Hepatic Physiology and the Surgical Patient

Hepatic Physiology and the Surgical Patient CHARLES G. CHILD, III, M.D., F.A.C.S.* MARY ANN PAYNE, PH.D., M.D.t

DURING the past several decades surgeons have become increasingly aware of the fact that patients suffering from hepatic damage do not tolerate major surgical procedures well. Initial recognition of the role the liver was ultimately to play in determining surgical success or failure undoubtedly appeared in connection with general anesthesia. As early as 1850 Casper1 called attention to the severe toxic effects which might be produced by chloroform. In 18872 Ungar demonstrated that fatty infiltration of the liver could be produced in dogs by inhalation of this then popular drug. By 1905 Bevan and FavilP had clearly defined hepatocellular injury due to chloroform. Interestingly enough, these authors also clearly appreciated that patients suffering from a debilitating disease were more susceptible to the noxious effects of chloroform anesthesia than were persons in good health. Liver damage, however, was not directly identified with any specific surgical disease until 1918 when Evarts Graham4 called attention to the fact that hepatitis frequently accompanied gallbladder infection. During the next few years the interest which centered around the mortality following biliary tract operations culminated in 1931 with the introduction by Heyd 5 of the hepatorenal syndrome. This diagnosis was frequently used to identify those unfortunate patients who, though they appeared in good health preoperatively, developed hyperpyrexia, jaundice, prostration, anuria, and died after a relatively simple surgical procedure. Although this concept enjoyed wide popularity for a time and was extensively elaborated by Boyce 6 in 1941, it has largely been discarded for lack of specificity. The syndrome undoubtedly included a number of states such as transfusion reaction, concealed hemorrhage, dehydration and heart failure. The shock kidney (lower nephron nephroFrom the Departments of Surgery and Medicine, New York Hospital-Cornell Medical Center, New York.

* Associate Professor of Clinical Surgery, Cornell University Medical College; Attending Surgeon, New York Hospital; Consultant, Mt. Vernon Hospital. t Instructor in Medicine, Cornell University Medical Department; Physician to Outpatient Department, New York Hospital. 599

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sis) went unrecognized. With improvement in preoperative and postoperative care many of these dreaded complications of major surgery have all but disappeared. As more and more attention was accorded the liver in its relationship to surgery, hepatic disease as such became the object of detailed clinical and laboratory investigation. Reliable, though not always clearly defined, tests of liver function were developed and exhaustively appraised. The relationship of the liver to nutrition was carefully analzyed, and practical programs of oral and parenteral alimentation developed. Recently the importance of being able to carry a patient with cirrhosis of the liver successfully through an extensive surgical operation has been brought into critical focus by Blakemore's7 demonstration that portal decompression can be life-saving. There still remain, of course, many unsolved hepatic riddles. Medicine and surgery are today, however, in a better position than ever before to delineate the relationships that are believed to exist between normal and abnormal liver function and the problems of surgery. It is the purpose of this chapter to review certain of the more recent developments in hepatic physiology and to attempt to point out wherein their application may prove useful in managing patients urgently requiring a major surgical operation. ANESTHESIA AND DRUGS

In recent years all drugs commonly employed as anesthetic agents have been extensively investigated with particular reference to their hepatotoxic potential,8 Furthermore, when a new anesthetic agent is developed its possible toxicity to the liver is often considered ahead of many of its other properties. As the articles upon this subject are reviewed, almost all drugs capable of producing a general anesthesia are found to have three physiologic effects in common: they produce a transient hypoglycemia, a partial depletion of liver glycogen, and as indicated by bromsulphalein retention, a temporary depression in liver function. Generally these agents also suppress the secretion of bile and bile salts. Although these effects are not wholly understood, and their importance cannot be clearly defined, they are presumed detrimental to the liver. Chloroform, vinyl ether and avertin are notoriously hepatotoxic and are well known for their ability to produce cirrhosis of the parenchymal cells. For this reason they are generally contraindicated and specifically so for use in patients suspected of having liver disease. Perhaps even more injurious to the liver than the specific toxic effect of the drug itself is the development during a major surgical procedure of hepatic hypoxia. This state has been shown to interfere seriously with the essential enzymatic activities of this organ. Surgical shock, therefore, with its attendant decrease in hepatic blood flow, must be guarded against particularly. Transient falls in blood pressure due to such factors as coeliac reflex, though less dangerous, are to be avoided. During a prolonged general anesthesia the anesthesiologist must ever be aware of the necessity for maintaining a high level of blood oxygenation. As will be emphasized in the following section the preoperative replenishment of

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hepatic glycogen and protein are also important in avoiding liver damage during anesthesia. From a review of the anesthetic agents currently available, cyclopropane, with or without curare, emerges as the drug of choice for use in patients known or suspected of having liver disease. Morphine should not be used either preoperatively or postoperatively because it is slowly detoxified by the insufficient liver. By depressing respiratory exchange it may in itself contribute to lowering blood oxygen. NUTRITION IN THE SURGICAL PATIENT

