508
ARTIFICIAL LIVER SUPPORT IN FULMINANT HEPATIC FAILURE* ROGER WILLIAMS, M.D., F.R.C.P. Director, Liver Unit Consultant Physician King's College Hospital and Medical School London, England
A LL our therapeutic endeavors in patients with fulminant hepatic failure are based on the premise that if their general condition can be maintained and specific complications can be controlled, survival is possible because of the well-known regenerative capacity of the liver. Regeneration is rapid in the rat after experimental hepatectomy and in man after resection for trauma, but we know little or nothing about the factors that affect regeneration in fulminant viral hepatitis-in which the hepatic injury may not be a single event but a continuing process. Nevertheless, there are a few instances in the literature in which complete restitution of normal liver structure has occurred, even in patients who had been in deep hepatic coma. It is, of course possible that when the initial insult is sufficiently severe, significant regeneration will never occur. In such cases the only foreseeable treatment would be transplantation, but I doubt whether it ever will be possible and reliable to make this judgment early in the clinical course. If the patient's condition is deteriorating despite full supportive therapy, some form of temporary liver support must be considered. Most frequently the patient is connected to an isolated but functioning pig's liver in an extracorporeal perfusion circuit. A human liver obtained from a cadaver very shortly after death can also be used. With a human liver, or the liver of a baboon-a possibility only in certain parts of the world-perfusion can be continued for up to 48 hours as compared with a maximum of six to eight hours for a pig's liver. Extracorporeal perfusion may be followed by improvement in laboratory tests and by an improvement in the level of consciousness, but such *Presented as part of A Day on the Liver held by the New York Academy of Medicine and the International Association for the Study of the Liver at the Academy March 7, 1974.
Bull. N. Y. Acad. Med.
ARTIFICIAL LIVER SUPPORT ARTIFICIAL LIVER
5 9 SUPPORT509~~~~~~~~~~~ 0
effects are usually temporary. The long-term results, over-all, are discouraging. Parbhoo,' in an analysis of world data, could find only nine survivors of 140 patients treated by 170 perfusions. DEVELOPMENT OF AN ARTIFICIAL LIVER-SUPPORT SYSTEM It seemed to us that only a completely artificial system could provide a reproducible system for the type of repeated support that is
needed by these patients. Abnormalities resulting from impairment of hepatic synthesis should be replaceable by appropriate intravenous infusion; such a support system would be concerned entirely with excretion. The aim must be to return to normal the plasma concentration of all the water-soluble substances which accumulate in hepatic failure, such as ammonia and methionine, as well as another group of potentially toxic substances, strongly bound to proteins in the blood, which include bilirubin and bile salts. Willson and his colleagues2 have shown that such protein-bound substances can be adsorbed effectively to certain resins, such as Dowex and XAD2, and activated charcoal can be used for the adsorption of water-soluble substances. The mechanics of the liver-support system are deceptively simple: the system consists essentially of a series of packed columns through which the patient's blood is perfused, each column subserving a particular aspect of excretion. But there is one major problem. Both XAD2 and activated charcoal need to be coated by a material which will prevent adsorption of white cells and platelets-this could be harmful to the patient-but at the same time would allow access to the substance to be removed. Recently we have shown, in studies of charcoal hemoperfusion for paracetamol overdose, that coating the charcoal with 4% by weight of polyhema will reduce platelet loss to acceptable levels without significantly impairing the adsorption of paracetamol.3 However, when XAD2 was coated in this way, adsorption of protein-bound substances was prevented. With the polymer chemists and bioengineers in our unit, we are looking at other resins and polymers which would be both biocompatible as well as efficient in adsorption. I shall describe some of our preliminary results with this liversupport system. First we used it in an animal model of hepatic failure, the dog, with hepatic necrosis produced by ligation of the hepatic artery some 24 hours after a portocaval shunt had been made.4 The Vol. 51, No. 4, April 1975
5 10
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survival of animals treated by hemoperfusion through coated charcoal was significantly greater than survival in controls. The otherwise progressive rise in blood ammonia was halted (Figure I). Perfusion through a column containing XAD2 produced a fall in the serum bilirubin level (Figure 2) but survival was not increased to the same extent, mainly because of hemorrhage developing as a result of the thrombocytopenia induced by hemoperfusion. Bull. N. Y. Acad. Med.
