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Liver Perfusion in Hepatic Coma
Liver Perfusion in Hepatic Coma ROBERT E. CONDON, M.D., M.S., F.A.C.S.* C. THOMAS BOMBECK, M.D. **
Hepatic coma is a state of disordered metabolism engendered by liver disease and characterized clinically by neurologic abnormalities. A variety of abnormal metabolites Circulating in the blood as well as many deviations from normal metabolic pathways have been identified in patients in hepatic coma. Nonetheless, it is a mark of our continuing ignorance of the complex metabolic derangements in hepatic coma that we continue to define the patient's clinical state in terms of neurologic symptoms and signs. Our scheme for clinical grading of hepatic coma is outlined in Table 1. It is important to define accurately the level of central nervous symptomatology which accompanies hepatic failure, since both the degree of coma and the nature of the liver disease influence the patient's prognosis. The mortality of patients suffering acute fulminating hepatic failure who reach grade IV coma is 85 per cent. If grade V coma ensues, the mortality is nearly 100 per cent. In contrast, a patient experiencing grade IV coma as a result of protein overload in the presence of portasystemic shunting has an expected mortality rate of but 20 per cent. Within the group of metabolic disabilities which produce hepatic coma (Table 2) are three acute clinical syndromes: (a) protein intoxication, (b) transient hepatic dysfunction, and (c) fulminating hepatic failure. The first two of these acute hepatic syndromes occur in patients who have cirrhosis or hepatic fibrosis and who have either natural or surgically created portasystemic shunts. The depth of coma in such cases rarely progresses beyond grade III; the prognosis for recovery is very good. Acute fulminating hepatic failure must be distinguished from other varieties of liver disease which also produce hepatiC coma, since the pathophysiology, prognosis, and therapy of this entity are quite distinctive. Acute, fulminating hepatic failure has the following characterFrom the Department of Surgery, University of Illinois College of Medicine, and the Surgical Services, University of Illinois Hospital, Chicago, Illinois 'Professor of Surgery "*Instructor in Surgery
Surgical Clinics of North America- Vol. 50, No.1, February, 1970
257
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Table 1. COMA GRADE
E.
CONDON, C. THOMAS BOMBECK
Grades of Coma in Hepatic Failure
CLINICAL DESIGNATION
CLINICAL CRITERIA
Precoma
Impaired mentation and orientation Irri tability Fine to course tremor Response to voice and pain: appropriate
Excitation
Inappropriate, manic behavior Slurred speech Coarse tremor Asterixis Response to voice and pain: appropriate
III
Somnolence
Lethargic but rousable Clonus, hyperactive reflexes Asterixis Response to voice: slow, appropriate Response to pain: protective withdrawal
IV
Coma
Unconscious Spastic; decerebrate posturing Response to voice: inappropriate or none Response to pain: slow, incomplete withdrawal
Preterminal
Flaccid; incontinent Response to voice: none Response to pain: none or inappropriate
II
V
istics. First, it occurs relatively suddenly in a patient who previously was quite well and who has no history of antecedent chronic liver disease. Secondly, it is often the result of probable viral hepatitis or follows exposure to halogenated hydrocarbon anesthetics. Third, it results in a massive disruption of intermediary metabolism associated with the rapid development of grade IV or V hepatic coma. Fourth, it usually culminates in death of the afflicted patient. The grim prognosis and the failure of more usual therapeutic measures to alter the course of patients suffering acute fulminating hepatic failure coma has led to the development of experimental, surgically oriented therapy. The last decade has seen the introduction of exchange blood transfusion, exchange plasmapheresis, homologous cross-circulation, heterologous baboon cross-circulation, homologous isolated liver perfusion, heterologous isolated bovine and porcine liver perfusion, and transplantation. All of these therapeutic modalities, when applied to patients in acute grade IV or grade V hepatic coma, share a record of very limited success. Our interest, stemming from a long experience in physiologic investigation using isolated bovine liver perfusion, has been with the application of this modality to the clinical treatment of acute fulminating hepatic failure.
PREPARATION OF THE PATIENT FOR LIVER PERFUSION Patients in deep hepatic coma and in whom death from liver failure is imminent are proposed by the medical staff as candidates for bovine
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Table 2. ACUTE*
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Clinical Syndromes Producing Hepatic Coma
CLINICAL SYNDROME
OR CHRONIC ONSET
CHRONIC LIVER DISEASE PRESENT?
NUMBERS OF FUNCTIONING HEPATOCYTES
Fulminating hepatic failure Protein intoxication Transient hepatocyte dysfunction Hepatocyte replacement Portasystemic encephalopathy End-stage hepatic failure
acute acute acute chronic chronic chronic
no yes yes no yes yes
~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
VOLUME OF PORTASYSTEMIC SHUNTING
TOTAL HEPATIC
DO NH3 LEVELS COR-
BLOOD FLOW
RELATE WITH SYMPTOMS?
nil
normal
+ +
~ ~ ~
no yes no no no no
nil
++ +++
~
~ ~
t t
*Acute onset implies progression from asymptomatic to fully symptomatic state in less than
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METABOLIC DEFICIT INVOLVES:
CHO
FAT
PROTEIN
++
+++
± ±
± ±
+ + ++
+ ++ +++
+++ +++ + + ++ +++
n o o ;::: ;.-
3 weeks.
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CONDON, C. THOMAS BOMBECK
Table 3. Criteria for Selecting Patients for Bovine Liver Perfusion 1. No antecedent history of chronic liver disease
2. 3. 4. 5.
Presence of biochemical and clinical evidence of massive hepatic necrosis Presence of grade IV or V coma Absence of other causes of coma, e.g., hypoglycemia, marked azotemia Absence of advanced age or of major chronic systemic disease which limits the patient's prognosis 6. Explicit and informed consent given by responsible relative 7. A judgment by the responsible attending physician, who is not a member of the perfusion team, that death is inevitable unless extraordinary therapeutic measures are taken
liver perfusion. Hypokalemia, hypochloremia, alkalosis, uremia, and hypoglycemia may accompany hepatic failure and must be treated vigorously prior to the final decision to proceed with liver perfusion. The criteria used for accepting patients for liver perfusion are listed in Table 3. As a group, these patients are extremely ill, as indicated by the multiple complications present before liver perfusion has been undertaken (Fig. 1). No patient has been sufficiently conscious to consent personally to bovine liver perfusion. In each case, the nature of the proposed treatment, its possible complications, and the probable prognosis have been discussed in detail with a responsible relative and consent has been obtained. The consent statement explicitly records the experimental nature of the treatment. Upon acceptance for liver perfusion, the patient is transferred to the surgical intensive care unit and placed in isolation. A large-bore catheter is passed retrogradely via the right brachial vein into the superior vena cava. This catheter is utilized both for infusion of fluids and for measurement of central venous pressure. A standard Teflon-Silastic arterial-venous shunt of the type used for renal hemodialysis is placed in the left forearm. The radial artery is dilated in order to accommodate the largest possible Teflon vessel tip. Strict aseptic precautions are maintained during placement of the arteriovenous shunt and the CVP catheter. The procedures preferably are carried out in the operating suite. All skin wounds and the puncture sites of the AV and
Oliguria; Azotemia GI Bleeding Pneumonia/Pulm. Insuff. Ascites; Anasarca Metab. Acidosis Cardiac Arrest Figure 1.
H.F.
V.K.
• • • • •
• • •
•
J.J.
• •
R.T.
B.C.
V.B.
D.S.
• •
•
• •
•
• • •
• •
Complications existing in patients prior to bovine liver perfusion.
