Journal of Hepatology 41 (2004) 89–96 www.elsevier.com/locate/jhep
Prophylactic phenytoin does not improve cerebral edema or survival in acute liver failure—a controlled clinical trial Vikram Bhatia, Yogesh Batra, Subrat Kumar Acharya* Department of Gastroenterology, All India Institute of Medical Sciences, Room No 3065, 3rd floor, teaching Block, New Delhi 110029, India
See Editorial, pages 152 –155
Background/Aims: Seizure activity in patients with acute liver failure (ALF) may increase cerebral oxygen requirements and worsen cerebral edema. Recently, prophylactic phenytoin has been recommended to suppress subclinical seizure activity evident on electroencephalographic monitoring. To determine the clinical utility of prophylactic phenytoin therapy in patients with ALF. Methods: Forty two patients with ALF were randomized. Twenty two patients were given prophylactic phenytoin and 22 patients acted as controls. The baseline clinical and biochemical features were similar in the two groups and patients with $ 2 poor prognostic variables were equally represented. Results: Sixteen patients in the phenytoin group, and 15 in the control group developed cerebral edema (P 5 0.38). Mechanical ventilation was required in 10 and 12 patients in the phenytoin and control groups, respectively, (P 5 0.77). Seizures occurred in 5 (22.7%) control patients and 5 (25%) phenytoin treated patients (P 5 0.86). Fourteen (70%) patients randomized to phenytoin and 15 (68.2%) control patients died (P 5 0.89). Conclusions: Seizure was common in patients with ALF. Prophylactic use of phenytoin did not prevent cerebral edema, seizures or need for mechanical ventilation, and did not improve survival. q 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Acute liver failure; Seizure; Phenytoin
1. Introduction Ammonia intoxication in experimental animals and patients with congenital hyperammonemic syndromes manifests with a hyperkinetic state, seizures and coma [1]. High ammonia levels and neurotransmitter alterations have been documented among patients with acute liver failure (ALF) [2,3]. In addition cerebral edema is a common complication. Therefore seizures would be commonly expected to occur in such patients. However the frequency of occurrence of seizures among patients with ALF, and their significance has not been adequately addressed. Indeed Blei in a recent editorial in Hepatology commented that ‘it is puzzling that overt seizures (in ALF) are so seldom observed’ [4]. Received 17 July 2003; received in revised form 16 March 2004; accepted 26 March 2004; available online 15 April 2004 * Corresponding author. Tel.: þ 91-11-265-93-627. E-mail address:
[email protected] (S.K. Acharya).
The true frequency of seizures in ALF patients is probably grossly underestimated due to early transplantation. Furthermore, many of the clinical signs of seizure activity may be masked by the use of sedatives or agents to induce neuromuscular paralysis among patients with ALF on mechanical ventilation. Seizures whether overt or subclinical, are likely to increase cerebral oxygen requirements and aggravate intracranial hypertension. Recently, Ellis et al. used bedside electroencephalographic (EEG) monitoring and recorded sub-clinical seizure activity in 13 (31%) out of 42 patients with ALF. All these patients were paralyzed and were on mechanical ventilation. On discontinuing paralysis in a subset of patients, tonic – clonic movements were documented [5]. The authors suggested that sub-clinical seizure activity might be common and unrecognized in these patients, and prophylactic use of anticonvulsant therapy was recommended in all comatose patients with ALF [5]. Transplant facilities are not yet available at our center,
0168-8278/$30.00 q 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2004.03.017
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and patients with ALF are managed conservatively till recovery or death. We have frequently observed seizures among our patients with ALF having cerebral edema which was associated with a uniformly poor outcome. Therefore the present study was designed to study the effect of prophylactic phenytoin administration on clinically relevant parameters, namely: cerebral edema, need for mechanical ventilation, clinical seizure activity, grade of encephalopathy, and survival.
2. Patients and study variables 2.1. Patients During March 2001 to July 2002, patients diagnosed as ALF and admitted to the Gastroenterology ward of the All India Institute of Medical Sciences (AIIMS), New Delhi were included in the study. ALF was diagnosed according to the International Association for the Study of Liver (IASL) criteria [6]. Patients in whom the diagnosis of ALF was not certain and patients whose nearest relative did not consent for inclusion in the study protocol were excluded.
2.2. Study variables ALF was defined by the occurrence of encephalopathy within 4 weeks of onset of symptoms in the absence of pre-existing liver disease [6,7]. The diagnosis was confirmed by the presence of sub-massive or massive necrosis in the postmortem liver biopsy specimen in patients who died. Pre-encephalopathy (PE) and icterus-encephalopathy (IE) periods were defined as the interval from the onset of prodrome and jaundice, respectively, to the onset of hepatic encephalopathy [7]. Admission to death interval was defined as the time interval from admission to death among the non-survivors. Grading of encephalopathy was done as follows [7,8]: Grade 1: Loss of sleep rhythm, drowsiness, confusion and flapping tremors. Grade 2: Features of grade 1 encephalopathy with loss of sphincter control in addition. Grade 3: Unconsciousness with no response to oral commands, but responding to painful stimuli. Grade 4: Deep unconscious state, with no response to pain. Cerebral edema was defined clinically by the presence of spontaneous or inducible decerebrate posturing, or by the presence of any two of: hypertension (BP $ 150/90 mmHg), bradycardia, pupillary changes or neurogenic hyperventilation [7,9]. Adverse prognostic factors. The following four prognostic factors were noted at admission [7]: 1. 2. 3. 4.