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Fig. 2. Changes in levels of bilirubin in controls and animals given resin-hemoperfusion. Reproduced by permission from Weston, M. J., Gazzard, B. G., Buxton, B. H., Winch, J., Flax, H., Machado, I., and Williams, R.: Effects of haemoperfusion through charcoal or XAD-2 resin on an animal mnodel of fulminant liver failure. Gut 15:484, 1974.
USE
CHARCOAL HEMOPERFUSION IN PATIENTS Encouraged by these results, since October 1973 we have used charcoal hemoperfusion in the treatment of patients with fulminant hepatic failure whose condition had deteriorated to grade IV coma (unconscious and not responsive to verbal command) despite full supportive measures. Details of the circuit used for hemoperfusion and of the preparation of the activated charcoal coated with a biocompatible polymer are given elsewhere, together with the findings in the first 2 2 patients so treated.5 OF
Vol. 51, No. 4, April 1975
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The causes of fulminant hepatic failure included acute viral hepatitis (type A in four cases, type B in six cases), paracetamol selfpoisoning (five cases), and single cases of hypersensitivity to various drugs (Table 1). The series represents consecutive patients with fulminant hepatic failure treated in the Liver Unit of King's College Hospital, except for three patients-two who died soon after admission and one who had sustained cerebral damage after prolonged hypoglycemia. All patients were treated with full supportive measures, including fresh-frozen plasma to correct the clotting defect, intravenous glucose, and intestinal sterilization with oral neomycin.6 When cerebral edema was suspected on clinical grounds-irregular respiration, sudden deepening of coma, or changes in pulse-rate and blood pressure-dexamethasone or intravenous glycerol was given, although without obvious benefit. Hemoperfusion was started only when the patient had shown signs of grade IV encephalopathy (according to the criteria of Trey et al.7) for at least 12 hours. The plan was to perfuse the patient for a period of four hours each day until consciousness (grade II encephalopathy) was regained. When hypotension or active bleeding was present perfusions were sometimes omitted for a day; in two patients who seemed to be deteriorating especially rapidly (Nos. 12 and i9) the duration of perfusion was prolonged to eight hours daily.
CLINICAL RESPONSE In all, 78 perfusions were carried out in the 22 patients (Table I). Although in general the perfusions were well tolerated, the central venous pressure usually fell 4 to 5 cm. during the perfusion and in some patients the flow of urine decreased. Transient hypotension often developed at the start of the perfusion, but this was usually reversible by infusion of plasma or blood. Eleven patients recovered consciousness within one to seven days after the first period of hemoperfusion. Six of these had three or more perfusions. Changes in the level of consciousness were rarely observed during the actual perfusion, the improvement being noted some 12 to 24 hours later. Three of the patients who recovered consciousness subsequently deteriorated again. Patient No. 2 improved to grade II encephalopathy after two perfusions, but lapsed into grade IV coma the next day, regaining consciousness again after a third perfusion. Another Vol. 51, No. 4, April 1975
5I4
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514
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* XCOLUMN PERFUSION
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Fig. 3. Serial liver function tests in patient No. 7: halothane-associated fulminant hepatic failure, four hemoperfusions. Reproduced by permission from Gazzard, B. G., Weston, M. J., Murray-Lyon, I. M., Flax, H., Record, C. O., Portmann, B., Langley, E. H., Mellon, P. J., Ward, M. B., and Williams, R.: Charcoal haemoperfusion in the treatment of fulminant hepatic failure. Lancet 1:1301, 1974.
patient (No. 9), with fulminant hepatic failure caused by ingestion of fungi (Amanita phalloides sp.), had very high levels of plasmaaspartate-aminotransferase (4,000 I.U. per liter). She became responsive to commands after the third perfusion but deteriorated again later that day and lapsed into grade IV coma. She recovered consciousness during a fourth perfusion and subsequently made an uninterrupted recovery. Patient No. 7, who was perfused on four occasions, became confused and psychotic some days after recovering full consciousness but did not require a further perfusion. One of the most surprising recoveries was in patient No. 6, a man of 22 who was perfused on three occasions. He had taken ioo paracetamol tablets (a total of 50 g.), lapsed into grade IV coma on the third day after admission, Bull. N. Y. Acad. Med.