• •
LIVER PERFUSION IN HEPATIC COMA
261
CVP catheters are covered with a generous amount of neomycin ointment and then with dry sterile gauze dressings. Dressings are changed daily. Intake and output of all fluids is recorded hourly and the patient is weighed once a day. Patients in hepatic coma usually have a markedly decreased capacity to excrete sodium and water loads. The daily volume of intravenous infusion should be limited to 1000 to 1500 mI. The intravenous fluid of choice is 10 or 20 per cent dextrose in water. The hypertonic sugar solutions are used in an attempt to provide a maximum amount of available calories. Twenty per cent dextrose often is only partially utilized; the excess sugar may be excreted in the urine, inducing an osmotic diuresis. In those patients with water overload hyponatremia, the induction of an osmotic diuresis may be helpful in restoring normal fluid balance. In hepatic failure, the ability to metabolize dextrose is maintained long after hepatic capacity to metabolize protein and fat has been lost. Nonetheless, in terminal hepatic failure, even carbohydrate is no longer utilized and such patients may develop hyperglycemia. Blood sugar should be measured at least once daily to insure that the carbohydrate is being metabolized. Water-soluble multiple B vitamins and ascorbic acid are administered with the intravenous fluids. Small doses of vitamin K, (in the form of Aqua-Mephyton) are also administered parenterally every other day. Even in the presence of anasarca, patients in hepatic coma usually exhibit marked renal sodium retention, a fact easily confirmed by measuring sodium concentration in a random urine specimen, where it will be found to be less than 5 mEq. per liter. No sodium-containing fluids are given intravenously, and sodium intake by other routes is kept at a minimum. Potassium supplements should be given intravenously unless the patient is in renal failure. For patients who excrete a liter of urine per day and who do not have hypokalemia, 60 mEq. of potassium phosphate should be added to each day's intravenous fluids. For patients who have a serum potassium level of less than 3.5 mEq. per liter and who are not in renal failure, 100 to 150 mEq. of potassium can be given per day, depending on the volume of intravenous fluids infused. The rate of intravenous fluid infusion should be regulated so that no more than 20 mEq. of potassium are administered per hour. A No. 18 French nasogastric tube is passed into the stomach and intermittent low suction is started. Many patients in deep hepatic coma hypersecrete acid gastric juice. The nasogastric tube effectively removes much of this secretion, reducing the ulcerogenic effects of excess acid on the gastric and duodenal mucosa. The tube also obviates inadvertent aspiration of gastric content and serves to warn of initiation of recurrence of gastrointestinal bleeding, a common complication in these patients. A Foley catheter is passed into the bladder and connected to a closed drainage system. Patients in coma often are incontinent; the catheter helps manage this problem and permits accurate recording of urine output. Crusts which accumulate at the urethral orifice are cleansed at
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least twice daily with aqueous benzalkonium chloride solution. The closed drainage system proximal to the collecting reservoir is not opened at any time. A body restraint jacket will keep the patient from falling out of bed but will not prevent motion in bed. Avoid restraining the patient in "spread eagle" fashion. Wrist and ankle restraints are used only if the patient becomes combative and assaultive during recovery from coma. Abdominal paracentesis should not be carried out unless the patient is in danger of perforating an umbilical hernia or has marked respiratory embarrassment secondary to elevation of the diaphragms. In such cases, remove only enough ascitic fluid to avoid these complications. Removal of larger quantities of fluid results only in reaccumulation and may produce acute depletion of circulating blood volume and the development of shock. The use of adrenocortical steroids in acute hepatic disease remains a controversial subject. Patients in deep hepatic coma with disordered intermediary metabolism and deficient generation of A TP energy sources might be expected to benefit from the membrane-stabilizing effects of steroids. Additionally, a sensitized patient being exposed to a large amount of heterologous antigen (bovine serum proteins) is in danger of anaphylaxis. Steroids should be of benefit in such a situation. On the other hand, there is the theoretical objection that steroids inhibit regeneration of hepatocytes and the pragmatic objection that they have not been demonstrated to be of benefit in any study of patients with fulminating hepatic failure. Despite objections to the use of steroids, we use intravenous hydrocortisone, 2000 mg. per day, or an equivalent steroid in all patients receiving heterologous liver perfusion. Sepsis is a frequent complication of advanced hepatic failure. We routinely prescribe a broad spectrum antibiotic for our patients. Currently, we are utilizing ampicillin, 2 gm. per day intravenously in four divided doses. If the patient has been or is bleeding from the gastrointestinal tract, we also use neomycin, 1 gm. every 4 hours administered via the nasogastric tube after purgation with 15 to 30 gm. of magnesium sulfate. Determinations of partial thromboplastin time, prothrombin content, fibrinogen concentration, platelet count, retraction of incubated clot, and euglobulin clot lysis time are carried out in all patients. Abnormalities of the clotting mechanism are frequent. If an abnormality is identified and the patient is bleeding, appropriate therapy is provided. Platelet concentrate packs, prepared from 3 or 4 blood units, are used if the patient has symptomatic thrombocytopenia. Fresh whole blood or fresh single-unit plasma is used, as appropriate, in patients demonstrating deficiencies of intrinsic clotting components. Epsilon-aminocaproic acid, 1 gm. every hour, is administered intravenously to patients who exhibit active fibrinolysis. Fibrinogen is administered only when fibrinolysis is under control and there is a persistent symptomatic hypofibrinogenemia. No drugs, other than those specifically indicated above, are given to patients in hepatic coma, because patients in hepatic failure are unable to metabolize most drugs. The result of administration of most
LIVER PERFUSION IN HEPATIC COMA
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drugs will be either an excessive or prolonged drug effect or a worsening of the state of hepatic coma. In particular, narcotics, barbiturates or other sedatives, thiazide diuretics, carbonic anhydrase inhibitors, and alcohol should not be given to these patients. Specific mention should be made of paraldehyde: it is extremely toxic and must never be administered. Narcotic drugs are never indicated in patients in hepatic coma, since they are incapable of perceiving somatic pain and there is, therefore, no rational reason for the administration of such drugs. Similarly, there is no need to administer barbiturates or other sedatives. The temptation to sedate is sometimes strong, since patients in grade II or III hepatic coma may be hypermanic, noisy, abusive, and generally difficult to manage. In the occasional patient in whom barbiturates must be administered to control convulsions, phenobarbital is the agent of choice, since an alternative renal route of excretion is available for this drug. Special precautions must be taken to assure safe discard of needles, razor and knife blades, and similar "sharps" which become contaminated by blood of patients suspected of having hepatitis. A clearly marked, covered steel can serves this purpose well. Personnel who inadvertently injure themselves with a potentially contaminated "sharp" should receive gamma globulin prophylaxis.
PREPARATION OF THE DONOR ANIMAL Prior to perfusion, a healthy bovine calf, weighing 80 to 90 lb., is obtained, kept in a clean corral and maintained on a milk and sucrose diet. Penicillin (10 million units) and streptomycin (1 gm.) is administered intramuscularly twice during the day prior to perfusion; if the proposed patient is known to be sensitive to penicillin, other appropriate antibiotics are used. On the day of perfusion, the donor animal is washed, restrained, and lightly anesthetized with intravenous sodium pentobarbital (20 mg. per kg. body weight). The animal is intubated through a tracheostomy, succinylcholine is administered, and anesthesia is then maintained by a mechanical respirator using a gas/oxygen mixture. The anesthetized animal is placed on a standard animal operating table, the chest and abdomen are vigorously scrubbed and shaved, and the operative area is prepared with 2 per cent tincture. In this and in all subsequent operative maneuvers, standard aseptic surgical technique is utilized. A long midline incision is made beginning at the suprasternal notch and is carried to the pubic symphysis. The peritoneal cavity is opened, the sternum is split in the midline, the diaphragm is incised to the vena caval hiatus and the entire incision is widely retracted. The mediastinal contents are detached from the right half of the sternum. A small incision is made in the pericardium to act as a vent. The gallbladder is retracted superiorly to expose the cystic duct, which is doubly ligated in continuity. The common bile duct is identified, transected at its junction with the duodenum and cannulated with a fine polyethylene tube. The liver is then gently retracted, at first toward the
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CONDON, C. THOMAS BOMBECK
left and then toward the right; the diaphragmatic attachments are taken down, the phrenic veins are ligated, and the diaphragm is then incised posteriorly around the vena cava. On the left side, dissection is continued inferiorly, mobilizing the vena cava to the level of the renal veins. The splenic vein is isolated at its junction with the superior mesenteric veins, ligated in continuity, and transected. The portal vein in the porta hepatis is dissected, all lymphatic and pancreatic tissue being removed. The animal is heparinized (500 units per kg.). The hepatic artery and portal vein are each isolated between ligatures and cannulated. The cannulas are connected to bottles of cold sterile flush solution (Normosol-R, pH 7.4). The inferior vena cava is transected and the liver is removed from the abdominal cavity. The purpose of the flush is to remove heterologous blood from the intrahepatic vasculature while reducing the temperature of the liver in order to minimize the damage consequent to anoxia. As flushing is completed, the open ends of the inferior vena cava and the hepatic arterial and portal venous catheters are clamped. The liver is then transferred to the perfusion apparatus and perfused with warm oxygenated blood in order to return the organ to normothermia. The period of cold, anoxic perfusion damages the liver. Although the effect is partially reversible on subsequent oxygenated, normothermic perfusion, in our experience the metabolic function of flushed livers has always been poorer than that of livers perfused with normothermic homologous blood in which no significant period of hypoxia is permitted.
BOVINE LIVER PERFUSION The perfusion apparatus consists of a small disc oxygenator, calibrated roller pumps, filters, a portal venous reservoir, a chamber to hold the liver, and a venous effluent reservoir, and it incorporates a heat exchanger (Fig. 2). Glass wool gravity filters remove platelets; stainless steel mesh filters in the pressure lines remove fibrin aggregates. Appropriate taps allow for continuous recordings of blood pressure, pH, and partial gas pressure, and provide for blood sampling. Hepatic arterial pressure is maintained between 100 and 150 mm. Hg, portal venous pressure between 10 and 15 mm. Hg, and pH in the range 7.35 to 7.50. The perfusion circuits are primed with a liter of compatible, heparinized, partially recalcified bank blood, diluted to hematocrit 30, providing optimum conditions for maximal oxygen transport at minimum viscosity. Perfusate temperature is kept at 38° C. We have thoroughly investigated perfusion via portal vein alone (unpublished data). We have not been so fortunate as others and find that even though total hepatic blood flow per gram of tissue is the same, hepatic function with perfusion only via the portal vein is not as effective as when both hepatic artery and portal vein are perfused. Following insertion of the excised liver into the perfusion circuit and establishment of normothermia in the organ, liver function is evaluated prior to beginning perfusion by the patient. The measures used to evaluate the patient and the isolated organ are listed in Table 4.
265
LIVER PERFUSION IN HEPATIC COMA
Filters
Oxygenator and Heat Exchanger
Figure 2. Schematic diagram of liver perfusion circuit. Note that the patient perfuses the isolated bovine liver in parallel, not in series, with the intrinsic pumps and oxygenator.
Only if function is satisfactory is heterologous perfusion of the patient conducted, since it is obviously useless to perfuse with a nonfunctioning or poorly functioning liver and expect the patient's over-all function to be bettered. When all is in readiness to proceed with perfusion of the patient, the apparatus containing the liver is brought to the patient's bedside. The arterial member of the patient's AV shunt is connected via Silas tic tubing to the oxygenator reservoir; the venous member via another Silastic tube to the venous effluent reservoir of the perfusion apparatus. Both of these Silastic tubes are led through a single occlusive roller pump head, so that venous return to the patient will exactly match arterial outflow. The use of the same pump for both inflow and outflow guards against either exsanguinating or overloading the patient during the course of perfusion. As high a rate of shunt pumping as the patient can easily tolerate is then established. Shunt flows of 3 to 7 ml. per kg. per minute have been achieved, allowing (in a 70 kg. man) over 12 liters per hour of the patient's blood to perfuse the isolated bovine liver. This system provides for (1) adequate volume flow of oxygenated blood to the liver, so that the isolated organ is not dependent on circulation from the patient for its function and survival, and, independently, (2) adequate volume flow from and to the patient via the liver to provide opportunity for the isolated organ to clear accumulated "toxins" from the patient's blood. In addition, should problems with the patient arise during or after donor hepatectomy (see Case 2, below), this system provides for maintaining the liver while a decision regarding perfusion is reached.