Probably no single subject in surgery has received greater clinical and laboratory attention in recent years than has that of nutrition. Ample evidence has been accumulated to prove that postoperative morbidity and mortality can be correlated directly with the degree of success with which nutritional deficiencies have been corrected preoperatively. In the majority of surgical patients these defects are due to one form or another of starvation. Anorexia, so frequently a concomitant of surgical disease, may result in simple limitation of dietary intake. Primary gastrointestinal disease may prevent adequate absorption of foodstuffs. In patients with hepatic disease yet another factor is evident; the damaged liver itself is unable to utilize nutritional elements successfully. In addition to these general nutritional factors the protein depleting effects of a surgical operation are well recognized, a negative nitrogen balance regularly follows almost any major surgical procedure. Furthermore, there appears a significant fall in the level of serum albumin which may persist for some time after operation. Appearing in the presence of low serum protein levels are several clinical states well recognized today as serious handicaps to satisfactory postoperative recovery. Edema of the lungs interferes with proper oxygenation of the blood and predisposes to pulmonary infection. Gastrointestinal malfunction secondary to interstitial overloading of the bowel wall not only inhibits dietary intake and assimilation, but also produces important degrees of intestinal obstruction. In this connection it has been repeatedly pointed out that, as serum protein levels fall below normal, water retention begins. As much as 10 to 12 pounds of water may be harbored in areas of low tissue tension before edema becomes evident peripherally. As the innumerable studies upon the relationship of the liver to malnutrition are examined two facts of primary significance to the surgeon become apparent: first, in starvation states fat is deposited in the liver cells and glycogen and protein disappear. Second, a liver heavily infiltrated with fat is unable to tolerate well the insults to which it may well be subjected during the course of a major surgical procedure. For instance, it has been clearly demonstrated that if dogs with fatty livers are subjected to hepatotoxin such as chloroform, they succumb to much smaller doses of the drug than do those animals in which the liver is normal. When Opie 9 demonstrated many years ago that the injurious effects of substances toxic to the liver could be appreciably lessened by increasing hepatic glycogen, the administration of large amounts of glu-

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cose to the patient with liver disease became axiomatic. More recently Ravdin10 and others have shown that by increasing the protein content of the liver an even greater degree of protection is afforded. , No matter what the ultimate solutions to these perplexing problems may be it is considered important today to attempt to protect not only the normal but also the abnormal liver by insuring a high carbohydrate and high protein intake. In the past, efforts have been made to eliminate fat from such therapeutic programs. The basis for this was largely teleological, and with Hoagland'sll questioning the necessity of restricting fat in liver disease several investigators have demonstrated that this substance facilitates liver regeneration. Fat is therefore added because it contributes significantly to the palatability of the diet and substantially raises the caloric intake. Today the surgeon must accept the obligation of protecting the normal liver from injury during the course of surgical operation. This responsibility becomes even more evident when patients with liver disease must undergo a major surgical procedure. Although hepatic reserve is enormous and the regenerative potential of this organ is high there are no completely satisfactory criteria for accurately estimating to what degree liver insufficiency exists in any given patient. All patients with demonstrable liver disease must be considered candidates for hepatic decompensation. In the remainder of this section, therefore, it will be assumed that the life of any patient manifesting the stigmata of liver damage is in jeopardy should a major operation become necessary. Dietary Protein

All patients with severely impaired liver function present varying degrees of hypoalbuminemia. Evidence that this defect is probably due to faulty hepatic synthesis of this substance is derived from the low fibrinogen and prothrombin levels which are so commonly seen in patients with advanced hepatic disease. At the present time there is no unanimity of opinion as to how successfully these low serum protein levels can be corrected by supplying additional amounts of dietary protein. Despite this it is customary to indulge in the forced feeding of protein during the preoperative and postoperative period. Where the oral route is available patients are encouraged to take from 150 to 200 grams of protein daily. In addition 500 to 600 grams of carbohydrate are included in the diet. Enough fat to make the dietary palatable is a practical necessity. At this point it is well to remember that merely ordering such a diet is no assurance that it will be eaten. A careful check of the patient's tray after each meal is important. Intensive dietary efforts such as these, even though successful, unfortunately cannot be relied upon to restore a low serum albumin level to normal. Persisting deficits must be corrected by transfusion of blood, plasma, and if necessary human serum albumin. In the postoperative period hepatic reserve may even be lower than preoperatively and a further fall in serum albumin due to the operation itself may make its appearance. Transfusion therapy, therefore, must be continued until serum albumin levels become stabilized.