ARTIFICIAL LIVER SUPPORT ARTIFICIAL LIVER
5 I5 515~~~~~~~~
SUPPORT
TABLE II. ARTERIAL PLATELET COUNT BEFORE AND DURING CHARCOAL HEMOPERFUSION: MEAN VALUE AND RANGE IN THOSE WHO DID AND IN THOSE WHO DID NOT RECOVER CONSCIOUSNESS
Platelet count (X 10', per mm.')
Before Group Recovered consciousness No improvement
During
No.
Mean
Range
Mean
Range
11 11
157 141
38-200 48-281
117 97
25-160 38-150
and had to be given artificial ventilation on the fourth day. He also developed acute tubular necrosis with anuria, which necessitated dialysis for nearly three weeks. But by the I oth week, when he was discharged from the hospital, both hepatic and renal function had been recovered almost completely. Of the I I patients who regained consciousness, io subsequently left the hospital clinically recovered and with practically normal liverfunction tests. The one exception was patient No. 8, who developed fatal septicemia secondary to a lung abscess some three weeks after his initial recovery. This patient and three patients who finally recovered (Nos. 6, 7, and i i) progressed, after regaining consciousness, to a phase of deep cholestasis lasting for several weeks with peak serum-bilirubin levels of 50, 33, 6o, and 32 mg. per ioo ml., respectively (Figure 3). Biopsy carried out during the recovery phase showed extensive hepatic necrosis, with areas of active regeneration in all patients. Necrosis was especially striking in the patient with mushroom poisoning; in this woman reticulin preparation also showed wide areas of collapsed reticulin which bridged portal tracts and centrilobular zones. A further biopsy in this patient five months later showed considerable improvement with some irregular residual scarring but a surprising restoration of the lobular pattern and no evidence of developing cirrhosis. Striking improvements were also seen in the other two patients who have had follow-up biopsies after a period of some months. FAILURES OF TREATMENT The ii patients who showed no improvement in levels of consciousness after hemoperfusion lived for up to IO days; one had been Vol. 51, No. 4, April 1975
5I6
R. WILLIAMS
CHARCOAL 2
HAEMOPERFUSION 3
4
CONC.
TYROSINE
DAYS OF TREATMENT
Fig. 4. The fall in plasma levels of three amino acids during four periods of hemoperfusion in patient No. 9. Reproduced by permission from Gazzard, B. G., Weston, M. J., Murray-Lyon, I. M., Flax, H., Record, C. O., Portmann, B., Langley, E. H., Mellon, P. J., Ward, M. B., and Williams, R.: Charcoal haemoperfusion in the treatment of fulminant hepatic failure. Laicet 1:1301, 1974.
perfused on nine occasions and IO had had three or more perfusions. Patients No. i8 and 22 improved sufficiently to allow them to come off the ventilator for a time; in two other patients the return of peripheral reflexes was observed. Analysis of the terminal clinical events and the necropsy findings in these i i patients showed that hemorrhage, which had been a major clinical problem during the lives of six patients, directly caused the death of three (Table II). In six patients death was attributed to herniation of the brain consequent on cerebral edema, some evidence of which was found at necropsy in nine of the i i patients. Both cereBull. N. Y. Acad. Med.
