinusoidal blood. Paralleling this was attenu- ation and disappearance of parenchymal cells with relatively little inflammatory reaction. Fatty vacuolization was mild and limited to the cells bordering on the necrotic zone. The appearance on histologic examination of specimens from the nine "unexplained" cases of massive hepatic necrosis varied considerably. Of the seven "unexplained" cases that followed halothane administration, six presented a lesion thought by the majority of the members of the Pathology Panel to simulate the lesions of viral or some drug-induced forms of hepatitis. In these lesions the hepatic cellular necrosis was coagu- lative and sinusoidal congestion was a minor fea- ture. Intralobular inflammation was variable and usually appeared as an intermixture of histio- cytes and neutrophils among the necrotic epithelial cells. The portal areas of some cases exhibited a lymphocytic exudate. Fatty degeneration was var- iable, but usually negligible. Briefly, there were nine "unexplained" cases of massive hepatic necrosis, seven after halo- thane. Six "unexplained" cases after halothane had a lesion simulating hepatitis, including one with histologic features that suggested superimposed shock. The lesions in the remaining three "un- explained" cases were consistent with shock; one followed administration of halothane, one followed cyclopropane, and one followed ethylene ("Other"). 178

DISCUSSION The National Halothane Study was designed to determine whether the use of halothane anes- thesia is followed by an increased incidence of massive hepatic necrosis (when compared with other anesthetic agents). An equally important objective was to compare halothane with other general anesthetics as to total hospital mortality within 6 weeks of anesthesia, because it was rec- ognized that, even if halothane were responsible for death from hepatic necrosis more often than were other anesthetics, the incidence would prob- ably be small, compared with an estimated over- all operative mortality rate of approximately 2 percent. Indeed, a slight superiority in over-all mortality for halothane could well outweigh any excess of deaths resulting from massive hepatic necrosis. The issue is one of public health, and from this point of view halothane is as safe as or safer than other commonly used anesthetics; its fatal effects on the liver, if any, are clinically negli- gible. It must be stated quite clearly that the data, although limited, do provide some evidence to suggest that halothane can damage the liver, and some to suggest that it does not. The evidence lending support to the possi- bility of a halothane-induced hepatic injury con- sists of the very small group of patients who died with clinical evidence of hepatic failure; the microscopic pattern of hepatic injury was consist- ent with drug-induced or viral hepatitis and most of these few patients had received halothane. The principal reasons for doubting that halo- thane damages the liver—more precisely, for doubting that these few "unexplained" cases of massive hepatic necrosis after halothane were caused by halothane—are the many known and suspected biases inherent in this study of hepatic data collected in the past. CLINICAL IMPLICATIONS There are many questions concerning the use of halothane in the clinical practice of anesthesia whose answers would be welcomed by the prac- ticing physician. Some of these can be provided. The over-all risk of massive hepatic necrosis after uncomplicated surgery performed with any of the commonly used anesthetic agents is so small that it can be totally disregarded as a factor in the choice of anesthetic agent under almost all circumstances. The data of the Study also allow us confidently to disclaim any special risk of fatal hepatic injury from halothane in patients under- going biliary tract surgery, some of whom can be assumed to have suffered some degree of preop- erative hepatic damage. The Study did not attempt to collect data on preoperative hepatic disease, except for the 82 cases finally identified as mas- sive hepatic necrosis, and therefore relatively little can be said about the risk of halothane in patients known preoperatively to suffer from dis- eases of the liver. Other reports of the use of halothane in patients suffering from advanced hepatic disease suggest that even here there may be no special danger. With the wide variety of anesthetic techniques and agents now available, however, some may choose to avoid the use of halothane under these special circumstances. The data collected allow us to say almost nothing about the risk of nonfatal hepatic injury. Hepatic morbidity is, of course, a consideration of no small interest and importance, and in the planning of the Study much attention was directed to the feasibility of obtaining data on nonfatal he- patic failure. It was considered essential, how- ever, in the design of a sound protocol for the study of past data, to choose a readily identifiable criterion of hepatic injury—hence the selection of pathologically confirmed massive necrosis. The difficulty that was later encountered in achieving reliable criteria for massive hepatic necrosis strongly suggests the correctness of this decision. Although data on nonfatal hepatic injury were not solicited, we do have information on previous operations of patients who ultimately died with massive necrosis. Approximately 80,000 (9 per- cent) of the patients in the Study, and 24 of the 82 patients (30 percent) who were found to have suf- fered massive hepatic necrosis at necropsy, underwent two or more operations in the same month or in consecutive months. If nonfatal he- patic injury were a frequent occurrence and, as has been suggested, predisposed to more severe later injury, one would expect to find evidence of hepatic injury after the earlier procedure. Care- ful study of these cases failed to show any such evidence. This does not, of course, prove that subclinical injury had not occurred (fewer than half the 82 patients with fatal massive hepatic necrosis gave clinical evidence of hepatic failure before death). But absence of clinical manifesta- tions of hepatic failure after previous exposure in this highly suspect group of patients does pro- vide some additional evidence of the infrequency of postoperative hepatic injury, fatal or nonfatal. The possibility of a special risk of hepatic injury after repeated exposures to halothane has attracted widespread interest. Many of the pub- lished cases of massive postoperative hepatic ne- crosis thought to be halothane-induced did follow multiple administrations of halothane. However, in reports of patients who have received 30 or more administrations, no hepatic injury was found. In the National Halothane Study, the incidence of massive hepatic necrosis was higher after two or more general anesthetics when halothane was used at least twice, than when it was not. Many of the clinical situations which were found to be as- sociated with higher incidences of hepatic ne- crosis (e.g., open-heart surgery and exploratory laparotomy) also frequently require multiple op- erations. Concerning the selection of anesthetic agent under these circumstances, obviously of 179

critical importance, we have relatively few data. With the issue unresolved, and perhaps unresolv- able, how should one proceed clinically? It is clearly unwarranted to suggest that halothane anesthesia should not be repeated, for it is under the difficult circumstances of emergency reop- eration that a wide choice of anesthetic agents may be most urgently needed. Furthermore, it would not be justifiable to suggest that halothane should not be used for more than one purely elec- tive operation. When, however, a patient has suffered unexplained fever and jaundice after ad- ministration of halothane, it is the opinion of some physicians that halothane should not be used for a subsequent operation. The basis for their recom- mendation is the usual medical doctrine that any treatment followed by ill effects should ordinarily not be repeated. Whatever the merits of such a recommendation, it is remarkable that there was not a single patient in the National Halothane Study who was jaundiced after the administration of halothane and died after a second administra- tion and was found at necropsy to have suffered massive or intermediate hepatic necrosis. Although attention has been directed to pa- tients who received halothane, the effect of other anesthetics should not be overlooked. Cyclo- propane was followed by a greater incidence of massive hepatic necrosis than any of the other anesthetics. Inasmuch as all but one of the 25 cases of massive necrosis that followed admin- istration of cyclopropane were classified as "ex- plained," there is reason to believe that the dis- proportionately large total number might well have been related to the selective use of cyclo- propane for patients in shock; but the possibility that cyclopropane damages the liver cannot be excluded. CONCLUSIONS Fatal postoperative massive hepatic necrosis was rare. It occurred primarily after operations associated with high death rates, and it could usually be explained on the basis of circulatory shock, sepsis, or previous hepatic disease. The possible rare occurrence of halothane-induced hepatic necrosis after single or multiple admin- istration could not be ruled out. 180

PART IV. THE STUDY OF DEATH RATES 334-553 O-69—13