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Table 4.
E. CONDON, C. THOMAS BOMBECK
Evaluation of Clinical Bovine Liver Perfusion IMMEDIATELY BEFORE PERFUSION
IMMEDIDURING PERFUSION
Patient BP, pulse, resp. CVP, EKG Rectal temp. Body weight Grade of coma EEG Urine output Arterial pH, Po" Pco 2 Serum electrolytes Blood glucose Blood urea nitrogen Hct., plasma Hgb. Serum proteins Fibrinogen Prothrombin time Clotting studies Serum bilirubin SGOT, SGPT Arterial NH3
x x x x x x x x x x x x x x x x x x x
Every 15 minutes Continuously Continuously
Donor Liver Ha, PV pressure, flow Perfusate pH, Po" Pco 2 Shunt volume flow Liver core temperature Oxygen consumption Lactate clearance Ammonia extraction Biopsy
x x x x x x x x
Continuously Continuously Continuously Continuously Every 30 minutes Hourly Every 2 hours
x x Hourly Every 30 minutes Every 2 hours Hourly Every 2 hours
ATELY AFTER PERFUSION
AS APPROPRIATE AFTER PERFUSION
x x x x x x x x x x x x x x x x x x x
x x x x x x x x x x x x x x x x x x x
x x x x x x x x
Anticoagulation is maintained by intermittent injection of heparin into the arterial outflow line, producing total body heparinization of the patient. Although total anticoagulation enhances the risk of bleeding complications in patients in hepatic failure, as a practical matter there is no alternative. Attempts to maintain regional heparinization of the extracorporeal apparatus have resulted, because of the high shunt volumes achieved, in gradual production of total patient anticoagulation despite administration of large amounts of protamine. Protamine, epsilon-aminocaproic acid, calcium chloride, and 2 units of human fibrinogen are readily available at the bedside for immediate treatment of any bleeding complications. At the conclusion of perfusion, protamine titration of the patient's blood is carried out and any residual heparin effect is neutralized. Perfusion also results in a depletion of platelets; we routinely administer a 3 or 4 unit platelet concentrate pack at the conclusion of each liver perfusion. A telethermometer probe is inserted in the rectum; if necessary, external warming is utilized to maintain the patient's temperature at 37 to 38° C. During perfusion, appropriate clinical and biochemical measurements of general status and of hepatic function are made (Table 4). The patient's arterial pH is maintained in the range 7.35 to 7.47 by intravenous administration of sodium bicarbonate solution.
LIVER PERFUSION IN HEPATIC COMA
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Hypotension or hypervolemia during perfusion may be avoided by continuous monitoring of arterial and central venous pressures and appropriate alterations of the rate of shunting. Perfusion is continued for up to 6 to 8 hours, as long as the perfused liver shows evidence of satisfactory function.
EVALUATION OF FUNCTION IN ISOLATED PERFUSED LIVERS We have found that many of the mgre traditional measures of hepatic function, such as bromsulphalein or ammonia clearance, while good measures of liver function in patients, are not adequate measures of function of an isolated, perfused liver. Indeed, a liver which is to all intents and purposes metabolically "dead" will still clear (though not metabolize) ammonia from the perfusate. The ability of the isolated liver to perform a metabolic task while vascular resistance to perfusion is normal, rather than simple clearance, is the sine qua non of function. Bile flow is not a sensitive guide to function. The volume of bile flow is most directly related to bile salt concentration in the perfusate and is much less responsive to changes in hepatocyte function. Bile flow always diminishes during prolonged perfusion, since bile is being removed continuously; flow volume will promptly increase if additional bile or Decholin is administered. In the experience of the authors and colleagues 1 with over 300 isolated liver perfusions, four measures provided sensitive indices of liver function: (1) total hepatic blood flow (must be at least 0.5 mI. per gm. per minute), (2) vascular resistance (must not be greater than 0.02 PRU in the portal vein or 1.0 PRU in the hepatic artery), (3) potassium gradient (HV-PV; must be negative), and (4) appearance of the perfused liver (coarse mottling is bad). All perfused livers which do not meet these criteria are considered functionally unsatisfactory. Clearance of infused lactate, lactate-pyruvate ratio, and SGOT and SGPT levels also have proved to be sensitive indicators of function. These measures, of course, are not immediately available during perfusion, since their determination in the laboratory requires time. They are useful, however, to quantify liver function and to confirm that significant necrosis has not occurred. The fact that bovine liver does not contain SGPT provides a ready means for identifying whether it is the patient's liver or the isolated bovine liver which is undergoing hepatocyte damage. An elevation of SGOT without concomitant elevation of SGPT indicates that necrosis of the bovine liver is the probable source of the enzyme; elevation of both enzymes by comparable amounts indicates that the probable source is the patient's liver.
CLINICAL LIVER PERFUSIONS: CASE REPORTS CASE 1. A 52 year old executive developed petechiae; diagnostic workup established that he had idiopathic thrombocytopenic purpura. An asymptomatic mediastinal mass was noted on chest x-rays. Liver function tests showed a total
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bilirubin of 2.0 mg. per 100 ml. and BSP retention of 25 per cent. He responded to steroid therapy with a rise in platelet count but relapsed 6 weeks later. Splenectomy under halothane anesthesia was carried out; 16 days later a subphrenic fluid collection was drained, again under halothane anesthesia. Two days after the second operation he was noted to be jaundiced and disoriented. Usual measures aimed at combating hepatic failure were initiated, but coma rapidly progressed; his SGOT peaked at 1450 units and subsequently declined (Fig. 3). On the twelfth day he had a cardiac arrest, required a tracheostomy, and subsequently required vasopressors. Urine output following this episode diminished to less than 100 mI. per day. He developed gastrointestinal bleeding and pneumonia. Three exchange transfusions, each of 12 liters of whole blood, were done without apparent benefit and the patient's condition was judged to be terminal. He was deeply comatose, hypotensive, anuric, and deeply jaundiced, and had intermittent respirations and focal seizures. He was hypoglycemic (44 mg. per 100 mI.), despite infusion of intravenous glucose, and had mild hypocalcemia (8.7 mg. per 100 mI.). Prothrombin time was 16 seconds longer than control; platelet count was 92,000 per cu. mm. An EEG was diffusely abnormal and consistent with hepatic coma. Blood pressure of 100 mm. Hg systolic, 50 diastolic was maintained only with a vasopressor drip. A femoral arteriovenous shunt was placed, utilizing the venous catheter previously placed for exchange transfusion; no anesthesia was required. Within 5 minutes of starting the patient on bovine liver perfusion, it was possible to turn off the vasopressor drip. He maintained a stable BP of 120 mm. Hg systolic, 70 diastolic throughout the perfusion. Within 20 minutes of the start of perfusion, he began to excrete urine for the first time in 4 days and made 17 ml. during the first hour and 46 ml. during the second. Biochemically, decreases
VK. JAN: 500 400
Blood Ammonio 300 (y%) 200
--
Bilirubin (mg%)
~
-
SGPT (SF units)
SGOT (SF units) o----
---
Prothrombin (%)
Urine Vol. (ml/hr)
100 30 20 10 300 200 100 0 300 200
Figure 3. Summary of the biochemical responses of patient No. 1. Exchange transfusions are indicated by "ET" and liver perfusion by the vertical shaded bar.
100 0 50 25 0 30 20 10 0
PNEUMONIA GI BLEEDING
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LIVER PERFUSION IN HEPATIC COMA
269
in bilirubin, ammonia, and urea were noted. After perfusion was terminated, he again became hypotensive and vasopressors were restarted; urine output terminated abruptly. He developed increasing respiratory difficulty despite respirator support, and he became acidotic (CO. of 12) and hyperkalemic. Four hours after perfusion he had another cardiac arrest and could not be resuscitated. Autopsy showed complete necrosis of the liver, pancreatitis, an extensive bilateral bronchopneumonia, and a benign mediastinal cyst. CASE 2. A 42 year old alcoholic-cirrhotic was found at home lying unconscious in a pool of dried blood and feces. He apparently had become jaundiced 2 weeks previously, had continued to drink, had had an upper gastrointestinal hemorrhage with both hematemesis and hematochezia, and had fainted. When he failed to awaken after 3 days, his wife called the police. On admission he was deeply comatose but did respond to painful stimuli. There was a purulent conjunctivitis, advanced pneumonia, numerous hematomas in the anterior abdominal wall, ascites, and pitting edema to the level of the axillae. Laboratory studies showed an elevated bilirubin, ammonia, and creatinine, hypokalemia, and a diffusely abnormal EEG consistent with severe hepatic coma. A tracheostomy was done to aspirate secretions and the patient maintained on a respirator. He required a constant vasopressor drip to maintain his blood pressure at 100 mm. Hg systolic. His urine output during the first hospital day was 350 mI.; during the second day it fell to less than 30 ml. Gastrointestinal bleeding continued slowly but steadily, and he was felt by his attendants to be in terminal hepatorenal failure. An arteriovenous shunt was placed; no anesthesia was required. While the liver was being prepared, the patient had a cardiac arrest. He responde!! to external cardiac massage, although a rapid drip of norepinephrine was subsequently required to maintain his blood pressure at 90 mm. Hg systolic. The patient was observed for an hour with no further deterioration in clinical state. It was decided to go ahead with the perfusion. During this unplanned period of waiting, the excised heterologous liver was perfused at normothermia and showed evidence of satisfactory function. This episode underscores the necessity of having a perfusion system which is adequate for maintenance of the liver apart from the blood flow contribution of the patient being treated. Bovine liver perfusion for a period of 2 hours was carried out using the technique outlined above. Within 10 minutes of the start of perfusion, it was possible to turn off the vasopressor drip. He maintained a blood pressure of 130 mm. Hg systolic, 80 diastolic throughout perfusion (except for one 5 minute period during which the blood pressure was transiently as low as 100/70) without need for vasopressors. He made no urine, and no other changes in clinical state or level of coma were noted. Biochemically, decreases in bilirubin, ammonia, and urea were seen. Following termination of the perfusion, he again became hypotensive and required increasing amounts of vasopressors. There was no apparent change in respiratory function. One hour after perfusion he had a second cardiac arrest and could not be resuscitated. Autopsy showed severe cirrhosis with nearly complete necrosis of hepatocytes, focal pancreatitis, an abscess in the right lower lung, esophageal varices, and multiple acute gastric ulcers. CASE 3. A 16 year old girl was admitted with a 4 week history of fatigue and jaundice. There possibly had been a similar episode 4 months earlier, lasting 4 or 5 weeks; there was no contact or transfusion history. The edge of the liver was just palpable; span percussed at 8 cm. Liver function tests showed a total bilirubin of 25.2 mg. per 100 mI., SGOT 270 units, prothrombin content 13.5 per cent. Intravenous glucose and high-dose steroid therapy was started, and bowel sterilization with neomycin also was begun. Within 36 hours of admission, the patient was in grade IV coma; the liver could no longer be palpated or percussed. The next day the patient was totally unresponsive. She was deeply jaundiced and having nearly continuous melena and dark brown returns from the nasogastric suction. Urine output was adequate (25 mI. per hour). The patient was found to be hypersecreting gastric acid (Fig. 4). Her acid secretory rate (determined from hand-aspirated nasogastric tube samples
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ROBERT E. CONDON, C. THOMAS BOMBECK
100 .2 80 ......