ARTIFICIAL LIVER SUPPORT
ARTIFICIAL
LIVER
SUPPORT
5I7
bral softening and hemorrhage seemed to have contributed to the final outcome in the remaining two of these i i patients. The necropsy finding of cerebral softening and edema in so many of the patients is very worrisome. It is difficult to know to what extent the softening was due to artificial respiration, although two patients with evidence of cerebral herniation had not had ventilation before death. We have previously seen patients who seemed to have suffered cerebral death at a time when hepatic function was improving.8 Other workers have also noted a high frequency of cerebral edema in acute hepatic failure. ELECTROENCEPHALOGRAM (EEG) AND LEVELS OF AMINO ACID IN RELATION TO HEMOPERFUSION A progressive improvement in EEG grading over the period of hemoperfusion support was observed in the patients who recovered consciousness, although at a particular time the correlation between EEG grade and level of consciousness was not exact. In the other I I patients no improvement was observed. Indeed, in several cases the EEG deteriorated even further during the perfusion. The plasma concentrations of most amino acids were greatly elevated before the start of the hemoperfusions in all the patients in whom measurements were carried out. Significant extraction of many of the amino acids by the column was demonstrated; these included phenylalanine, tyrosine, and methionine. Concentrations rose again before the next perfusion (Figure 4). The fall toward normal during the periods of perfusion could not be correlated exactly with improvement in the grade of coma but alterations in brain levels are likely to be of more relevance than blood levels. EFFECTS OF HEMOPERFUSION ON COAGULATION AND BLOOD PLATELETS Some fall in platelet count across the column was found during each of the 42 perfusions investigated in I2 patients. This decline was less than 30% of the preinfusion level in 35 instances. On the remaining seven occasions, which represented two perfusions in one patient and single perfusions in five patients, the fall was as great as 3o to 6o% of the preperfusion level. It is clear that some platelets were lost during hemoperfusion. In three patients bleeding first occurred during hemoperfusion and recurred during subsequent perfusions. Since the Vol. 51, No. 4, April 1975
5 I 8
R. WILLIAMS
blood-platelet count in at least two of these patients had fallen by about so% on the day after the first perfusion, although extraction by the column had not been striking, platelets may have been damaged during perfusion and this may have led to subsequent sequestration and destruction in the reticuloendothelial system.
CONCLUSION Unfortunately, hepatologists know only too well that each new treatment for hepatic failure appears to have the best success when introduced, but significantly lower rates of recovery are obtained with subsequent experience. Nevertheless, our series is quite large and represents considerable experience of a relatively rare condition, and so we are encouraged. I should also like to reemphasize that only an artificial and hence repeatable as well as reproducible form of liver support can be adequate for the management of these patients. REFERENCES
1. Parbhoo, S.: Personal communication, 1972. 2. Willson, R. A., Hofman, A. F., and Kuster, G. G. R.: Toward an artificial liver: II. Removal of cholephilic and anions from dogs with biliary obstruction by haemoperfusion through charged and uncharged resins. Gastroenterology 66:93, 1974. 3. Gazzard, B. G., Langley, P. G., Weston, M. J., Dunlop, E. H., and Williams, R.: Polymer coating of activated charcoal and its effects on biocompatibility and paracetamol binding. Clin. Sci. Molc. Med. 47:97, 1974. 4. Weston, M. J., Gazzard, B. G., Buxton, B. H., Winch J., Flax, H., Machado A., and Williams R.: Effects of haemoper-
5.
6. 7.
8.
fusion through charcoal or XAD-2 resin on an animal model of fulminant liver failure. Gut 15:482, 1974. Gazzord, B. G. Weston, M. J., MurrayLyon, I. M., Flax, H., Record, C. O., Portmann, B., Langley, P. G., Dunlop, E. H., Mellon, P. J., Ward, M. B., and Williams, R.: Charcoal haemoperfusion in the treatment of fulminant hepatic failure. Lancet 1:1301, 1974. Williams, R.: Fulminant viral hepatitis. Clin. Gastroent. 3:419, 1974. Trey, C., Burns, D. G., and Saunders, S. J.: Treatment of hepatic coma by exchange blood transfusion. New Eng. J. Med. 274:473, 1966. Williams, R.: tIepatic encephalopathy. J. Roy. Coll. Phys. 8:63, 1973.