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Parenteral Therapy

In the patient requiring extensive protein therapy there is no wholly satisfactory substitute for the oral ingestion of biologically active protein. For one reason or another, however, this route is all too frequently either partially or completely unavailable. Under such circumstances restitution therapy must be undertaken intravenously. Although PetersI2 has justly criticized many of the conclusions made upon the basis of the innumerable nitrogen balance studies reported during recent years, it is generally conceded today that a positive balance may ~e achieved in the patient with a normal liver by the use of blood and plasmaI3 and of human serum albumin. 14 Whether or not this is the case is perhaps not as important as the fact that low serum albumin levels can be returned to normal and maintained at levels sufficiently near normal to carry patients through an urgently needed operation. Insofar as the individual with hepatic disease is concerned there is even less assurance that states of positive nitrogen balance can be obtained parenterally. Reliance, therefore, may have to be placed entirely upon transfusion therapy. In the use of human serum albumin a special note of warning is in order. Too rapid elevation of serum levels with this substance may so precipitously overload the circulating blood volume that patients with liver disease are promptly thrown into congestive heart failure. The subject of parenteral protein administration cannot be considered complete without mention of the numerous amino acid preparations which are available. At present there is much confusion concerning the degree of positive nitrogen balance which can be obtained in patients with normal livers. Although precise information as to the fate of parenterally injected amino acids is still unavailable, most workers in this field agree that their use, particularly if supplemented by adequate calories, lessens the demands placed upon tissue proteins. 16 At least one fact is evident in the use of these solutions: serum protein levels are not rapidly restored to normal by their administration. In the patient with hepatic disease little information is available regarding the usefulness of these solutions. It is postulated by some that a damaged liver cannot use these substances as building blocks from which to synthesize essential proteins. The large amounts of water in which they must be administered constitute a special hazard to those patients whose tendency to retain water is notorious. In the patient with hepatic disease who requires parenteral protein therapy the best results are obtained by the infusion of human serum protein. Transfusions; Vitamin K

Although perhaps not primarily a nutritional problem, prothrombin deficiency in the patient with impaired liver function merits special attention. As hepatic decompensation develops, dangerously low prothrombin levels are frequently encountered. These cannot be improved by the administration of vitamin K alone because the production of prothrombin depends upon adequate liver function. Where such deficits occur in patients requiring a surgical procedure the surest corrective

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mechanism available is transfusion with fresh blood or plasma. This method can only be considered effective for twelve to twenty-four hours and transfusions must be repeated frequently after operation until all danger of hemorrhage is past. In spite of these facts there is, however, a definite clinical impression that even in advanced liver disease vitamin K may be helpful, for with its use the bleeding tendency seems to be better controlled. Dietary Supplements

Because choline and methionine are thought to aid in the mobilization of fat already deposited within the liver, these substances are generally included in the preoperative and postoperative regimen of patients suffering nutritional deficiencies and hepatic disease. Although their effectiveness in liver disease has never been conclusively demonstrated, they are not harmful and may possibly be of some benefit. It has also been shown repeatedly that patients with advanced liver disease are deficient in all fat-soluble vitamins. This is due to the poor absorption of these substances which takes place in the absence of bile salts. Severe osteoporosis and even collapsed vertebrae are not infrequently seen in these individuals. Large amounts of vitamins A and D particularly are, therefore, considered important dietary supplements. Salt Restriction

Many patients with advanced cirrhosis are unable to excrete the sodium ion normally. This doubtless contributes to the incapacitating water retention so characteristic of this disease. A recent advance in the management of such patients has been use of low salt diets and mercurial diuretics. With the development of salt poor protein supplements it!is now possible to force as much as 150 to 175 grams of protein daily while restricting the total salt intake to 1 gram or less. In this connection it must be pointed out that patients with cirrhosis who are being maintained upon such a rigorous program as this may develop the typical picture of severe sodium depletion. Particularly must this be considered should additional sodium be lost through vomiting, diarrhea, or extensive perspiration. Since patients with a severe surgical disease frequently sustain one or more of these extrarenal losses of sodium, the existence of a state of sodium depletion should be carefully investigated and corrected prior to undertaking any operative treatment. In the identification of sodium depletion much reliance may have to be placed upon clinical signs and symptoms, for laboratory aids may be either unavailable or misleading. Values for serum sodium can be obtained quickly only in laboratories equipped with it flame photometer; in the presence of hemoconcentration normal serum values may give an entirely erroneous picture of total body sodium. A patient known to be upon a low sodium diet who gives a history of vomiting and/or diarrhea, and extreme weakness, and who presents signs of tissue dehydration and a low blood pressure may be presumed to be suffering from a depleted

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body sodium. If sodium deficits are demonstrated they can be corrected by the intravenous administration of isotonic sodium chloride. Without extensive amounts of water 3 or 5 per cent solutions of sodium chloride can be given. ORAL CHOLECYSTOGRAPHY IN LIVER DISEASE

Ever since oral cholecystography became widely accepted as an important diagnostic technic, the medical profession has generally believed it should not be used in the jaundiced patient. This conviction has apparently been based on the ill-defined fear of some toxic effect of the dye upon the liver. Further, the test itself was believed valueless in the jaundiced state. Actually neither of these misgivings has materialized. With the increasing recognition of the importance of differentiating viral hepatitis from extrahepatic obstructive jaundice, attention has again been focused upon the question of whether or not oral cholecystography is dangerous to patients with elevated serum bilirubin levels. The most informative article upon this subject is that of Readinger and Swift.l6 After administering cholecystographic dyes to a large number of patients with viral hepatitis these authors convinced themselves that these agents are not toxic to the diseased liver. Furthermore, they demonstrated that even in moderately severe jaundice the gallbladder could be visualized, provided the two-dose technic was employed. In over 90 per cent of those whose serum bilirubin was less than 11 mg. per 100 cc. and whose bromsulphalein retention was less than 30 per cent, the gallbladder was successfully visualized. DUODENAL DRAINAGE