+
::c (if 60 Figure 4. Decrease in gastric acid hypersecretion associated with liver perfusion in patient No.3.
E
40 20
-30
o
30
60
90
Time (min.) every 15 minutes) in the 2 hours prior to perfusion was 105 mEq. per hour! Acid secretion fell to 5 per cent of the baseline rate after the first hour of perfusion and ranged from 5.4 to 37.2 mEq. per hour during perfusion. Four hours of liver perfusion resulted in a decrease in bilirubin from 28.8 to 12.5 mg. per 100 ml. and similar improvement in other biochemical determinations. A third perfusion was planned, but just before it could be started the patient had a massive hematemesis followed by cardiac arrest, and she expired. At autopsy the liver was a small, soft necrotic mass. CASE 4. A 31 year old woman entered the hospital complaining of 5 days of progressive nausea and vomiting with chills and fever during the day of admission. The liver was not palpable and its span percussed 6 cm. The next morning she was noted to be jaundiced. A diagnosis of viral hepatitis was made. Over the next 48 hours, her condition rapidly deteriorated and she became deeply jaundiced, oliguric, hyperreflexic, and then deeply comatose. An isolated perfused liver was set up as described above and patient perfusion carried out for 4 hours, exchanging 48 liters of blood. There was no change in her clinical condition although there was considerable improvement biochemically: bilirubin fell from 68.4 to 28.8 mg. per 100 ml. (Fig. 5). A second 4 hour perfusion exchanging 60 liters was carried out on the next day, again with biochemical improvement. During and after this second perfusion, the level of coma lightened and she began to show spontaneous muscular movements. A third perfusion was carried out the day following, and a fourth perfusion on the day after that. The patient's level of coma became noticeably lighter. An electroencephalogram showed increased frequency of activity. By the fourth evening she was lucid and remained so for the next 3 days. Disorientation then recurred. Initially this was ascribed to recurring hepatic coma, but later it was shown to be due to hypoxia (arterial POz was 50 mm. Hg). Endotracheal intubation and assistance with a respirator resulted in some clearing of her mentation. However, over the next 5 days she developed progressive respiratory insufficiency and eventually died. At autopsy, the liver showed evidence of hepatitis with cholestasis. There were broad areas of necrosis but many hepatocytes were preserved. There were numbers of binucleate cells and some hepatic plates were two or more cells thick. The lungs showed extensive basilar bronchopneumonia; widespread hyaline membranes were noted, even in areas such as the apices not involved with pneumonia.
271
LIVER PERFUSION IN HEPATIC COMA
v'B.
DEC:
12
13
14
15
16 17 18 19 20 21 22 23
Coma? Level 2
-~
Bilirubin
30
(mg%) 20 10
SGOT SF units
600
~
400
500
300 2
Prothrombin (+sec's)
--
4 6
8
1000
Gammo Globulin 800
(mg%) 600 -400
GI BLEEDING
I RESP.
FAILURE
It
Figure 5. Biochemical responses and alteration of coma following multiple bovine liver perfusions in patient No.4. Each liver perfusion is indicated by a vertical shaded bar.
CASE 5. A 19 year old girl with a classic story of acute fulminating hepatitis was seen shortly after admission, when she was in grade IV coma. The next day she was totally flaccid and having a brisk gastrointestinal hemorrhage. Bleeding was treated and controlled. Isolated liver perfusion was carried out as detailed above. There was biochemical improvement but no change in clinical status as a result of perfusion. The pattern of a biochemical improvement that failed to correlate with the clinical state was much like that of the patients cited above. This patient died of recurrent massive gastrointestinal bleeding during the night following perfusion. In tlIis patient, static compliance of the lungs was decreased (0.74 liters per cm. H 2 0) and was not altered by perfusion. Gastric secretion (mEq. per hour) in the 2 hours before perfusion was 18.0 and 18.2 but fell to 5.1 in the first hour and to 1.6 in the second hour of perfusion. CASE 6. A 20 year old girl entered with a 10 day history of progressive jaundice. She had had a blood clot 6 weeks previously; otlIerwise tlIere was no history of contact or injection. A diagnosis of viral hepatitis was made; the patient was put to bed and given a high-calorie diet. Her condition remained stable for 2 weeks; she then developed edema and shortly afterward became incoherent. Her condition progressively deteriorated; 4 days later she was oliguric and in grade IV coma. Perfusion was carried out on the next day using the technique outlined above and with the same general result as has been recorded following initial isolated liver perfusion of other patients: improvement in some biochemical parameters
272
ROBERT E. CONDON, C. THOMAS BOMBECK
without any clear improvement in clinical state. About 16 hours following her first perfusion, the patient had a cardiac arrest and was resuscitated. The next morning, the patient had a second cardiac arrest; resuscitation was not successful. At autopsy there was extensive necrosis of the liver. CASE 7. A 62 year old man sustained multiple fractures but no significant visceral injuries in an automobile accident. On admission to the hospital, liver function tests were normal. Four days after the accident and again 10 days later, he received a halothane anesthetic to permit reduction and fixation of his fractures. Two days after the second operation he was noted to be jaundiced. His condition steadily deteriorated over the next 2 weeks. His SGOT reached 2125 units. He became oliguric and hyperkalernic. Peritoneal dialysis controlled the elevated potassium, but did not otherwise alter the clinical course. Exchange blood transfusion was carried out without producing improvement. By the eighteenth day following his second halothane anesthetic and operation, the patient was in grade V coma, deeply jaundiced, and anuric, with anasarca and severe metabolic acidosis. Bovine liver perfusion was carried out for 4 hours and produced marked biochemical improvement, lowering the bilirubin and ammonia levels by approximately 50 per cent. The patient's level of consciousness improved and he responded, though not entirely appropriately, to spoken voice (grade III coma). By the following morning, deep coma had recurred. The patient had been totally anuric for the preceding 4 days; he was now severely hyperkalemic and having cardiac arrhythmias. Hemodialysis restored the potassium and BUN levels toward normal, but did not result in any change in coma. A second bovine liver perfusion was conducted, which produced further improvement in biochemical parameters but no change in clinical state. On the next day the patient underwent a simultaneous liver perfusion and renal hemodialysis. After 2 hours of perfusion, the patient's level of consciousness had improved from grade V to grade II. He responded appropriately to spoken voice and was able to converse briefly with his wife. Perfusion was continued for 5 hours; the patient's improved clinical state persisted when perfusion was discontinued. Shortly after midnight that night, the patient had a sudden episode of hypotension followed by cardiac arrest. Resuscitation was not successful. At autopsy there was widespread necrosis of the liver, anasarca, pancreatitis, and bronchopneumonia.
SUMMARY AND CONCLUSIONS Our experience in treating patients in acute severe hepatic failure by means of bovine liver perfusion can be summarized as follows: 1. All patients were improved biochemically; the biochemical response did not correlate with clinical symptoms, nor was the biochemical response of any value in predicting the patient's clinical course. 2. Three of seven patients had a definite improvement in clinical symptoms as reflected in lightening of coma from grade IV or V to grade II or III, accompanied by return of capacity to respond to spoken voice. 3. One patient recovered from coma and also showed stabilization of hepatic function; this patient subsequently succumbed to respiratory failure. 4. A variety of observations have been made of patient responses during bovine liver perfusion, including: (a) decreased gastric acid hypersecretion; (b) elimination of hypotension and need for vasopressors and, in one patient, (c) resumption of urine output.
LIVER PERFUSION IN HEPATIC COMA
273
5. Complications have been frequent, both before and after liver perfusion. Renal failure has partially responded to usual therapeutic measures including hemodialysis. Gastrointestinal bleeding has been more difficult to manage. Correction of specific clotting defects by administration of fresh blood or plasma, fibrinogen, or epsilon-aminocaproic acid will restore the clotting mechanism temporarily, but has not prevented fatal bleeding from ulcers of the duodenum or stomach. What of the future? Bovine liver perfusion has been as successful (or as unsuccessful) as any other of the newer experimental methods of treating acute, fulminating hepatic failure. It must be recognized and accepted that none of the newer experimental therapies have really altered the prognosis of acute, fulminating hepatic failure. Liver perfusion, as well as many of the other experimental therapies, requires a considerable expenditure of time, energy, and resources by the investigative team. Patients selected for such investigations, therefore, should be limited. The main thrust of the future should continue to be in the research laboratory, directed to the development of more effective clinical therapy.