Bull. N. Y. Acad. Med.
ARTIFICIAL LIVER SUPPORT IN FULMINANT HEPATIC FAILURE* ROGER WILLIAMS, M.D., F.R.C.P. Director, Liver Unit Consultant Physician King's College Hospital and Medical School London, England
A LL our therapeutic endeavors in patients with fulminant hepatic failure are based on the premise that if their general condition can be maintained and specific complications can be controlled, survival is possible because of the well-known regenerative capacity of the liver. Regeneration is rapid in the rat after experimental hepatectomy and in man after resection for trauma, but we know little or nothing about the factors that affect regeneration in fulminant viral hepatitis-in which the hepatic injury may not be a single event but a continuing process. Nevertheless, there are a few instances in the literature in which complete restitution of normal liver structure has occurred, even in patients who had been in deep hepatic coma. It is, of course possible that when the initial insult is sufficiently severe, significant regeneration will never occur. In such cases the only foreseeable treatment would be transplantation, but I doubt whether it ever will be possible and reliable to make this judgment early in the clinical course. If the patient's condition is deteriorating despite full supportive therapy, some form of temporary liver support must be considered. Most frequently the patient is connected to an isolated but functioning pig's liver in an extracorporeal perfusion circuit. A human liver obtained from a cadaver very shortly after death can also be used. With a human liver, or the liver of a baboon-a possibility only in certain parts of the world-perfusion can be continued for up to 48 hours as compared with a maximum of six to eight hours for a pig's liver. Extracorporeal perfusion may be followed by improvement in laboratory tests and by an improvement in the level of consciousness, but such *Presented as part of A Day on the Liver held by the New York Academy of Medicine and the International Association for the Study of the Liver at the Academy March 7, 1974.
Bull. N. Y. Acad. Med.
ARTIFICIAL LIVER SUPPORT ARTIFICIAL LIVER
5 9 SUPPORT509~~~~~~~~~~~ 0
effects are usually temporary. The long-term results, over-all, are discouraging. Parbhoo,' in an analysis of world data, could find only nine survivors of 140 patients treated by 170 perfusions. DEVELOPMENT OF AN ARTIFICIAL LIVER-SUPPORT SYSTEM It seemed to us that only a completely artificial system could provide a reproducible system for the type of repeated support that is
needed by these patients. Abnormalities resulting from impairment of hepatic synthesis should be replaceable by appropriate intravenous infusion; such a support system would be concerned entirely with excretion. The aim must be to return to normal the plasma concentration of all the water-soluble substances which accumulate in hepatic failure, such as ammonia and methionine, as well as another group of potentially toxic substances, strongly bound to proteins in the blood, which include bilirubin and bile salts. Willson and his colleagues2 have shown that such protein-bound substances can be adsorbed effectively to certain resins, such as Dowex and XAD2, and activated charcoal can be used for the adsorption of water-soluble substances. The mechanics of the liver-support system are deceptively simple: the system consists essentially of a series of packed columns through which the patient's blood is perfused, each column subserving a particular aspect of excretion. But there is one major problem. Both XAD2 and activated charcoal need to be coated by a material which will prevent adsorption of white cells and platelets-this could be harmful to the patient-but at the same time would allow access to the substance to be removed. Recently we have shown, in studies of charcoal hemoperfusion for paracetamol overdose, that coating the charcoal with 4% by weight of polyhema will reduce platelet loss to acceptable levels without significantly impairing the adsorption of paracetamol.3 However, when XAD2 was coated in this way, adsorption of protein-bound substances was prevented. With the polymer chemists and bioengineers in our unit, we are looking at other resins and polymers which would be both biocompatible as well as efficient in adsorption. I shall describe some of our preliminary results with this liversupport system. First we used it in an animal model of hepatic failure, the dog, with hepatic necrosis produced by ligation of the hepatic artery some 24 hours after a portocaval shunt had been made.4 The Vol. 51, No. 4, April 1975
5 10
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survival of animals treated by hemoperfusion through coated charcoal was significantly greater than survival in controls. The otherwise progressive rise in blood ammonia was halted (Figure I). Perfusion through a column containing XAD2 produced a fall in the serum bilirubin level (Figure 2) but survival was not increased to the same extent, mainly because of hemorrhage developing as a result of the thrombocytopenia induced by hemoperfusion. Bull. N. Y. Acad. Med.