Although perhaps of limited usefulness, tube drainage of the duodenum and microscopic examination of the cells and secretions withdrawn do have a place in the differential diagnosis of certain hepatic and biliary tract disturbances. The usual situation in which examination of the duodenal contents may playa helpful role in establishing a diagnosis is found in patients who have had a cholecystectomy. Because of the subsequent development of jaundice they are then suspected of harboring a common duct stone or a malignant pancreaticoduodenal cancer. If bile is not obtained, all that can be deduced is that complete common duct obstruction exists. If, however, bile is withdrawn, the identification of calcium bilirubin ate or cholesterol crystals is of importance for they are pathognomonic of calculus disease. The identification of pus cells indicates a biliary tract infection. Examination of the duodenal contents by the Papanicolaou smear technic may reveal malignant cells. If identified their diagnostic significance is important; little importance, however, can be attached to a negative result for this is one of the most difficult areas from which to retrieve cells for cytologic examination. In the patient with jaundice the recovery of normal bile excludes calculus and extrahepatic malignant disease and points toward an intrahepatic lesion.

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THE DIFFERENTIAL DIAGNOSIS BETWEEN SO-CALLED MEDICAL AND SURGICAL JAUNDICE

In recent years the incidence of viral hepatitis has increased alarmingly. Furthermore, it has been repeatedly demonstrated that patients suffering from this disease withstand an exploratory celiotomy poorly. These two facts have served to emphasize the importance of differentiating jaundice secondary to viral hepatitis from that due to extrahepatic obstruction. Recently a patient with viral hepatitis was explored at the New York Hospital under cyclopropane anesthesia. The procedure required forty-five minutes for its completion. He died twelve hours later. Microscopic examination of a liver biopsy obtained at the operating table failed to reveal any serious abnormality; at postmortem massive necrosis was present in this organ. The importance, therefore, of recognizing this infectious disease cannot be overemphasized. Despite the great significance currently attached to a battery of liver function tests the diagnosis of viral hepatitis is primarily clinical and rests substantially upon the history and physical examination. Anorexia, so characteristic of the disease, is a valuable clue and the patient should be questioned carefully about its presence in relation to the evening meal. Nausea, excessive fatigue, and mental depression are also outstanding symptoms. A history of exposure to persons with jaundice as well as a record of parenteral injections within six months are particularly important, for not only can this disease be transmitted from person to person but also by contaminated needles and syringes. The physical examination should include a careful evaluation of the liver for a smooth tender edge. Shock tenderness, if it be elicited, is an important sign of hepatitis. About one-third of the patients with this disease will present an enlarged, tender spleen, and occasionally a generalized lymphadenopathy can be demonstrated. In establishing a diagnosis of viral hepatitis the laboratory is most useful. Prior to the clinical appearance of jaundice bile can be identified in the urine by slowly adding 2 per cent methylene blue to a fresh specimen. Persistence of a green color after the fifth drop indicates the presence of bile. If a paper strip, impregnated with barium chloride, is dipped in urine, a yellow line of pigment is concentrated at the surface. In the presence of bile this pigment turns blue upon the addition of Fouchet's reagent. If the important clinical signs and symptoms are present and bile is detected by either of these easily performed tests, viral hepatitis must be suspected. Urobilinogen may usually be demonstrated in the urine of patients during the preicteric stage of hepatitis. Its presence is detected by the tube dilution method of Wallace and DiamondI7 or by the comparator block technic of Watson. IS During the early period of hepatitis the question of operation seldom arises. As the disease progresses through the first week, however, it enters a period of biliary obstruction. Jaundice appears and deepens. The patients are patently ill. It is at this time that its differentiation:from extrahepatic obstruction is most difficult. As the laboratory tests per-

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formed at this time merely reflect the progressive biliary obstruction, reliance may have to be placed even more upon the history and physical examination. Bilirubin retention and the elevation of the alkaline phosphatase are not at all diagnostic. The stool is g(;lnerally acholic and the urobilinogen which was present in the urine earlier may now disappear. It is during this period, from about the fifth to the tenth day of the disease, that incorrect diagnoses are usually made and these patients unhappily subjected to operation. During the second and third week of viral hepatitis signs of parenchymal injury appear and the well-known cephalin flocculation and thymol turbidity tests become positive. With the identification of liver cell damage, the diagnosis of viral hepatitis becomes reasonably secure. In interpreting these tests it is well to recall that in older patients and occasionally in young individuals they may be only weakly positive or not positive at all. In many severe cases of hepatitis the obstructive phase may continue for many weeks and the surgeon will be sorely tempted to recommend operation. At the moment there is no simple solution to this dilemma. Only a most critical review of the history, the physical examination, the clinical and laboratory studies can be depended upon to give the correct answer in the majority of instances. The development of a specific test for infectious hepatitis is an ideal which has not yet been achieved. That such may be forthcoming is intimated by a skin test which is being studied extensively by Stokes, Henle and Drake. 19 At present it is too early to draw any specific conclusions from these studies. It seems probable, however, that this test will prove more important as an epidemiologic test than as a specific aid in . diagnosis. Once viral hepatitis has been excluded with reasonable certainty, the clinician must also face the question of whether or not the patient is suffering from chronic liver disease. In individuals suspected of having early cirrhosis, the bromsulphalein retention test may be helpful indeed. A blood level exceeding 4 mg. per 100 cc. forty-five minutes after the administration of 5 mg. per kilogram of body weight may be the only reflection of the presence of liver disease. Credence should not be given positive results obtained by this test if it was performed within several days after a febrile episode. While total serum protein levels may remain constant until advanced hepatic degeneration is present, a reversal of the albumin-globulin ratio may be detected earlier. An elevated serum globulin is a sensitive indicator of chronic liver disease and a low or diminished serum albumin is one of the most constant defects of patients with cirrhosis. Of the tests of parenchymal damage, the cephalin flocculation correlates most closely with the degree of hepatic cellular malfunction. In patients for whom a major surgical operation is contemplated, a low serum albumin and a high serum bilirubin together carry the gravest prognostic significance. THE EFFECTS OF COMMON DUCT OBSTRUCTION UPON THE LIVER