REFERENCE 1. Hornbeck, C~ T., Hiava, C., Condon, R. E., and Nyhus, L. M.: Parameters of normal liver function in the isolated perfused bovine liver. In Norman, J. C., ed.: Organ Perfusion and Preservation. New York, Appleton-Century-Crofts, 1968. University of Illinois College of Medicine Chicago, Illinois 60612
Hepatic coma is a state of disordered metabolism engendered by liver disease and characterized clinically by neurologic abnormalities. A variety of abnormal metabolites Circulating in the blood as well as many deviations from normal metabolic pathways have been identified in patients in hepatic coma. Nonetheless, it is a mark of our continuing ignorance of the complex metabolic derangements in hepatic coma that we continue to define the patient's clinical state in terms of neurologic symptoms and signs. Our scheme for clinical grading of hepatic coma is outlined in Table 1. It is important to define accurately the level of central nervous symptomatology which accompanies hepatic failure, since both the degree of coma and the nature of the liver disease influence the patient's prognosis. The mortality of patients suffering acute fulminating hepatic failure who reach grade IV coma is 85 per cent. If grade V coma ensues, the mortality is nearly 100 per cent. In contrast, a patient experiencing grade IV coma as a result of protein overload in the presence of portasystemic shunting has an expected mortality rate of but 20 per cent. Within the group of metabolic disabilities which produce hepatic coma (Table 2) are three acute clinical syndromes: (a) protein intoxication, (b) transient hepatic dysfunction, and (c) fulminating hepatic failure. The first two of these acute hepatic syndromes occur in patients who have cirrhosis or hepatic fibrosis and who have either natural or surgically created portasystemic shunts. The depth of coma in such cases rarely progresses beyond grade III; the prognosis for recovery is very good. Acute fulminating hepatic failure must be distinguished from other varieties of liver disease which also produce hepatiC coma, since the pathophysiology, prognosis, and therapy of this entity are quite distinctive. Acute, fulminating hepatic failure has the following characterFrom the Department of Surgery, University of Illinois College of Medicine, and the Surgical Services, University of Illinois Hospital, Chicago, Illinois 'Professor of Surgery "*Instructor in Surgery
Surgical Clinics of North America- Vol. 50, No.1, February, 1970
257
258
ROBERT
Table 1. COMA GRADE
E.
CONDON, C. THOMAS BOMBECK
Grades of Coma in Hepatic Failure
CLINICAL DESIGNATION
CLINICAL CRITERIA
Precoma
Impaired mentation and orientation Irri tability Fine to course tremor Response to voice and pain: appropriate
Excitation
Inappropriate, manic behavior Slurred speech Coarse tremor Asterixis Response to voice and pain: appropriate
III
Somnolence
Lethargic but rousable Clonus, hyperactive reflexes Asterixis Response to voice: slow, appropriate Response to pain: protective withdrawal
IV
Coma
Unconscious Spastic; decerebrate posturing Response to voice: inappropriate or none Response to pain: slow, incomplete withdrawal
Preterminal
Flaccid; incontinent Response to voice: none Response to pain: none or inappropriate
II
V
istics. First, it occurs relatively suddenly in a patient who previously was quite well and who has no history of antecedent chronic liver disease. Secondly, it is often the result of probable viral hepatitis or follows exposure to halogenated hydrocarbon anesthetics. Third, it results in a massive disruption of intermediary metabolism associated with the rapid development of grade IV or V hepatic coma. Fourth, it usually culminates in death of the afflicted patient. The grim prognosis and the failure of more usual therapeutic measures to alter the course of patients suffering acute fulminating hepatic failure coma has led to the development of experimental, surgically oriented therapy. The last decade has seen the introduction of exchange blood transfusion, exchange plasmapheresis, homologous cross-circulation, heterologous baboon cross-circulation, homologous isolated liver perfusion, heterologous isolated bovine and porcine liver perfusion, and transplantation. All of these therapeutic modalities, when applied to patients in acute grade IV or grade V hepatic coma, share a record of very limited success. Our interest, stemming from a long experience in physiologic investigation using isolated bovine liver perfusion, has been with the application of this modality to the clinical treatment of acute fulminating hepatic failure.
PREPARATION OF THE PATIENT FOR LIVER PERFUSION Patients in deep hepatic coma and in whom death from liver failure is imminent are proposed by the medical staff as candidates for bovine
r
< OJ
">-0 "'q" OJ
:5'"
z
Z :::c:
Table 2. ACUTE*
OJ
Clinical Syndromes Producing Hepatic Coma
CLINICAL SYNDROME
OR CHRONIC ONSET
CHRONIC LIVER DISEASE PRESENT?
NUMBERS OF FUNCTIONING HEPATOCYTES
Fulminating hepatic failure Protein intoxication Transient hepatocyte dysfunction Hepatocyte replacement Portasystemic encephalopathy End-stage hepatic failure
acute acute acute chronic chronic chronic
no yes yes no yes yes
~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
VOLUME OF PORTASYSTEMIC SHUNTING
TOTAL HEPATIC
DO NH3 LEVELS COR-
BLOOD FLOW
RELATE WITH SYMPTOMS?
nil
normal
+ +
~ ~ ~
no yes no no no no
nil
++ +++
~
~ ~
t t
*Acute onset implies progression from asymptomatic to fully symptomatic state in less than
'tj
;.-
...,
METABOLIC DEFICIT INVOLVES:
CHO
FAT
PROTEIN
++
+++
± ±
± ±
+ + ++
+ ++ +++
+++ +++ + + ++ +++
n o o ;::: ;.-
3 weeks.
Nl (j{ (I:J
260
ROBERT
E.
CONDON, C. THOMAS BOMBECK
Table 3. Criteria for Selecting Patients for Bovine Liver Perfusion 1. No antecedent history of chronic liver disease
2. 3. 4. 5.
Presence of biochemical and clinical evidence of massive hepatic necrosis Presence of grade IV or V coma Absence of other causes of coma, e.g., hypoglycemia, marked azotemia Absence of advanced age or of major chronic systemic disease which limits the patient's prognosis 6. Explicit and informed consent given by responsible relative 7. A judgment by the responsible attending physician, who is not a member of the perfusion team, that death is inevitable unless extraordinary therapeutic measures are taken
liver perfusion. Hypokalemia, hypochloremia, alkalosis, uremia, and hypoglycemia may accompany hepatic failure and must be treated vigorously prior to the final decision to proceed with liver perfusion. The criteria used for accepting patients for liver perfusion are listed in Table 3. As a group, these patients are extremely ill, as indicated by the multiple complications present before liver perfusion has been undertaken (Fig. 1). No patient has been sufficiently conscious to consent personally to bovine liver perfusion. In each case, the nature of the proposed treatment, its possible complications, and the probable prognosis have been discussed in detail with a responsible relative and consent has been obtained. The consent statement explicitly records the experimental nature of the treatment. Upon acceptance for liver perfusion, the patient is transferred to the surgical intensive care unit and placed in isolation. A large-bore catheter is passed retrogradely via the right brachial vein into the superior vena cava. This catheter is utilized both for infusion of fluids and for measurement of central venous pressure. A standard Teflon-Silastic arterial-venous shunt of the type used for renal hemodialysis is placed in the left forearm. The radial artery is dilated in order to accommodate the largest possible Teflon vessel tip. Strict aseptic precautions are maintained during placement of the arteriovenous shunt and the CVP catheter. The procedures preferably are carried out in the operating suite. All skin wounds and the puncture sites of the AV and
Oliguria; Azotemia GI Bleeding Pneumonia/Pulm. Insuff. Ascites; Anasarca Metab. Acidosis Cardiac Arrest Figure 1.
H.F.
V.K.
• • • • •
• • •
•
J.J.
• •
R.T.
B.C.
V.B.
D.S.
• •
•
• •
•
• • •
• •
Complications existing in patients prior to bovine liver perfusion.