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USE
CHARCOAL HEMOPERFUSION IN PATIENTS Encouraged by these results, since October 1973 we have used charcoal hemoperfusion in the treatment of patients with fulminant hepatic failure whose condition had deteriorated to grade IV coma (unconscious and not responsive to verbal command) despite full supportive measures. Details of the circuit used for hemoperfusion and of the preparation of the activated charcoal coated with a biocompatible polymer are given elsewhere, together with the findings in the first 2 2 patients so treated.5 OF
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ARTIFICIAL LIVER SUPPORT
ARTTFTCTAL
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5T3
The causes of fulminant hepatic failure included acute viral hepatitis (type A in four cases, type B in six cases), paracetamol selfpoisoning (five cases), and single cases of hypersensitivity to various drugs (Table 1). The series represents consecutive patients with fulminant hepatic failure treated in the Liver Unit of King's College Hospital, except for three patients-two who died soon after admission and one who had sustained cerebral damage after prolonged hypoglycemia. All patients were treated with full supportive measures, including fresh-frozen plasma to correct the clotting defect, intravenous glucose, and intestinal sterilization with oral neomycin.6 When cerebral edema was suspected on clinical grounds-irregular respiration, sudden deepening of coma, or changes in pulse-rate and blood pressure-dexamethasone or intravenous glycerol was given, although without obvious benefit. Hemoperfusion was started only when the patient had shown signs of grade IV encephalopathy (according to the criteria of Trey et al.7) for at least 12 hours. The plan was to perfuse the patient for a period of four hours each day until consciousness (grade II encephalopathy) was regained. When hypotension or active bleeding was present perfusions were sometimes omitted for a day; in two patients who seemed to be deteriorating especially rapidly (Nos. 12 and i9) the duration of perfusion was prolonged to eight hours daily.
CLINICAL RESPONSE In all, 78 perfusions were carried out in the 22 patients (Table I). Although in general the perfusions were well tolerated, the central venous pressure usually fell 4 to 5 cm. during the perfusion and in some patients the flow of urine decreased. Transient hypotension often developed at the start of the perfusion, but this was usually reversible by infusion of plasma or blood. Eleven patients recovered consciousness within one to seven days after the first period of hemoperfusion. Six of these had three or more perfusions. Changes in the level of consciousness were rarely observed during the actual perfusion, the improvement being noted some 12 to 24 hours later. Three of the patients who recovered consciousness subsequently deteriorated again. Patient No. 2 improved to grade II encephalopathy after two perfusions, but lapsed into grade IV coma the next day, regaining consciousness again after a third perfusion. Another Vol. 51, No. 4, April 1975
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* XCOLUMN PERFUSION
0
2, 000z ASPARTATE AMINO TRANSFERASE i.u/L
PLASMA
BILIRUBDN ing/100 ml.
PROTHROMBIN TDIE RATIO
2-
2
4
ff
2
DAYS
4
6
WEEKS
TIME
Fig. 3. Serial liver function tests in patient No. 7: halothane-associated fulminant hepatic failure, four hemoperfusions. Reproduced by permission from Gazzard, B. G., Weston, M. J., Murray-Lyon, I. M., Flax, H., Record, C. O., Portmann, B., Langley, E. H., Mellon, P. J., Ward, M. B., and Williams, R.: Charcoal haemoperfusion in the treatment of fulminant hepatic failure. Lancet 1:1301, 1974.