Obstructive jaundice amenable to surgical treatment generally occurs in or about the common duct and is usually due to a stone or to cancer.

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The jaundice may be gradual in onset; it may be intermittent; or it may appear abruptly. The physiologic disturbances produced not only adversely affect the biliary tree and hepatic cells but also result in several important general systemic manifestations. Furthermore, the clinical problems may vary further, depending upon whether or not infection is or becomes associated with the obstruction. Where the common duct becomes suddenly and completely obstructed, there is marked distention of all of the biliary radicals. If, however, obstruction is incomplete or intermittent, as is frequent in calculus disease, and accompanied by infection, the dilatation of the biliary tree may not be marked. Associated with the increased intrahepatic pressure, and perhaps in a measure associated with decreased portal blood flow, degenerative changes appear in the liver cells. These may progress to atrophy. Whatever the cause of the obstruction, the ability of the liver cells to regenerate and to return to normal once the obstruction is relieved is phenomenal. Only where the obstruction is long-standing and accompanied by infection do the typical changes of biliary cirrhosis appear. The laboratory and clinical evidences of impaired liver function have been considered above. The systemic effects of obstructive jaundice are due primarily to the absence of bile from the intestinal tract and the accumulation of bile constituents in the blood. In the absence of bile salts in the intestine, there are marked disturbances in the absorption of fat. In addition, important amounts of the fat-soluble vitamins A and D are lost. Of perhaps even greater importance than the fat and vitamin losses is the fact that protein absorption is interfered with by the presence of excess undigested fat in the gastrointestinal tract. Meat fibers are actually coated with fat and their rate through the gut accelerated. Since adequate amounts of protein are considered essential in all forms of liver damage, a nutritionally vicious circle is established where the fat in the diet is not abrsorbed normally. Hypoprothrombinemia with its attendant hemorrhagic diathesis is of frequent occurrence in the patient with obstructive jaundice. Prior to the discovery of vitamin K and its clinical application, severe hemorrhage was a complication most feared in patients who had to be operated upon during a period of deep jaundice. With the demonstration that this defect could be corrected in the majority of instances by the oral ingestion of vitamin K together with bile salts or by hypodermic injection of one of the many naphthoquinone derivatives, hemorrhage no longer constitutes a severe problem in the management of one of these patients. In addition to its obvious therapeutic uses, the prothrombin response to vitamin K has proved a valuable test of liver function. A patient whose prolonged prothrombin time fails to respond to parenteral vitamin K administration must be considered to possess a severely damaged liver. Although many patients with obstructive jaundice manifestly present enlarged livers, it is of note that splenic enlargement is rarely observed. Furthermore, although there are many case reports of prolonged common duct obstruction due to traumatic stricture, it is a matter of some

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interest to note how few of these patients develop clinically significant esophageal varices and portal hypertension. THE HEMODYNAMICS OF THE EXTRAHEPATIC CIRCULATION TO THE LIVER

