Cerebral Edema: A Major Complication of Massive Hepatic Necrosis

GASTROENTEROLOGY

Vol. 61, No.6

Copyright ©1971 by The Williams & Wilkins Co.

Printed in U.S.A.

LIVER PHYSIOLOGY AND DISEASE

CEREBRAL EDEMA: A MAJOR COMPLICATION OF MASSIVE HEPATIC NECROSIS ATHOL J. WARE, M .B.B.S., M.R.A.C.P., ANTHONY N. D'AGOSTINO, M.D., BURTON COMBES, M .D.

AND

Liver-Gastrointestinal Unit, The Department of Internal Medicine , and the Department of Pathology, The University of Texas Southwestern Medical School at Dalills, Texas

A review was conducted of 32 patients dying of massive hepatic necrosis and subject to complete autopsy examination. Sixteen of the 32 patients were found to have cerebral edema and 4 of these had evidence of cerebellar and/or uncal herniation. Those patients with cerebral edema were younger, had a more prolonged period of stage IV coma, and were less likely to have terminal azotemia and acidosis than the patients without cerebral edema. The pathogenesis of the cerebral edema in these patients is unknown but it does not appear to be related to secondary complications causing cerebral hypoxia nor to any specific form of therapy. Massive hepatic necrosis is a serious disorder with a very high mortality rate. 1 Major complications frequently occur in patients with this illness and these potentially reversible lesions are often responsible for the patient's death. In the absence of specific therapy for the underlying disease, much of our therapeutic effort is aimed at preventing such complications or treating them as they occur. Infection, bleeding, renal failure, acute gastrointestinal ulceration, and pancreatitis are all Received June 24, 1971. Accepted July 22, 1971. Address reprint requests to: Dr. Burton Combes, Professor of Internal Medicine, Department of Internal Medicine, University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, Texas 75235. This study was supported in part by the United States Public Health Service Research Grant AM 13757 and Training Grant Ti AM 5490 from the National Institutes of Health. Dr. Combes is the recipient of Research Career Program Award 5-K3-AM-18,250 from the National Institutes of Health, United States Public Health Service. The authors are indebted to Mrs. Margaret Gignac for preparation of the manuscript.

well established sequelae of this syndrome. 1• 2 Less well recognized is the occurrence of cerebral edema and raised intracranial pressure. We have been impressed by the frequency with which this phenomenon has been present in our patients dying with massive necrosis of the liver and have reviewed the experience of this unit since 1958 with respect to the neuropathology of these patients.

Material The case records of 48 patients diagnosed as having massive hepatic necrosis at Parkland Memorial Hospital from 1958 through 1970 were available. The records of 5 patients with this diagnosis, seen at other Dallas hospitals during the same time period, were also included. The patients had all been seen in consultation by members of this unit. Twenty-nine of these patients have been reported previously' and the criteria for inclusion in this review were the same as were used at that time. Eight of the 53 cases survived the illness. Of the 45 who died, complete autopsies had been performed in 32 whereas autopsy material was not available in the remaining 13. Pertinent clinical and laboratory features were extracted from the case records and au-

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topsy protocols and the microscopic sections of autopsy specimens were reviewed.

Findings Cerebral edema was described in 16 of the 32 patients whose brains were examined at autopsy. This was manifested by flattening of the gyri with partial obliteration of the sulci, compression and narrowing of the lateral ventricles, and poor differentiation of white and gray matter on section. Herniation of the cerebellar tonsils through the foramen magnum was observed in 3 cases, 1 of whom also had uncal herniation. A 4th patient had developed uncal herniation alone. No focal cerebral lesions were found in any of the patients. In an attempt to assess the frequency with which cerebral edema is found in postmortem examinations, we reviewed the protocols of those patients whose autopsies were performed immediately before and after those of each of the 28 patients with massive hepatic necrosis carried out at this hospital. Those who died with a specific cerebral lesion were excluded from consideration. The mean age of these 56 patients was 61 years with a range of 5 to 90 years and 3 of them were noted to have cerebral edema. Since subsequent analysis of our data on patients with massive hepatic necrosis indicated that cerebral edema occurs more frequently in persons under 30 years of age (see below) a review of the autopsy records of an additional group of 35 patients below this age limit (mean age 19 years) who died of noncerebral causes between June 1968 and December 1969 was carried out. Of this group 2 were found to have cerebral edema. None of the control patients had evidence of herniation or coning. While we recognize the limitations of such retrospective analysis of autopsy records, these findings suggest to us that the high incidence of cerebral edema found in our patients with massive hepatic necrosis is related to the disorder and is not merely a reflection of a high frequency of this change in general autopsy material. They also suggest that variability in recognition of this complication by prosectors performing these exami-