patient (No. 9), with fulminant hepatic failure caused by ingestion of fungi (Amanita phalloides sp.), had very high levels of plasmaaspartate-aminotransferase (4,000 I.U. per liter). She became responsive to commands after the third perfusion but deteriorated again later that day and lapsed into grade IV coma. She recovered consciousness during a fourth perfusion and subsequently made an uninterrupted recovery. Patient No. 7, who was perfused on four occasions, became confused and psychotic some days after recovering full consciousness but did not require a further perfusion. One of the most surprising recoveries was in patient No. 6, a man of 22 who was perfused on three occasions. He had taken ioo paracetamol tablets (a total of 50 g.), lapsed into grade IV coma on the third day after admission, Bull. N. Y. Acad. Med.
ARTIFICIAL LIVER SUPPORT ARTIFICIAL LIVER
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TABLE II. ARTERIAL PLATELET COUNT BEFORE AND DURING CHARCOAL HEMOPERFUSION: MEAN VALUE AND RANGE IN THOSE WHO DID AND IN THOSE WHO DID NOT RECOVER CONSCIOUSNESS
Platelet count (X 10', per mm.')
Before Group Recovered consciousness No improvement
During
No.
Mean
Range
Mean
Range
11 11
157 141
38-200 48-281
117 97
25-160 38-150
and had to be given artificial ventilation on the fourth day. He also developed acute tubular necrosis with anuria, which necessitated dialysis for nearly three weeks. But by the I oth week, when he was discharged from the hospital, both hepatic and renal function had been recovered almost completely. Of the I I patients who regained consciousness, io subsequently left the hospital clinically recovered and with practically normal liverfunction tests. The one exception was patient No. 8, who developed fatal septicemia secondary to a lung abscess some three weeks after his initial recovery. This patient and three patients who finally recovered (Nos. 6, 7, and i i) progressed, after regaining consciousness, to a phase of deep cholestasis lasting for several weeks with peak serum-bilirubin levels of 50, 33, 6o, and 32 mg. per ioo ml., respectively (Figure 3). Biopsy carried out during the recovery phase showed extensive hepatic necrosis, with areas of active regeneration in all patients. Necrosis was especially striking in the patient with mushroom poisoning; in this woman reticulin preparation also showed wide areas of collapsed reticulin which bridged portal tracts and centrilobular zones. A further biopsy in this patient five months later showed considerable improvement with some irregular residual scarring but a surprising restoration of the lobular pattern and no evidence of developing cirrhosis. Striking improvements were also seen in the other two patients who have had follow-up biopsies after a period of some months. FAILURES OF TREATMENT The ii patients who showed no improvement in levels of consciousness after hemoperfusion lived for up to IO days; one had been Vol. 51, No. 4, April 1975
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CHARCOAL 2
HAEMOPERFUSION 3
4
CONC.
TYROSINE
DAYS OF TREATMENT
Fig. 4. The fall in plasma levels of three amino acids during four periods of hemoperfusion in patient No. 9. Reproduced by permission from Gazzard, B. G., Weston, M. J., Murray-Lyon, I. M., Flax, H., Record, C. O., Portmann, B., Langley, E. H., Mellon, P. J., Ward, M. B., and Williams, R.: Charcoal haemoperfusion in the treatment of fulminant hepatic failure. Laicet 1:1301, 1974.
perfused on nine occasions and IO had had three or more perfusions. Patients No. i8 and 22 improved sufficiently to allow them to come off the ventilator for a time; in two other patients the return of peripheral reflexes was observed. Analysis of the terminal clinical events and the necropsy findings in these i i patients showed that hemorrhage, which had been a major clinical problem during the lives of six patients, directly caused the death of three (Table II). In six patients death was attributed to herniation of the brain consequent on cerebral edema, some evidence of which was found at necropsy in nine of the i i patients. Both cereBull. N. Y. Acad. Med.