Current interest in the treatment of carcinoma of the head of the pancreas and of portal hypertension has served to.focus attention on the portal vein and hepatic artery. For many years it has been generally believed by the medical profession that sudden and complete occlusion of the portal vein in man is promptly fatal. This conviction can be attributed to the fact that such occlusion of this vessel in the dog, cat and other common laboratory animals is followed by death within fifteen to sixty minutes. It has been demonstrated that here death is due to depletion of the circulating blood volume into the splanchnic venous bed. Child and his associates,'o" 20b however, have proved that one of the primates, the Macaca mulatta monkey, survives uneventfully following ligature or resection of the portal vein. After demonstrating that this monkey tolerates sudden portal occlusion, they performed similar experiments in seven patients with inoperable carcinoma. All of these survived the immediate postoperative period, though, of course, they all ultimately died of cancer. The results of these experiments were then directly applied to extending the usefulness of pancreaticoduodenectomy as a radical operation for pancreatic cancer. One of the demonstrated defects of this procedure, as currently performed in man, lies in the fact that it has to be abandoned wherever the portal or superior mesenteric veins are involved in the malignant growth. This frustrating situation provided a challenge to develop a method whereby the portal vein could be removed together with the growth. At first pancreaticoduodenectomy with resection of the portal vein was attempted in the M acaca mulatta monkey in one stage. All the animals died due to uncontrollable blood loss from the field of operation. After the discovery that the portal hypertension produced by occlusion of the portal vein subsides almost completely within a week a two-stage operation was devised. At the first stage the portal vein was simply occluded; at the second stage it was found possible in this monkey to resect the head of the pancreas, the duodenum and the portal and mesenteric veins en bloc. A similar two-stage operation was performed in one human for metastatic melanoma. The details of these experiments and the one operation performed in man will be reported elsewhere.'! Although the usefulness of resection of the portal vein as a surgical operation has yet to be established, it is at least apparent that this vessel can be successfully suddenly and completely occluded in the M acaca mulatta monkey and in man. Aneruysms of the hepatic artery are encountered often enough to be more than a mere surgical curiosity. Because these are prone to rupture there exists every incentive to attempt their removal. To accomplish this without interrupting the arterial blood supply to the liver has generally proved impossible. Just as in the case of the portal vein it has been maintained that occlusion of the hepatic artery is fatal. In the dog this is certainly true unless, as has been recently demonstrated by Markowitz" and confirmed by Chau, Goldbloom and Gurd23 and others, the animal is given large doses of penicillin or aureomycin. These drugs apparently prevent an anaerobic'infection in the liver to which the animal generally succumbs. In the Macaca Mulatta monkey Child and his associates24 have demonstrated that the hepatic artery can be resected successfully without the use of antibiotics. Schilling, McKee and Milt 26 have shown that in the dog survival after ligation of the hepatic artery can regularly be obtained provided the proximal segment

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of this vessel is implanted into the portal vein. The arteriovenous fistula so created oxygenates the liver adequately. In treating patients with portal hypertension secondary to cirrhosis of the liver, Rienhoff26 and Berman, Koenig and Muller 27 have recently reported several patients who survived ligation of their hepatic artery. Great caution, however, must be exercised in applying this success to patients in whom the liver is normal. Grant, Fitts and Ravdin28 have recently reviewed the subject of ligation of the hepatic artery in man for aneurysm of the vessel. They point out that such recent developments as have been mentioned above may eventually help to solve the problem. As yet, however, none of these has been tested in man. It must still be concluded, therefore, that man, except under unusual circumstances, does not survive ligation of his hepatic artery. PORTAL VENOGRAPHY

Stimulated by the ever-growing interest in venography Child20a • 20b. 29 and Moore and Bridenbaugh30 have demonstrated the safety and feasibility of roentgen visualization of the portal system. Employing 25 per cent and on occasion 70 per cent Diodrast, the portal vein, the superior mesenteric vein and the intrahepatic branches of the portal vein can be well outlined. Invasion of these vessels by pancreatic cancer and their occlusion by thrombus have been demonstrated. In several patients the information obtained from such roentgenograms has proved most helpful. In carcinoma of the head of the pancreas operability has been decided. That a portacaval shunt would be impractical was demonstrated in another patient. Representative portal venograms are reproduced in Figures 185, 186 and 187. Although the practical applications of this technic cannot be predicted at the present time, portal venography is feasible and may ultimately prove a useful diagnostic method. SERUM (TRANSFUSION) HEPATITIS

With the striking increase in the incidence of serum jaundice in the general population, the hazards of blood and plasma transfusions have become of major concern to the surgeon. 3! The magnitude of this problem becomes more apparent as the high proportion of subclinical cases of hepatitis and the existence of carrier states are recognized. The virus, presumed to be the etiologic factor concerned, is present and transmissible during the incubation period of the disease. Therefore, even donors who fail to give a history of jaundice may be harboring the etiologic agent. Sterilization of plasma has been attempted using ultraviolet irradiation. Recently some doubt has been cast on the efficacy of this method. 32 • 33 Because of the narrow margin between inactivation of the virus and denaturation of the protein, this is a procedure demanding great technical precision. It is. conceivable that generalizations are not valid and that each sterilizing unit should be evaluated independently. The limiting factor in reaching any conclusion regarding inactivation of hepatitis virus is the long and cumbersome trial in human volunteers which at present is the only assay method available. Storage of plasma at room temperature has been suggested and may eventually be judged

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the method of choice. 34 At the present time there is no accepted satisfactory method affording protection from serum hepatitis when blood or plasma is administered. The protection of the patient from transmission of this virus by way of contaminated syringes is an easier problem to solve but one requiring constant vigilance. One one-hundredth of a milliliter of contaminated

Fig. 185. Normal portal venogram. Here the superior mesenteric and portal veins are clearly outlined. The intrahepatic venous radicals are well visualized. (From author's paper in Radiology, Nov., 1951.)

material is all that is needed to introduce the virus into a new host. The multiple dose technic for giving injections to a series of patients is an unacceptable practice. In withdrawing blood change of needles without interval sterilization of the syringe is one common errOr still generally . unrecognized as a hazard. Syringes and needles, including those used for finger punctures, should be sterilized by autoclaving or boiling for a minimum of fifteen minutes. The use of gamma globulin as a protection against infectious hepatitis is promising. 36 In serum hepatitis results are still under evaluation but

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it would appear that an initial injection at the time of administration of the blood or plasma followed in a month by a second injection warrants further clinical trial. The usual dose is 0.06 ml. per pound of body weight.