• •
LIVER PERFUSION IN HEPATIC COMA
261
CVP catheters are covered with a generous amount of neomycin ointment and then with dry sterile gauze dressings. Dressings are changed daily. Intake and output of all fluids is recorded hourly and the patient is weighed once a day. Patients in hepatic coma usually have a markedly decreased capacity to excrete sodium and water loads. The daily volume of intravenous infusion should be limited to 1000 to 1500 mI. The intravenous fluid of choice is 10 or 20 per cent dextrose in water. The hypertonic sugar solutions are used in an attempt to provide a maximum amount of available calories. Twenty per cent dextrose often is only partially utilized; the excess sugar may be excreted in the urine, inducing an osmotic diuresis. In those patients with water overload hyponatremia, the induction of an osmotic diuresis may be helpful in restoring normal fluid balance. In hepatic failure, the ability to metabolize dextrose is maintained long after hepatic capacity to metabolize protein and fat has been lost. Nonetheless, in terminal hepatic failure, even carbohydrate is no longer utilized and such patients may develop hyperglycemia. Blood sugar should be measured at least once daily to insure that the carbohydrate is being metabolized. Water-soluble multiple B vitamins and ascorbic acid are administered with the intravenous fluids. Small doses of vitamin K, (in the form of Aqua-Mephyton) are also administered parenterally every other day. Even in the presence of anasarca, patients in hepatic coma usually exhibit marked renal sodium retention, a fact easily confirmed by measuring sodium concentration in a random urine specimen, where it will be found to be less than 5 mEq. per liter. No sodium-containing fluids are given intravenously, and sodium intake by other routes is kept at a minimum. Potassium supplements should be given intravenously unless the patient is in renal failure. For patients who excrete a liter of urine per day and who do not have hypokalemia, 60 mEq. of potassium phosphate should be added to each day's intravenous fluids. For patients who have a serum potassium level of less than 3.5 mEq. per liter and who are not in renal failure, 100 to 150 mEq. of potassium can be given per day, depending on the volume of intravenous fluids infused. The rate of intravenous fluid infusion should be regulated so that no more than 20 mEq. of potassium are administered per hour. A No. 18 French nasogastric tube is passed into the stomach and intermittent low suction is started. Many patients in deep hepatic coma hypersecrete acid gastric juice. The nasogastric tube effectively removes much of this secretion, reducing the ulcerogenic effects of excess acid on the gastric and duodenal mucosa. The tube also obviates inadvertent aspiration of gastric content and serves to warn of initiation of recurrence of gastrointestinal bleeding, a common complication in these patients. A Foley catheter is passed into the bladder and connected to a closed drainage system. Patients in coma often are incontinent; the catheter helps manage this problem and permits accurate recording of urine output. Crusts which accumulate at the urethral orifice are cleansed at
262
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CONDON, C. THOMAS BOMBECK
least twice daily with aqueous benzalkonium chloride solution. The closed drainage system proximal to the collecting reservoir is not opened at any time. A body restraint jacket will keep the patient from falling out of bed but will not prevent motion in bed. Avoid restraining the patient in "spread eagle" fashion. Wrist and ankle restraints are used only if the patient becomes combative and assaultive during recovery from coma. Abdominal paracentesis should not be carried out unless the patient is in danger of perforating an umbilical hernia or has marked respiratory embarrassment secondary to elevation of the diaphragms. In such cases, remove only enough ascitic fluid to avoid these complications. Removal of larger quantities of fluid results only in reaccumulation and may produce acute depletion of circulating blood volume and the development of shock. The use of adrenocortical steroids in acute hepatic disease remains a controversial subject. Patients in deep hepatic coma with disordered intermediary metabolism and deficient generation of A TP energy sources might be expected to benefit from the membrane-stabilizing effects of steroids. Additionally, a sensitized patient being exposed to a large amount of heterologous antigen (bovine serum proteins) is in danger of anaphylaxis. Steroids should be of benefit in such a situation. On the other hand, there is the theoretical objection that steroids inhibit regeneration of hepatocytes and the pragmatic objection that they have not been demonstrated to be of benefit in any study of patients with fulminating hepatic failure. Despite objections to the use of steroids, we use intravenous hydrocortisone, 2000 mg. per day, or an equivalent steroid in all patients receiving heterologous liver perfusion. Sepsis is a frequent complication of advanced hepatic failure. We routinely prescribe a broad spectrum antibiotic for our patients. Currently, we are utilizing ampicillin, 2 gm. per day intravenously in four divided doses. If the patient has been or is bleeding from the gastrointestinal tract, we also use neomycin, 1 gm. every 4 hours administered via the nasogastric tube after purgation with 15 to 30 gm. of magnesium sulfate. Determinations of partial thromboplastin time, prothrombin content, fibrinogen concentration, platelet count, retraction of incubated clot, and euglobulin clot lysis time are carried out in all patients. Abnormalities of the clotting mechanism are frequent. If an abnormality is identified and the patient is bleeding, appropriate therapy is provided. Platelet concentrate packs, prepared from 3 or 4 blood units, are used if the patient has symptomatic thrombocytopenia. Fresh whole blood or fresh single-unit plasma is used, as appropriate, in patients demonstrating deficiencies of intrinsic clotting components. Epsilon-aminocaproic acid, 1 gm. every hour, is administered intravenously to patients who exhibit active fibrinolysis. Fibrinogen is administered only when fibrinolysis is under control and there is a persistent symptomatic hypofibrinogenemia. No drugs, other than those specifically indicated above, are given to patients in hepatic coma, because patients in hepatic failure are unable to metabolize most drugs. The result of administration of most
LIVER PERFUSION IN HEPATIC COMA
263
drugs will be either an excessive or prolonged drug effect or a worsening of the state of hepatic coma. In particular, narcotics, barbiturates or other sedatives, thiazide diuretics, carbonic anhydrase inhibitors, and alcohol should not be given to these patients. Specific mention should be made of paraldehyde: it is extremely toxic and must never be administered. Narcotic drugs are never indicated in patients in hepatic coma, since they are incapable of perceiving somatic pain and there is, therefore, no rational reason for the administration of such drugs. Similarly, there is no need to administer barbiturates or other sedatives. The temptation to sedate is sometimes strong, since patients in grade II or III hepatic coma may be hypermanic, noisy, abusive, and generally difficult to manage. In the occasional patient in whom barbiturates must be administered to control convulsions, phenobarbital is the agent of choice, since an alternative renal route of excretion is available for this drug. Special precautions must be taken to assure safe discard of needles, razor and knife blades, and similar "sharps" which become contaminated by blood of patients suspected of having hepatitis. A clearly marked, covered steel can serves this purpose well. Personnel who inadvertently injure themselves with a potentially contaminated "sharp" should receive gamma globulin prophylaxis.
PREPARATION OF THE DONOR ANIMAL Prior to perfusion, a healthy bovine calf, weighing 80 to 90 lb., is obtained, kept in a clean corral and maintained on a milk and sucrose diet. Penicillin (10 million units) and streptomycin (1 gm.) is administered intramuscularly twice during the day prior to perfusion; if the proposed patient is known to be sensitive to penicillin, other appropriate antibiotics are used. On the day of perfusion, the donor animal is washed, restrained, and lightly anesthetized with intravenous sodium pentobarbital (20 mg. per kg. body weight). The animal is intubated through a tracheostomy, succinylcholine is administered, and anesthesia is then maintained by a mechanical respirator using a gas/oxygen mixture. The anesthetized animal is placed on a standard animal operating table, the chest and abdomen are vigorously scrubbed and shaved, and the operative area is prepared with 2 per cent tincture. In this and in all subsequent operative maneuvers, standard aseptic surgical technique is utilized. A long midline incision is made beginning at the suprasternal notch and is carried to the pubic symphysis. The peritoneal cavity is opened, the sternum is split in the midline, the diaphragm is incised to the vena caval hiatus and the entire incision is widely retracted. The mediastinal contents are detached from the right half of the sternum. A small incision is made in the pericardium to act as a vent. The gallbladder is retracted superiorly to expose the cystic duct, which is doubly ligated in continuity. The common bile duct is identified, transected at its junction with the duodenum and cannulated with a fine polyethylene tube. The liver is then gently retracted, at first toward the
264
ROBERT
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CONDON, C. THOMAS BOMBECK
left and then toward the right; the diaphragmatic attachments are taken down, the phrenic veins are ligated, and the diaphragm is then incised posteriorly around the vena cava. On the left side, dissection is continued inferiorly, mobilizing the vena cava to the level of the renal veins. The splenic vein is isolated at its junction with the superior mesenteric veins, ligated in continuity, and transected. The portal vein in the porta hepatis is dissected, all lymphatic and pancreatic tissue being removed. The animal is heparinized (500 units per kg.). The hepatic artery and portal vein are each isolated between ligatures and cannulated. The cannulas are connected to bottles of cold sterile flush solution (Normosol-R, pH 7.4). The inferior vena cava is transected and the liver is removed from the abdominal cavity. The purpose of the flush is to remove heterologous blood from the intrahepatic vasculature while reducing the temperature of the liver in order to minimize the damage consequent to anoxia. As flushing is completed, the open ends of the inferior vena cava and the hepatic arterial and portal venous catheters are clamped. The liver is then transferred to the perfusion apparatus and perfused with warm oxygenated blood in order to return the organ to normothermia. The period of cold, anoxic perfusion damages the liver. Although the effect is partially reversible on subsequent oxygenated, normothermic perfusion, in our experience the metabolic function of flushed livers has always been poorer than that of livers perfused with normothermic homologous blood in which no significant period of hypoxia is permitted.
BOVINE LIVER PERFUSION The perfusion apparatus consists of a small disc oxygenator, calibrated roller pumps, filters, a portal venous reservoir, a chamber to hold the liver, and a venous effluent reservoir, and it incorporates a heat exchanger (Fig. 2). Glass wool gravity filters remove platelets; stainless steel mesh filters in the pressure lines remove fibrin aggregates. Appropriate taps allow for continuous recordings of blood pressure, pH, and partial gas pressure, and provide for blood sampling. Hepatic arterial pressure is maintained between 100 and 150 mm. Hg, portal venous pressure between 10 and 15 mm. Hg, and pH in the range 7.35 to 7.50. The perfusion circuits are primed with a liter of compatible, heparinized, partially recalcified bank blood, diluted to hematocrit 30, providing optimum conditions for maximal oxygen transport at minimum viscosity. Perfusate temperature is kept at 38° C. We have thoroughly investigated perfusion via portal vein alone (unpublished data). We have not been so fortunate as others and find that even though total hepatic blood flow per gram of tissue is the same, hepatic function with perfusion only via the portal vein is not as effective as when both hepatic artery and portal vein are perfused. Following insertion of the excised liver into the perfusion circuit and establishment of normothermia in the organ, liver function is evaluated prior to beginning perfusion by the patient. The measures used to evaluate the patient and the isolated organ are listed in Table 4.
265
LIVER PERFUSION IN HEPATIC COMA
Filters
Oxygenator and Heat Exchanger
Figure 2. Schematic diagram of liver perfusion circuit. Note that the patient perfuses the isolated bovine liver in parallel, not in series, with the intrinsic pumps and oxygenator.
Only if function is satisfactory is heterologous perfusion of the patient conducted, since it is obviously useless to perfuse with a nonfunctioning or poorly functioning liver and expect the patient's over-all function to be bettered. When all is in readiness to proceed with perfusion of the patient, the apparatus containing the liver is brought to the patient's bedside. The arterial member of the patient's AV shunt is connected via Silas tic tubing to the oxygenator reservoir; the venous member via another Silastic tube to the venous effluent reservoir of the perfusion apparatus. Both of these Silastic tubes are led through a single occlusive roller pump head, so that venous return to the patient will exactly match arterial outflow. The use of the same pump for both inflow and outflow guards against either exsanguinating or overloading the patient during the course of perfusion. As high a rate of shunt pumping as the patient can easily tolerate is then established. Shunt flows of 3 to 7 ml. per kg. per minute have been achieved, allowing (in a 70 kg. man) over 12 liters per hour of the patient's blood to perfuse the isolated bovine liver. This system provides for (1) adequate volume flow of oxygenated blood to the liver, so that the isolated organ is not dependent on circulation from the patient for its function and survival, and, independently, (2) adequate volume flow from and to the patient via the liver to provide opportunity for the isolated organ to clear accumulated "toxins" from the patient's blood. In addition, should problems with the patient arise during or after donor hepatectomy (see Case 2, below), this system provides for maintaining the liver while a decision regarding perfusion is reached.