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nations is an unlikely explanation for the frequency with which cerebral edema was found in patients with massive hepatic necrosis. Microscopic examination of the brain was not helpful in separating those patients with cerebral edema macroscopically from those not showing this change. Edema of the brain may be very difficult to demonstrate microscopically because of the dehydration produced in fixing the tissue. Large swollen glial cells were prominent in the gray matter in 14 patients, 5 of whom had macroscopic cerebral edema. Similar changes were observed in the white matter as well in 5 of these 14 cases, 4 of whom had edema macroscopically. The sections from the other patients were unremarkable except for one instance (in a patient with edema) where microscopic evidence of focal ischemic cortical necrosis was found. Comparison was made between those patients with, and those without, cerebral edema with regard to a number of clinical and biochemical features which might be anticipated to bear a causal relationship to the development of such edema (table 1). Four of these features were found to be distributed with statistically significant disparity between the two groups. Age (fig. 1). Cerebral edema was much more common in the young. Fourteen of 18 patients under 30 years of age demonstrated the change compared with 2 of 14 patients who were older than 30 years. The mean age of those with cerebral edema was 21 years (range 1 to 54), while the mean age of those patients without edema was 47 years (range 18 to 74). Duration of stage IV coma. Twelve of the 16 patients with cerebral edema remained in stage IV coma for more than 24 hr prior to death, compared with just 3 of 16 patients without cerebral edema. Nine of those with edema were in stage IV coma for more than 48 hr. The 3 patients without edema who had prolonged periods of deep coma remained in this state for 2, 4, and 13 days prior to death. Renal failure (fig. 2). Four patients with cerebral edema had a blood urea ni-

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TABLE 1. Incidence of clinical and biochemical features in patients dying of massive hepatic necrosis with and without cerebral edema Patients

with cerebral edema

Patients without

cerebral

Pvalue0

80

(/)

a:

edema

>-

4 12

•

< 0.001

--·-• ••

--~-4

12

13 3

< 0.002

..•

':

w z

14 2

••

70

~

Age

<30 yr >30 yr Duration of stage IV coma• < 24 hr >24 hr Blood urea nitrogen at death < 20 mg/100 ml 20 mg/100 ml or > Blood pH within 24 hr of death < 7.38 >7.44 Sex Male Female Cause of hepatic necrosis Viral hepatitis Halothane hepatitis Acute hemorrhage Present Absent Major infection Present Absent Terminal hypotension >2 hr < 2 hr Lowest blood sugar < 40 mg/ 100 ml > 40 mg/ 100 ml Lowest hemoglobin < 10 g/100 ml > 10 g/ 100 ml Peak bilirubin level < 20 mg/ 100 ml > 20 mg/ 100 ml Total days with encephalopathy <5 days >5 days Lowest serum sodium < 130 mEq/liter > 130 mEq/liter

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LNER PHYSIOLOGY AND DISEASE

•

• : : •

•

o~--L-------L----­

EDEMA

NO

EDEMA

12 4

3 10

< 0.002

2

6 0

< 0.05

4

5

5

11

11

NS<

14 2

12

5

3 13

NS

11

6 10

4

NS

12

NS

4

NS

7

7

9

9

2 14

3 13

NS

4

7 9

NS

12 6 10

6 10

NS

11

8 8

NS

5

3 13

8 8

NS

• Statistical analysis was performed using Fisher's exact probability test for small numbers, and where appropriate, x2 analysis. • Patient in deep coma, cannot be aroused. May or may not respond to noxious stimuli. Tremor absent. c NS, not significant statistically.