Fig. 186. Obstrllctionof the portal vein by cancer. Here the superior mesenteric and portal veins are not visualized. Instead, the dye outlines an extensive system of collaterals which bypass the point of obstruction. The tumor which lay in the head of the pancreas is marked "T". (From author's paper in Radiology, Nov., 1951.)

THE LIVER AND IRREVERSIBLE SHOCK

During the past few years data has been accumulated indicating that the liver is implicated in irreversible shock. In 19-;16 Frank, Seligman and Fine36 demonstrated that this state could be prevented by viviperfusion of the liver. They accounted for this phenomenon by the fact that during these experiments the oxygen concentration of the hepatic blood was maintained at norma:! levels. In their most recent article on this subject these investigators37 have presented evidence indicating that during hemorrhagic shock in the dog there is severe

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constriction of the portal and hepatic veins. That this results in increased intrahepatic vascular resistance and concomitant impedance in blood flow through the liver is reflected in the elevations in portal pressure which were consistently observed during shock. Employing very different experimental technics Shorr and his associates 38 have likewise indicated that the irreversible stage of shock is due to hepatic failure. In explanation these authors postulate the presence of vasodilator and vasoexcitor substances which are elaborated by the liver

Fig. 187. Portal hypertension due to thrombosis of the portal vein. Here the superior mesenteric vein is irregular and the portal vein is not visualized. A tortuous splenic vein is outlined and the puddles or-dye high in the left upper quadrant are interpreted as varices at the gastric cardia. (From author's paper in Radiology, Nov., 1951.)

and kidney respectively. Normally the equitable balance which exists between these two factors maintains the tone of the peripheral vascular bed. During periods of hypoxia, however, large amounts of the depressor substance accumulate in the blood stream. This is due both to an overproduction of this material by the liver and to failure of the enzymatic systems necessary for its inactivation. Since large amounts of this substance have been found in the blood of animals and patients during shock, it has been suggested that these humoral factors are responsible for the phenomenon of irreversibility. The evidence produced by these as well as other investigators seems to indicate a severe derangement of liver physiology in shock. Hypoxia appears to be of primary importance in initiating a train of events

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which, if not corrected, may well lead to the death of the patient. In dealing surgically with patients manifesting low reserves of liver function every effort should be directed, therefore, toward insuring at all times maximum oxygenation of the liver. Sedatives and anesthetic agents should be chosen carefully. The arterial blood pressure should be zealously defended against periods of even transient hypotension. The liberal use of blood transfusion and oxygen therapy may make the difference between surgical success and failure. REFERENCES 1. Casper, quoted by L. G. Guthrie: On the Fatal Effects of Chloroform on Children Suffering from a Peculiar Condition of Fatty Liver. Lancet 2: 10,1903. 2. Ungar, E.: Uber tiidtliche Nachwirkungen der Chloroforminhalationen. Vrtljschr. f. gerichtl. Med. 47: 98, 1887. 3. Bevan, A. and Favill, H. B.: Acid Intoxication and Late Poisonous Effects of Anesthetics; Hepatic Toxemia; Acute Degeneration of the Liver Following Chloroform and Ether Anesthesia. J.A.M.A. 45: 691, 1905. 4. Graham, E. A.: Hepatitis; a Constant Accompaniment of Cholecystitis. Surg., Gynec. & Obst. 26: 521,1918. 5. Heyd, C. G.: "Liver Deaths" in Surgery of the Gallbladder. J.A.M.A. 97: 1847, 1931. 6. Boyce, F. F.: Role of the Liver in Surgery. Baltimore, C. C Thomas, 1941. 7. Blakemore, A. H.: Portacaval Shunt for Portal Hypertension. Follow-up Results in Cases of Cirrhosis of the Liver. J.A.M.A. 145: 1335, 1951. 8. Huggill, J. T.: Liver Function and Anesthesia. Anesthesiology 11: 567, 1950. 9. Opie, E. L. and Alford, L. B.: The Influence of Diet on Hepatic Necrosis and Toxicity of Chloroform. J.A.M.A. 62: 895,1914. 10. Ravdin, 1. S.: Surgical Jaundice. Internat. Abstr. Surg. 89: 209,1949. 11. Hoagland, C. L.: The Therapy of Liver Diseases. Bull. New York Acad. Med. 21: 537,1945. 12. Peters, J. P.: Effect of Injury and Disease on Nitrogen Metabolism. Am. J. Med. 8: 611,1950. 13. Allen, J. G., Egner, W., Brandt, M. B. and Phemister, D. B.: Use of Blood and Plasma in Correction of Protein Deficiencies in Surgical Patients. Ann. Surg. 131: 1, 1950. 14. Fletcher, A. G., Gimbel, N. S. and Riegel, C.: Parenteral Nutrition with Human Serum Albumin as the Source of Protein in the Early Postoperative Period. Surg., Gynec. & Obst. 90: 151, 1950. 15. Ellison, E. H., McCleery, R. S., Zollinger, R. M. and Case, C. T.: The influence of Caloric Intake upon the Fate of Parenteral Nitrogen. Surgery 26: 374,1949. . 16. Readinger, H. M. and Swift, W. E. et al; Oral Cholecystography~in~Patients with Viral Hepatitis. Am. J. Med. 8: 611, 1950. : :.. ., 17. Wallace, G. B. and Diamond, J. S.: The Significance of Urobilinogen in the Urine as a Test for Liver Function-With a Description of a Simple Quantitative Method for Its Estimation. Arch. Int. Med. 35: 698, 1925. 18. Watson, C. J., Schwartz, E. S. et al.: A Simple Method for the Quantitative Recording of the Ehrlich Reaction as Carried out with Urine and Feces. Am. J. Clin. Path. 14: 605, 1944. 19. Henle, G., Drake, M. Henle, W. and Stokes, J. Jr.: A Skin Test for Infectious Hepatitis. Proc. Soc. Exper. BioI. & Med. 73: 603, 1950. 20a. Child, C. G.: Acute Occlusion by Ligature of the Portal Vein in the Macacus rhesus Monkey. Proc. Soc. Exper. BioI. & Med. 70: 332, 1949. 20b. Child, C. G., Milnes, R. F., Holswade, G. R. and Gore, A. L.: Sudden and Complete Occlusion of the Portal Vein in the Macaca Mulatta Monkey. Ann. Surg. 132: 475, 1950.