266
ROBERT
Table 4.
E. CONDON, C. THOMAS BOMBECK
Evaluation of Clinical Bovine Liver Perfusion IMMEDIATELY BEFORE PERFUSION
IMMEDIDURING PERFUSION
Patient BP, pulse, resp. CVP, EKG Rectal temp. Body weight Grade of coma EEG Urine output Arterial pH, Po" Pco 2 Serum electrolytes Blood glucose Blood urea nitrogen Hct., plasma Hgb. Serum proteins Fibrinogen Prothrombin time Clotting studies Serum bilirubin SGOT, SGPT Arterial NH3
x x x x x x x x x x x x x x x x x x x
Every 15 minutes Continuously Continuously
Donor Liver Ha, PV pressure, flow Perfusate pH, Po" Pco 2 Shunt volume flow Liver core temperature Oxygen consumption Lactate clearance Ammonia extraction Biopsy
x x x x x x x x
Continuously Continuously Continuously Continuously Every 30 minutes Hourly Every 2 hours
x x Hourly Every 30 minutes Every 2 hours Hourly Every 2 hours
ATELY AFTER PERFUSION
AS APPROPRIATE AFTER PERFUSION
x x x x x x x x x x x x x x x x x x x
x x x x x x x x x x x x x x x x x x x
x x x x x x x x
Anticoagulation is maintained by intermittent injection of heparin into the arterial outflow line, producing total body heparinization of the patient. Although total anticoagulation enhances the risk of bleeding complications in patients in hepatic failure, as a practical matter there is no alternative. Attempts to maintain regional heparinization of the extracorporeal apparatus have resulted, because of the high shunt volumes achieved, in gradual production of total patient anticoagulation despite administration of large amounts of protamine. Protamine, epsilon-aminocaproic acid, calcium chloride, and 2 units of human fibrinogen are readily available at the bedside for immediate treatment of any bleeding complications. At the conclusion of perfusion, protamine titration of the patient's blood is carried out and any residual heparin effect is neutralized. Perfusion also results in a depletion of platelets; we routinely administer a 3 or 4 unit platelet concentrate pack at the conclusion of each liver perfusion. A telethermometer probe is inserted in the rectum; if necessary, external warming is utilized to maintain the patient's temperature at 37 to 38° C. During perfusion, appropriate clinical and biochemical measurements of general status and of hepatic function are made (Table 4). The patient's arterial pH is maintained in the range 7.35 to 7.47 by intravenous administration of sodium bicarbonate solution.
LIVER PERFUSION IN HEPATIC COMA
267
Hypotension or hypervolemia during perfusion may be avoided by continuous monitoring of arterial and central venous pressures and appropriate alterations of the rate of shunting. Perfusion is continued for up to 6 to 8 hours, as long as the perfused liver shows evidence of satisfactory function.
EVALUATION OF FUNCTION IN ISOLATED PERFUSED LIVERS We have found that many of the mgre traditional measures of hepatic function, such as bromsulphalein or ammonia clearance, while good measures of liver function in patients, are not adequate measures of function of an isolated, perfused liver. Indeed, a liver which is to all intents and purposes metabolically "dead" will still clear (though not metabolize) ammonia from the perfusate. The ability of the isolated liver to perform a metabolic task while vascular resistance to perfusion is normal, rather than simple clearance, is the sine qua non of function. Bile flow is not a sensitive guide to function. The volume of bile flow is most directly related to bile salt concentration in the perfusate and is much less responsive to changes in hepatocyte function. Bile flow always diminishes during prolonged perfusion, since bile is being removed continuously; flow volume will promptly increase if additional bile or Decholin is administered. In the experience of the authors and colleagues 1 with over 300 isolated liver perfusions, four measures provided sensitive indices of liver function: (1) total hepatic blood flow (must be at least 0.5 mI. per gm. per minute), (2) vascular resistance (must not be greater than 0.02 PRU in the portal vein or 1.0 PRU in the hepatic artery), (3) potassium gradient (HV-PV; must be negative), and (4) appearance of the perfused liver (coarse mottling is bad). All perfused livers which do not meet these criteria are considered functionally unsatisfactory. Clearance of infused lactate, lactate-pyruvate ratio, and SGOT and SGPT levels also have proved to be sensitive indicators of function. These measures, of course, are not immediately available during perfusion, since their determination in the laboratory requires time. They are useful, however, to quantify liver function and to confirm that significant necrosis has not occurred. The fact that bovine liver does not contain SGPT provides a ready means for identifying whether it is the patient's liver or the isolated bovine liver which is undergoing hepatocyte damage. An elevation of SGOT without concomitant elevation of SGPT indicates that necrosis of the bovine liver is the probable source of the enzyme; elevation of both enzymes by comparable amounts indicates that the probable source is the patient's liver.
CLINICAL LIVER PERFUSIONS: CASE REPORTS CASE 1. A 52 year old executive developed petechiae; diagnostic workup established that he had idiopathic thrombocytopenic purpura. An asymptomatic mediastinal mass was noted on chest x-rays. Liver function tests showed a total
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bilirubin of 2.0 mg. per 100 ml. and BSP retention of 25 per cent. He responded to steroid therapy with a rise in platelet count but relapsed 6 weeks later. Splenectomy under halothane anesthesia was carried out; 16 days later a subphrenic fluid collection was drained, again under halothane anesthesia. Two days after the second operation he was noted to be jaundiced and disoriented. Usual measures aimed at combating hepatic failure were initiated, but coma rapidly progressed; his SGOT peaked at 1450 units and subsequently declined (Fig. 3). On the twelfth day he had a cardiac arrest, required a tracheostomy, and subsequently required vasopressors. Urine output following this episode diminished to less than 100 mI. per day. He developed gastrointestinal bleeding and pneumonia. Three exchange transfusions, each of 12 liters of whole blood, were done without apparent benefit and the patient's condition was judged to be terminal. He was deeply comatose, hypotensive, anuric, and deeply jaundiced, and had intermittent respirations and focal seizures. He was hypoglycemic (44 mg. per 100 mI.), despite infusion of intravenous glucose, and had mild hypocalcemia (8.7 mg. per 100 mI.). Prothrombin time was 16 seconds longer than control; platelet count was 92,000 per cu. mm. An EEG was diffusely abnormal and consistent with hepatic coma. Blood pressure of 100 mm. Hg systolic, 50 diastolic was maintained only with a vasopressor drip. A femoral arteriovenous shunt was placed, utilizing the venous catheter previously placed for exchange transfusion; no anesthesia was required. Within 5 minutes of starting the patient on bovine liver perfusion, it was possible to turn off the vasopressor drip. He maintained a stable BP of 120 mm. Hg systolic, 70 diastolic throughout the perfusion. Within 20 minutes of the start of perfusion, he began to excrete urine for the first time in 4 days and made 17 ml. during the first hour and 46 ml. during the second. Biochemically, decreases
VK. JAN: 500 400
Blood Ammonio 300 (y%) 200
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~
-
SGPT (SF units)
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---
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Urine Vol. (ml/hr)
100 30 20 10 300 200 100 0 300 200
Figure 3. Summary of the biochemical responses of patient No. 1. Exchange transfusions are indicated by "ET" and liver perfusion by the vertical shaded bar.
100 0 50 25 0 30 20 10 0
PNEUMONIA GI BLEEDING
@
e
~
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in bilirubin, ammonia, and urea were noted. After perfusion was terminated, he again became hypotensive and vasopressors were restarted; urine output terminated abruptly. He developed increasing respiratory difficulty despite respirator support, and he became acidotic (CO. of 12) and hyperkalemic. Four hours after perfusion he had another cardiac arrest and could not be resuscitated. Autopsy showed complete necrosis of the liver, pancreatitis, an extensive bilateral bronchopneumonia, and a benign mediastinal cyst. CASE 2. A 42 year old alcoholic-cirrhotic was found at home lying unconscious in a pool of dried blood and feces. He apparently had become jaundiced 2 weeks previously, had continued to drink, had had an upper gastrointestinal hemorrhage with both hematemesis and hematochezia, and had fainted. When he failed to awaken after 3 days, his wife called the police. On admission he was deeply comatose but did respond to painful stimuli. There was a purulent conjunctivitis, advanced pneumonia, numerous hematomas in the anterior abdominal wall, ascites, and pitting edema to the level of the axillae. Laboratory studies showed an elevated bilirubin, ammonia, and creatinine, hypokalemia, and a diffusely abnormal EEG consistent with severe hepatic coma. A tracheostomy was done to aspirate secretions and the patient maintained on a respirator. He required a constant vasopressor drip to maintain his blood pressure at 100 mm. Hg systolic. His urine output during the first hospital day was 350 mI.; during the second day it fell to less than 30 ml. Gastrointestinal bleeding continued slowly but steadily, and he was felt by his attendants to be in terminal hepatorenal failure. An arteriovenous shunt was placed; no anesthesia was required. While the liver was being prepared, the patient had a cardiac arrest. He responde!! to external cardiac massage, although a rapid drip of norepinephrine was subsequently required to maintain his blood pressure at 90 mm. Hg systolic. The patient was observed for an hour with no further deterioration in clinical state. It was decided to go ahead with the perfusion. During this unplanned period of waiting, the excised heterologous liver was perfused at normothermia and showed evidence of satisfactory function. This episode underscores the necessity of having a perfusion system which is adequate for maintenance of the liver apart from the blood flow contribution of the patient being treated. Bovine liver perfusion for a period of 2 hours was carried out using the technique outlined above. Within 10 minutes of the start of perfusion, it was possible to turn off the vasopressor drip. He maintained a blood pressure of 130 mm. Hg systolic, 80 diastolic throughout perfusion (except for one 5 minute period during which the blood pressure was transiently as low as 100/70) without need for vasopressors. He made no urine, and no other changes in clinical state or level of coma were noted. Biochemically, decreases in bilirubin, ammonia, and urea were seen. Following termination of the perfusion, he again became hypotensive and required increasing amounts of vasopressors. There was no apparent change in respiratory function. One hour after perfusion he had a second cardiac arrest and could not be resuscitated. Autopsy showed severe cirrhosis with nearly complete necrosis of hepatocytes, focal pancreatitis, an abscess in the right lower lung, esophageal varices, and multiple acute gastric ulcers. CASE 3. A 16 year old girl was admitted with a 4 week history of fatigue and jaundice. There possibly had been a similar episode 4 months earlier, lasting 4 or 5 weeks; there was no contact or transfusion history. The edge of the liver was just palpable; span percussed at 8 cm. Liver function tests showed a total bilirubin of 25.2 mg. per 100 mI., SGOT 270 units, prothrombin content 13.5 per cent. Intravenous glucose and high-dose steroid therapy was started, and bowel sterilization with neomycin also was begun. Within 36 hours of admission, the patient was in grade IV coma; the liver could no longer be palpated or percussed. The next day the patient was totally unresponsive. She was deeply jaundiced and having nearly continuous melena and dark brown returns from the nasogastric suction. Urine output was adequate (25 mI. per hour). The patient was found to be hypersecreting gastric acid (Fig. 4). Her acid secretory rate (determined from hand-aspirated nasogastric tube samples
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100 .2 80 ......