FIG. 1. Age of patients with massive hepatic necrosis.

trogen (BUN) greater than 20 mg per 100 ml at death. Ten patients without edema were azotemic. More definitive tests of renal function were not consistently available in these patients so we have probably underestimated the true incidence of renal insufficiency in patients dying with massive hepatic necrosis. Blood pH (fig. 3). Blood gas determinations were available m 14 patients within 24 hr of death. The blood pH in 5 of 7 patients with cerebral edema was normal or alkalotic. Two showed moderate acidosis (pH 7.34 and 7.27) and 1 of these had septicemia. The pH in 6 of 7 patients without edema was acidotic, severely so in 3 (pH < 7.15), 1 of whom had a serious infection. The other patient had a normal pH. No significant difference between the two groups was found with respect to sex distribution, the cause of the hepatic necrosis, the presence of acute hemorrhage, infection, hypotension, hypoglycemia, anemia, or the height of the serum bilirubin level. Many and varied forms of therapy were used in these patients, mcluding exchange transfusion, steroids, and peritoneal dialysis. There was no correlation between the use of any of these maneuvers and the presence or absence of cerebral edema (table 2). The need for artificial ventilation and vasopressors was also found to have been equal in the two groups of patients. A reasonably accurate assessment of fluid balance was possible in 11 patients

LIVER PHYSIOLOGY AND DISEASE

880 160 140 120 ~ 0 Cl

E

z :::)

80

.

60

•

100

ai

•

40

• • •

,

•

..•

20 0

NO EDEMA

FIG . 2. Blood urea nitrogen (B.U.N.) at death of patients with massive hepatic necrosis.

7.6

•

----~-----------• 7.3 • 7.2 • 7.1 •• 7. 0 '---"'-------'-7.5 7.4 ----·---------·---

..

EDEMA

NO

EDEMA FIG. 3. Blood pH within 24 hr of death of patients with massive hepatic necrosis.

with, and in 12 patients without, cerebral edema. The quantity of fluid given orally and intravenously, as well as urine and gastric drainage volumes, were recorded. Mean daily fluid intake for patients with cerebral edema over the final 4 days of illness was 2980 ml, whereas mean daily fluid output was 1760 ml. The mean value for positive fluid balance was 1240 ml per day. For patients without cerebral edema, mean daily fluid intake over the same time interval was 1930 ml, with a daily fluid output of 550 ml. Thus the mean daily positive fluid balance for the group was 1290 ml. These figures do not allow for insensible fluid loss nor for diarrheal losses when present and are thus an overestimate of the daily positive fluid balance. Nevertheless, fluid balance was similar in the two groups. It seems unlikely, therefore, that cerebral edema was the direct result of excessive fluid administration.

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Further evidence against this possibility was provided by the distribution of the findings of ascites and peripheral edema in these patients at autopsy. Ascitic fluid in excess of 200 ml was found in 6 and peripheral edema was noted in 4 patients with cerebral edema. Eight patients in this group had neither ascites nor peripheral edema. Nine of the patients without cerebral edema had ascites at autopsy while 6 were found to have peripheral edema. Only 4 of this group had neither sign of fluid accumulation. If fluid overload was responsible for cerebral edema a higher incidence of ascites and edema might be expected in patients with this complication. This was not the case. The following case reports illustrate the course followed by some of the patients with cerebral edema and underline some of the difficulties involved in diagnosing and treating this complication . Case 1-D. F. This 14-year-old Negro boy was admitted to Parkland Memorial Hospital on January 28, 1969 with a 5-day history of dark urine, light stools, icterus, and right upper quadrant discomfort. He had not been exposed to any drugs, blood tranfusions, or known cases of hepatitis. On admission he was febrile, alert, oriented, and icteric. His liver was tender and palpable 4 em below the right costal margin. Initial investigations included a serum bilirubin, 16.2 mg per 100 ml (6.8 mg per 100 ml direct); alkaline phosphatase, 61.5 King-Armstrong units; serum glutamic oxaloacetic transaminase (SGOT), 2400 Karmen units per ml ; hemoglobin 12.8 g per 100 ml, white blood count (WBC) , 5150 (11 ~ ;, atypical lymphocytes). His prothrombin time was 13 sec (control of 11 sec). The BUN, electrolytes, glucose, TABLE

2. Th erapy in 32 patients with massive hepatic necrosis No Ex- Peri to· Asspe- Stechange n eal Vasopres- sisted cific roids transfu d ia lrespi thersion ysis sors ration apy