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21. Child, C. G., Holswade, G. R., McClure, R. D., Gore, A. L. and O'Neill, E. A.: Pancreaticoduodenectomy with Resection of the Portal Vein in the Macaca Mulatta Monkey and in Man. Surg., Gynec. & Obst. (to be published). 22. Markowitz, J., Rappaport, A. and Scott, A. C.: Prevention of Liver Necrosis Following Ligation of Hepatic Artery. Proc. Soc. Exper. BioI. & Med. 70: 305, 1949. 23. Chau, A. Y. S., Goldbloom, V. C. and Gurd, F. N.: Clostridial Infection as a Cause of Death after Ligation of the Hepatic Artery. Arch. Surg. 63 390,1951. 24. Child, C. G.: Studies on the Hepatic Circulation in the Macaca Mulatta Monkey and in Man. Presentation at the Surgeons Forum of the Am. College of Surgeons, November, 1951. 25. Schilling, J. A., McKee, J. W. and Wilt, W.: Experimental Hepatic-Portal Anastomosis; Surg., Gynec. & Obst. 90: 473, 1950. 26. Rienhoff, W. F., Jr.: Ligation of the Hepatic and Splenic Arteries in the Treatment of Portal Hypertension with a Report of Six Cases. Preliminary Report. Bull. Johns Hopkins Hosp. 88: 368,1951. 27. Berman, J. K., Koenig, H. and Muller, L. P.: Ligation of Hepatic and Splenic Arteries in Treatment of Portal Hypertension. Ann. New York Acad. Sc. Arch. Surg. 63: 397, 1951. 28. Grant, J. L., Fitts, W. T. and Ravdin, 1. S.: Aneurysm of the Hepatic Artery. Surg., Gynec. & Obst. 91: 527, 1950. 29. Child, C. G.: Portal Venography: Preliminary Report. Radiology (to be published) . ?O. Moore, G. E. and Bridenbaugh, R. B.: Portal Venography. Surgery 28: 827, 1950. 31. Ginzburg, L., Sussman, L. N. and Auerhahn, H.: Post transfusion Viral Hepatitis as a Surgical Complication. Surg., Gynec. & Obst. 92: 492, 1951. 32. Barnett, R. N., Fox, R. A. and Snavely J. G.: Hepatitis Following the Use of Irradiated Human Plasma. J.A.M.A. 144: 226, 1950. 33. Rosenthal, N., ,Bassen, F. A. and Michael, S. R.: Probable Transmission of Viral Hepatitis by Ultraviolet-Irradiated Plasma. J.A.M.A. 144: 224, 1950. 34. Allen, J. G. et al: Homologous Serum Jaundice and Its Relation to Methods of Plasma Storage. J.A.M.A. 144: 1069, 1950. 35. Stokes, J. Jr., Blanchard, M., Neefe, J. R., Gellis, S. S. and Wade, G. R.: Methods of Protection against Homologous Serum Hepatitis. J.A.M.A. 138: 336, 1948. 36. Seligman, A. M., Frank, H. A. and Fine, J.: Traumatic Shock; Hemodynamic Effects of Alterations of Blood Viscosity in Normal Dogs and in Dogs in Shock. J. Clin. Investigation 25: 1, 1946. 37. Friedman, E. W., Frank, H. A. and Fine, J.: Portal Circulation in Experimental Hemorrhagic Shock; in vivo Roentgen Ray Studies. Ann. Surg. 134: 70, 1951. 38. Schorr, E. Zweifach, B. W. and Furchgott, R. F.: Hepato-renal Factors in Circulatory Homeostasis. III. The Influence of Humoral Factors of Heppatorenal Origin on the Vascular Reactions to Hemorrhage. 49: 571,1948.