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ARTIFICIAL
LIVER
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bral softening and hemorrhage seemed to have contributed to the final outcome in the remaining two of these i i patients. The necropsy finding of cerebral softening and edema in so many of the patients is very worrisome. It is difficult to know to what extent the softening was due to artificial respiration, although two patients with evidence of cerebral herniation had not had ventilation before death. We have previously seen patients who seemed to have suffered cerebral death at a time when hepatic function was improving.8 Other workers have also noted a high frequency of cerebral edema in acute hepatic failure. ELECTROENCEPHALOGRAM (EEG) AND LEVELS OF AMINO ACID IN RELATION TO HEMOPERFUSION A progressive improvement in EEG grading over the period of hemoperfusion support was observed in the patients who recovered consciousness, although at a particular time the correlation between EEG grade and level of consciousness was not exact. In the other I I patients no improvement was observed. Indeed, in several cases the EEG deteriorated even further during the perfusion. The plasma concentrations of most amino acids were greatly elevated before the start of the hemoperfusions in all the patients in whom measurements were carried out. Significant extraction of many of the amino acids by the column was demonstrated; these included phenylalanine, tyrosine, and methionine. Concentrations rose again before the next perfusion (Figure 4). The fall toward normal during the periods of perfusion could not be correlated exactly with improvement in the grade of coma but alterations in brain levels are likely to be of more relevance than blood levels. EFFECTS OF HEMOPERFUSION ON COAGULATION AND BLOOD PLATELETS Some fall in platelet count across the column was found during each of the 42 perfusions investigated in I2 patients. This decline was less than 30% of the preinfusion level in 35 instances. On the remaining seven occasions, which represented two perfusions in one patient and single perfusions in five patients, the fall was as great as 3o to 6o% of the preperfusion level. It is clear that some platelets were lost during hemoperfusion. In three patients bleeding first occurred during hemoperfusion and recurred during subsequent perfusions. Since the Vol. 51, No. 4, April 1975
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blood-platelet count in at least two of these patients had fallen by about so% on the day after the first perfusion, although extraction by the column had not been striking, platelets may have been damaged during perfusion and this may have led to subsequent sequestration and destruction in the reticuloendothelial system.
CONCLUSION Unfortunately, hepatologists know only too well that each new treatment for hepatic failure appears to have the best success when introduced, but significantly lower rates of recovery are obtained with subsequent experience. Nevertheless, our series is quite large and represents considerable experience of a relatively rare condition, and so we are encouraged. I should also like to reemphasize that only an artificial and hence repeatable as well as reproducible form of liver support can be adequate for the management of these patients. REFERENCES
1. Parbhoo, S.: Personal communication, 1972. 2. Willson, R. A., Hofman, A. F., and Kuster, G. G. R.: Toward an artificial liver: II. Removal of cholephilic and anions from dogs with biliary obstruction by haemoperfusion through charged and uncharged resins. Gastroenterology 66:93, 1974. 3. Gazzard, B. G., Langley, P. G., Weston, M. J., Dunlop, E. H., and Williams, R.: Polymer coating of activated charcoal and its effects on biocompatibility and paracetamol binding. Clin. Sci. Molc. Med. 47:97, 1974. 4. Weston, M. J., Gazzard, B. G., Buxton, B. H., Winch J., Flax, H., Machado A., and Williams R.: Effects of haemoper-
5.
6. 7.
8.
fusion through charcoal or XAD-2 resin on an animal model of fulminant liver failure. Gut 15:482, 1974. Gazzord, B. G. Weston, M. J., MurrayLyon, I. M., Flax, H., Record, C. O., Portmann, B., Langley, P. G., Dunlop, E. H., Mellon, P. J., Ward, M. B., and Williams, R.: Charcoal haemoperfusion in the treatment of fulminant hepatic failure. Lancet 1:1301, 1974. Williams, R.: Fulminant viral hepatitis. Clin. Gastroent. 3:419, 1974. Trey, C., Burns, D. G., and Saunders, S. J.: Treatment of hepatic coma by exchange blood transfusion. New Eng. J. Med. 274:473, 1966. Williams, R.: tIepatic encephalopathy. J. Roy. Coll. Phys. 8:63, 1973.
Bull. N. Y. Acad. Med.