With edema Without edema .

cerebral 4

9

2

3

8

7

6

6

1

2

6

4

cerebral

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LNER PHYSIOLOGY AND DISEASE

serum proteins, and urinalysis were normal. A glucose 6-phosphate dehydrogenase assay showed red cell deficiency of this enzyme. Four days after admission he developed pruritus and this, with his abdominal discomfort, remained his only symptom over the next 2 weeks. During this time his bilirubin rose to a peak of 34 mg per 100 ml, the alkaline phosphatase remained >50 K.A. units, the SGOT was > 4000 Karmen units per ml, and the prothrombin time gradually increased, despite parenteral vitamin K, to 20 sec. On February 11, he became drowsy and lethargic and by the 13th manifested an obvious flapping tremor. Despite the institution of cleansing enemata, oral neomycin, and intravenous glucose infusions, the encephalopathy progressed to hallucinations, delerium, and agitation. Persistent vomiting and abdominal cramps developed. His urine output was adequate throughout the illness and the BUN and electrolytes remained within normal limits. On the 18th of February his agitation had subsided, he was lethargic and disoriented, but not in deep coma. He died suddenly the next day without further preceding deterioration. At autopsy the liver weighed 550 g and demonstrated the changes of massive hepatic necrosis. The brain weighed 1450 g. It was markedly edematous and showed uncal herniation. Microscopically there were large swollen glial cells in both the white and gray matter. Apart from patchy bronchopneumonia, edema of the right colon, and hyperplasia of the lymph nodes, the rest of the examination was unremarkable. Case 2-D. W. This 18-year-old Caucasian girl was admitted to Parkland Memorial Hospital on June 12th, 1970 with a 4day history of fever, malaise, nausea, vomiting, dark urine, and jaundice. On the day of admission she was found to be drowsy, confused, and ataxic. Five weeks prior to admission she had received prophylactic ')'-globulin when her boyfriend developed uncomplicated hepatitis. She had been sharing a needle with him for self-administration of amphetamine prior

881

to this time. Examination revealed mild icterus fever, somnolence, and disorientation, but no focal neurological signs. Her pupils and fundi were thought to be normal. The bilirubin was 6.0 mg per 100 ml, the SGOT > 3000 U per ml, the prothrombin time 62 sec, and the WBC 10,600. The hemoglobin, blood glucose, BUN, and electrolytes were normal. Soon after admission she had a grand mal seizure and remained thereafter in deep coma with decerebrate opisthotonic movements in response to painful stimuli. At lumbar puncture, the opening pressure was 140 mm of saline and the fluid was normal in all respects. She was begun on a regimen of protein exclusion, enemata, intravenous fluids, and neomycin. On the following day her clinical status was unchanged but her discs were felt to show early papilledema. Repeat lumbar puncture revealed a pressure > 300 mm of saline. She was given an infusion of 25 g of mannitol which produced a brisk diuresis. Her clinical state remained unchanged although the swelling of her optic discs was felt to be diminished. On the 2nd hospital day she suffered a sudden respiratory arrest and her pupils became fixed and dilated. She was supported with assisted ventilation for a further 24 hr and pronounced dead on the 3rd hospital day. At autopsy the liver weighed 600 g and showed changes typical of massive hepatic necrosis. The brain weighed 1460 g and was markedly edematous. There was herniation and acute hemorrhagic necrosis of the cerebellar tonsils. Microscopic examination showed typical swollen astrocytes in both gray and white matter. Case 3-M. S. This 23-year-old Caucasian woman was admitted to the Presbyterian Hospital of Dallas on November 15th, 1970, unresponsive and icteri c. She had been discharged from the same hospital in September 1970 following an episode diagnosed as serum hepatitis thought to have been contracted by self-administration of drugs. Her follow-up visits had shown progressive improvement in ~er liver function tests and she had felt qmte well when last seen 3 weeks prior to her final admission. Increasing malaise, nau-