+
::c (if 60 Figure 4. Decrease in gastric acid hypersecretion associated with liver perfusion in patient No.3.
E
40 20
-30
o
30
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Time (min.) every 15 minutes) in the 2 hours prior to perfusion was 105 mEq. per hour! Acid secretion fell to 5 per cent of the baseline rate after the first hour of perfusion and ranged from 5.4 to 37.2 mEq. per hour during perfusion. Four hours of liver perfusion resulted in a decrease in bilirubin from 28.8 to 12.5 mg. per 100 ml. and similar improvement in other biochemical determinations. A third perfusion was planned, but just before it could be started the patient had a massive hematemesis followed by cardiac arrest, and she expired. At autopsy the liver was a small, soft necrotic mass. CASE 4. A 31 year old woman entered the hospital complaining of 5 days of progressive nausea and vomiting with chills and fever during the day of admission. The liver was not palpable and its span percussed 6 cm. The next morning she was noted to be jaundiced. A diagnosis of viral hepatitis was made. Over the next 48 hours, her condition rapidly deteriorated and she became deeply jaundiced, oliguric, hyperreflexic, and then deeply comatose. An isolated perfused liver was set up as described above and patient perfusion carried out for 4 hours, exchanging 48 liters of blood. There was no change in her clinical condition although there was considerable improvement biochemically: bilirubin fell from 68.4 to 28.8 mg. per 100 ml. (Fig. 5). A second 4 hour perfusion exchanging 60 liters was carried out on the next day, again with biochemical improvement. During and after this second perfusion, the level of coma lightened and she began to show spontaneous muscular movements. A third perfusion was carried out the day following, and a fourth perfusion on the day after that. The patient's level of coma became noticeably lighter. An electroencephalogram showed increased frequency of activity. By the fourth evening she was lucid and remained so for the next 3 days. Disorientation then recurred. Initially this was ascribed to recurring hepatic coma, but later it was shown to be due to hypoxia (arterial POz was 50 mm. Hg). Endotracheal intubation and assistance with a respirator resulted in some clearing of her mentation. However, over the next 5 days she developed progressive respiratory insufficiency and eventually died. At autopsy, the liver showed evidence of hepatitis with cholestasis. There were broad areas of necrosis but many hepatocytes were preserved. There were numbers of binucleate cells and some hepatic plates were two or more cells thick. The lungs showed extensive basilar bronchopneumonia; widespread hyaline membranes were noted, even in areas such as the apices not involved with pneumonia.
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16 17 18 19 20 21 22 23
Coma? Level 2
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Gammo Globulin 800
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I RESP.
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It
Figure 5. Biochemical responses and alteration of coma following multiple bovine liver perfusions in patient No.4. Each liver perfusion is indicated by a vertical shaded bar.
CASE 5. A 19 year old girl with a classic story of acute fulminating hepatitis was seen shortly after admission, when she was in grade IV coma. The next day she was totally flaccid and having a brisk gastrointestinal hemorrhage. Bleeding was treated and controlled. Isolated liver perfusion was carried out as detailed above. There was biochemical improvement but no change in clinical status as a result of perfusion. The pattern of a biochemical improvement that failed to correlate with the clinical state was much like that of the patients cited above. This patient died of recurrent massive gastrointestinal bleeding during the night following perfusion. In tlIis patient, static compliance of the lungs was decreased (0.74 liters per cm. H 2 0) and was not altered by perfusion. Gastric secretion (mEq. per hour) in the 2 hours before perfusion was 18.0 and 18.2 but fell to 5.1 in the first hour and to 1.6 in the second hour of perfusion. CASE 6. A 20 year old girl entered with a 10 day history of progressive jaundice. She had had a blood clot 6 weeks previously; otlIerwise tlIere was no history of contact or injection. A diagnosis of viral hepatitis was made; the patient was put to bed and given a high-calorie diet. Her condition remained stable for 2 weeks; she then developed edema and shortly afterward became incoherent. Her condition progressively deteriorated; 4 days later she was oliguric and in grade IV coma. Perfusion was carried out on the next day using the technique outlined above and with the same general result as has been recorded following initial isolated liver perfusion of other patients: improvement in some biochemical parameters
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without any clear improvement in clinical state. About 16 hours following her first perfusion, the patient had a cardiac arrest and was resuscitated. The next morning, the patient had a second cardiac arrest; resuscitation was not successful. At autopsy there was extensive necrosis of the liver. CASE 7. A 62 year old man sustained multiple fractures but no significant visceral injuries in an automobile accident. On admission to the hospital, liver function tests were normal. Four days after the accident and again 10 days later, he received a halothane anesthetic to permit reduction and fixation of his fractures. Two days after the second operation he was noted to be jaundiced. His condition steadily deteriorated over the next 2 weeks. His SGOT reached 2125 units. He became oliguric and hyperkalernic. Peritoneal dialysis controlled the elevated potassium, but did not otherwise alter the clinical course. Exchange blood transfusion was carried out without producing improvement. By the eighteenth day following his second halothane anesthetic and operation, the patient was in grade V coma, deeply jaundiced, and anuric, with anasarca and severe metabolic acidosis. Bovine liver perfusion was carried out for 4 hours and produced marked biochemical improvement, lowering the bilirubin and ammonia levels by approximately 50 per cent. The patient's level of consciousness improved and he responded, though not entirely appropriately, to spoken voice (grade III coma). By the following morning, deep coma had recurred. The patient had been totally anuric for the preceding 4 days; he was now severely hyperkalemic and having cardiac arrhythmias. Hemodialysis restored the potassium and BUN levels toward normal, but did not result in any change in coma. A second bovine liver perfusion was conducted, which produced further improvement in biochemical parameters but no change in clinical state. On the next day the patient underwent a simultaneous liver perfusion and renal hemodialysis. After 2 hours of perfusion, the patient's level of consciousness had improved from grade V to grade II. He responded appropriately to spoken voice and was able to converse briefly with his wife. Perfusion was continued for 5 hours; the patient's improved clinical state persisted when perfusion was discontinued. Shortly after midnight that night, the patient had a sudden episode of hypotension followed by cardiac arrest. Resuscitation was not successful. At autopsy there was widespread necrosis of the liver, anasarca, pancreatitis, and bronchopneumonia.
SUMMARY AND CONCLUSIONS Our experience in treating patients in acute severe hepatic failure by means of bovine liver perfusion can be summarized as follows: 1. All patients were improved biochemically; the biochemical response did not correlate with clinical symptoms, nor was the biochemical response of any value in predicting the patient's clinical course. 2. Three of seven patients had a definite improvement in clinical symptoms as reflected in lightening of coma from grade IV or V to grade II or III, accompanied by return of capacity to respond to spoken voice. 3. One patient recovered from coma and also showed stabilization of hepatic function; this patient subsequently succumbed to respiratory failure. 4. A variety of observations have been made of patient responses during bovine liver perfusion, including: (a) decreased gastric acid hypersecretion; (b) elimination of hypotension and need for vasopressors and, in one patient, (c) resumption of urine output.
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5. Complications have been frequent, both before and after liver perfusion. Renal failure has partially responded to usual therapeutic measures including hemodialysis. Gastrointestinal bleeding has been more difficult to manage. Correction of specific clotting defects by administration of fresh blood or plasma, fibrinogen, or epsilon-aminocaproic acid will restore the clotting mechanism temporarily, but has not prevented fatal bleeding from ulcers of the duodenum or stomach. What of the future? Bovine liver perfusion has been as successful (or as unsuccessful) as any other of the newer experimental methods of treating acute, fulminating hepatic failure. It must be recognized and accepted that none of the newer experimental therapies have really altered the prognosis of acute, fulminating hepatic failure. Liver perfusion, as well as many of the other experimental therapies, requires a considerable expenditure of time, energy, and resources by the investigative team. Patients selected for such investigations, therefore, should be limited. The main thrust of the future should continue to be in the research laboratory, directed to the development of more effective clinical therapy.
REFERENCE 1. Hornbeck, C~ T., Hiava, C., Condon, R. E., and Nyhus, L. M.: Parameters of normal liver function in the isolated perfused bovine liver. In Norman, J. C., ed.: Organ Perfusion and Preservation. New York, Appleton-Century-Crofts, 1968. University of Illinois College of Medicine Chicago, Illinois 60612