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LNER PHYSIOLOGY AND DISEASE

sea, recurrence of icterus, and confusion had developed in the few days before her return to the hospital. Physical examination on admission revealed a stuporous icteric woman with no focal neurological signs. Her liver and spleen were impalpable. Initial laboratory studies included: BUN, 3 mg per 100 ml ; bilirubin, 23 mg per 100 ml ; alkaline phosphatase, 4 Bodansky units; SGOT, 890 U per ml ; prothrombin time, 40 sec ; hemoglobin, 12.0 g per 100 ml; WBC, 9500; and normal electrolytes. She was started on a standard precoma regimen, including intravenous fluids, cleansing enemata, and oral neomycin. By November 17th she was in stage IV coma, flaccid, with bilateral plantar extensor responses. At lumbar puncture the cerebrospinal fluid ( CSF) pressure was recorded as greater than 300 mm of saline. Steroids were begun with 4 mg of Decadron intramuscularly every 4 hr. Mannitol infusions of 37.5 to 50 g intravenously every 4 hr were instituted together with 40 mg of furosemide daily. A brisk diuresis ensued and was maintained with a urinary output between 3 and 4 liters per day. Restriction of fluid replacement permitted an initial negative fluid balance of about 1500 ml in the first 36 hr. Subsequently, input and output of fluids were maintained equivalently. Despite this therapy, her condition remained unchanged over the next 2 days when papilledema was observed and her pupils became fixed and dilated. The bilirubin was 30 mg per 100 ml and the prothrombin time 54 sec. Grand mal seizures were observed and required intravenous Valium for partial control. For the last 12 hr of her life she required automatic assisted ventilation and her blood pressure was maintained only with an Aramine infusion. At autopsy the brain weighed 1540 g and showed marked cerebral edema with no evidence of herniation. The liver showed typical changes of massive hepatic necrosis. The examination was otherwise unremarkable.

Discussion Cerebral edema has seldom been men-

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tioned in previous papers detailing experience with massive hepatic necrosis. '· a- 7 Walshe, 8 reviewing the literature in 1951, stressed the normal macroscopic appearance of the brain in previous reports and specifically noted the absence of signs of raised intracranial pressure in the 10 new cases he described at that time. Lucke 9 gives passing reference to the occurrence of cerebral edema in some of the patients he described and, more recently, Pirola et al. 10 have drawn attention to its possible significance in precipitating death in patients with massive hepatic necrosis. Our experience not only supports this concept but in addition indicates that cerebra.! edema is more commonly found in such patients than was previously thought. It was probably an immediate cause of death in 4 of our patients and was present in half of those coming to autopsy. To what extent raised intracranial pressure influenced the neurological state of these other patients cannot be determined . However it is tempting to believe that a high intracranial pressure would augment the depression of cerebral function induced by encephalopathy alone. The premorbid diagnosis of cerebral edema in patients with acute liver failure is extremely difficult. Patients in stage IV hepatic coma, without cerebral edema, may manifest many of the physical signs generally associated with raised intracranial pressure. Walshe 8 has stressed the dilated pupils, the brisk deep tendon reflexes, the clonus and extensor plantar responses frequently seen in such patients. The development of papilledema or the loss of retinal venous pulsations are more definitive signs of cerebral hypertension. These were noted in only 2 of our patients but careful repeated neurological examinations of these comatose patients were not recorded and it is likely that these signs were more frequently present than observed. Measurement of the cerebrospinal fluid pressure at lumbar puncture would seem to be both a dangerous" and unreliable 12 way to confirm the presence of a high intracranial pressure. In 1 of our patients (case 2) the rise in CSF pressure readings over 24 hr did suggest the diag-

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LIVER PHYSIOLOGY AND DISEASE

nosis but the herniation and necrosis of her cerebellar tonsils, seen at autopsy, may have been the price of the knowledge the procedure afforded. Another patient, not subject to autopsy, suffered a respiratory arrest while lumbar puncture was being attempted. In the absence of a safe definitive means of diagnosis, and because of the frequency with which this association was found, a low threshold of suspicion for the development of cerebral edema should be maintained in all patients with massive hepatic necrosis. Perhaps frequent, careful neurological examination of these patients will result in a higher yield of premorbid diagnosis. Having made the diagnosis, our means of dealing with this complication are few and of uncertain value. Large doses of steroids have been found effective in reducing the raised intracranial pressure associated with cerebral neoplasms. 13 A number of authors have suggested that steroids may also be of therapeutic value in massive hepatic necrosis. •. 6 If this should prove to be true, then conceivably, one way in which this benefit might be mediated may be through a reduction of cerebral edema. The other commonly used means of reducing raised intracranial pressure is with osmotic diuretics such as mannitol or urea 13 • 14 • 15 usually coupled with furosemide. This therapy is thought to be of value in the short term only. The use of such agents would be limited in patients with massive hepatic necrosis by the presence of renal impairment, but they may be of value if renal function is adequate. Because of the risks of hemorrhage and infection a surgical approach aimed at cerebral decompression would seem to be out of the question in these gravely ill patients. In 1 of our patients (case 3) an attempt was made to treat this complication of her acute liver failure. Large doses of steroids, intravenous infusions of Mannitol every 4 hr, and daily injections of Furosemide resulted in a sustained diuresis. The patient remained in deep coma however and at autopsy was found to have marked cerebral edema. It would seem that, in this 1 patient at least, intensive therapy was without effect.

883

The pathogenesis of cerebral edema in these patients is unclear. The lack of association with other major complications of massive hepatic necrosis such as shock, infection, and hemorrhage suggests that it bears a direct relationship to the acute liver injury, and is not simply the result of anoxic cerebral damage consequent to one of these other factors . Nevertheless, it seems likely that cerebral hypoxia plays some role in its genesis. Cerebral blood flow and oxygen consumption are depressed in hepatic encephalopathy, and, in general, there is a progressive fall in oxygen consumption with increasing neurological impairment! 6 • 17 • 19 To what extent these changes are the result of prolonged hyperventilation with respiratory alkalosis or to toxins, such as ammonia, present in the blood of patients with severe liver damage is not clear. In the absence of measurements of such parameters in our patients, it is not possible to state whether the presence of cerebral edema correlates with the extent of depression of cerebral oxygen consumption. Such an analysis must await further study. Acidosis and renal failure were infrequently present in patients with cerebral edema but were commonly found in patients without cerebral edema. This may indicate that death in patients with edema was precipitated before these complications could ensue, or else that factors present in acidosis and uremia protect against the development of cerebral edema. The association between edema and a prolonged period of stage IV coma is consistent with either a causal or resultant relationship. At this time we can only speculate as to what these associations mean. Whatever the cause, in our experience, cerebral edema does occur frequently in patients with massive hepatic necrosis and in 4 of our patients it was probably an immediate cause of death. An attempt to prevent these deaths by the premorbid diagnosis and therapy of this complication is obviously warranted. Whether or not such therapy as is currently available will be effective in reducing cerebral edema and whether this will improve the mortality rate of this grave illness remains to be shown.

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LNER PHYSIOLOGY AND DISEASE REFERENCES

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10:898-903, 1969 11. Munro D, Sisson WR: Hernia through the incisura of the tentorium cerebelli in connection with craniocerebral trauma. New Eng J Med 247 :699708, 1952 12. Kaufman GE, Clark K : Continuous simultaneous monitoring of intraventricular and cerevical subarachnoid cerebrospinal fluid pressure to indicate development of cerebral or tonsillar herniation. J Neurosurg 33:145-150, 1970 13. Phillipon J , Guyot JF: Donnees actuelles sur l'oedeme cerebral. II. Aspects therapeutiques. Presse Med 76:2393-2194, 1968 14. Eiben RM : Acute brain swelling (toxic encephalopathy) . Pediat Clin N Amer 14:797-808, 1967 15. Shenkin HA, Bouzarth WF: Methods of reducing intracranial pressure: role of cerebral circulation. New Eng J Med 282 :1465-1471, 1970 16. Fazekas JP, Ticktin HE, Ehrmantraut WR, et a! : Cerebral metabolism in hepatic insufficiency. Amer J Med 21:843-849, 1956 17. Posner JB, Plum F : The toxic effects of carbon dioxide and acetazolamide in hepatic encephalopathy. J Clin Invest 39:1246-1258, 1960 18. James IM , Nashat S, Sampson D, et a!: Effects of induced metabolic alkalosis in hepatic encephalopathy. Lancet (ii) 1106-1108, 1969 19. Polli E, Poro GB, Maiolo AT: Cerebral metabolism after portacaval shunt. Lancet 1:153, 1969