Age $ 40 years Clinical evidence of cerebral edema at admission Serum bilirubin $15 mg/dl, and Prothrombin time (PT) prolongation by $25 s over controls
At our center the presence of one, two and three or more of these adverse prognostic makers have been documented to predict a 56.1, 80.9 and 93% mortality rate, respectively [7]. Cause of death. The immediate antecedent event occurring within 12 h of death, in the absence of any other possible factor that could cause a fatal outcome, was considered as the cause of death.
3. Methods All patients were admitted in the Gastroenterology intensive care unit (ICU). History was obtained from the attendants of the patient and a detailed clinical examination was performed at admission. All patients were subsequently clinically evaluated 2 hourly by the ICU resident and had continuous, non-invasive cardiac, oxygen saturation and blood pressure monitoring. Baseline blood biochemistry and hemogram was obtained. Blood sugar was checked at least 2 hourly. Neurological assessment was done once daily and on any sign of deterioration. The parameters noted were: grade of coma, presence of spontaneous or induced decerebration, pupillary size and reaction, presence of any focal neurological deficit. The distribution of tonic –clonic jerking in patients with seizures and any other involuntary movement was noted. Blood glucose, serum sodium, blood urea, and serum creatinine were estimated 12 hourly. Daily microbiological surveillance was also done with cultures of all body fluids. Viral markers. Serum sample from each patient was tested for hepatitis B surface antigen (HBsAg), IgM antibody against hepatitis B core antigen (IgM anti-HBc), and IgM antibody against hepatitis A virus (IgM anti-HAV) using commercial immunosorbent assay (ELISA) test kits (Organon, Teknika, The Netherlands). IgM antibody to ORF-1, ORF-2 and ORF-3 of hepatitis E virus (HEV) and HEV RNA were tested by methods developed at our institute [10,11]. Anti-hepatitis C (HCV) antibody was tested by using a 3rd generation, in-house ELISA method [11]. HCV-RNA was tested by reverse transcription nested polymerase chain reaction, using primers from the 50 nontranslated region, if appropriate by methods already described [12]. Ammonia estimation. Arterial ammonia was estimated within 24 h of admission by enzymatic method (Randox Lab Ltd, UK) based on its reaction with a-oxoglutarate in the presence of glutamate dehydrogenase. 3.1. Treatment schedule Standard treatment protocol included prophylactic parenteral antibiotics (cefotaxime and cloxacillin), stress ulcer prophylaxis with intravenous ranitidine, inotropic support with dopamine and/or nor-adrenaline with an aim to maintain mean arterial pressure (MAP) at more than 60 mmHg. Elective ventilation was used for all patients in grade 4 coma and those in grade 3 coma with evidence of cerebral edema. Sedation or long acting muscle-paralyzing agents were not used in any patient. Cerebral edema was managed conservatively by mannitol given as bolus infusions in a dose of 0.5 –1.0 g/kg body weight as a 20% solution. Seizures were managed by diazepam and additional mannitol bolus. Subsequently phenytoin was initiated in those who were in the control group.
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3.2. Randomization
4.1. Clinical and biochemical profile
Based on the number of adverse prognostic factors present at admission, patients were divided into the following two groups:
The age of the included patients ranged from 14 to 70 years with a mean (SD) age of 27.2 (10.8) years. There were 29 females and 13 males. Of the 29 females, 12 (41.4%) were pregnant. The pre-encephalopathy interval was 2 – 25 days with a mean (SD) of 9.3 (6.7) days. The icterusencephalopathy interval was 0– 25 days with a mean (SD) of 6.4 (6.5) days. Prothrombin time at admission was prolonged by 2– 48 s, with a mean (SD) of 27.6 (15.4) s, while bilirubin level varied from 5.3 to 42 mg/dl with a mean (SD) of 16.5 (8.0) mg/dl. The alanine aminotransferase (ALT) levels at admission ranged from 175 to 4640 IU/l with a mean (SD) level of 1074.7 (864.3) IU/l. The mean (SD) values of serum creatinine, sodium, glucose, and oxygen saturation among all patients were 0.7 (0.5) mg/dl, 135.2 (20.5) mmol/l, 243.0 (152.3) mg/dl and 97.5 (2.0)%, respectively, at admission. The MAP was 57.2 (9.9) mmHg. Arterial ammonia levels were estimated within 24 h of admission in 25 patients and varied from 30.2 to 798 mmol/l with a mean (SD) of 274.2 (228.5) mmol/l and 95% confidence interval (CI) of 228.5 –319.9 mmol/l. At admission 10, 7 and 25 patients were in grade 2, 3 and 4 encephalopathy, respectively. Over initial 72 h only 11 patients improved to a lesser coma grade while in the remaining 31 the severity of encephalopathy remained unchanged or worsened. Twenty two patients (52.4%) had clinical evidence of cerebral edema at admission, and another 9 patients developed overt features of cerebral edema after hospitalization. No patient developed renal failure in this study.
Group I: One or no adverse prognostic factors. Group II: Two or more adverse prognostic factors. Patients in each of the above two groups were then randomized (stratified randomization) by means of a computer generated random number list to receive either prophylactic phenytoin therapy in addition to the standard therapy (regime A) or standard treatment alone (regime B). The dose of phenytoin used was 15 mg/kg infusion in saline initially at a rate no more than 50 mg/minute, followed by 100 mg intravenous doses at 8 hourly intervals for a duration of 3 days or death. 3.3. Outcome measures The primary outcome measure compared between patients receiving regimen A and regimen B was survival, and the secondary outcome measures were: a change in the grade of coma, prevention or a reduction of overt clinical features of cerebral edema, need for mechanical ventilation and the occurrence of seizures 3.4. End points 1. Completion of 3 days of treatment 2. Death 3.5. Analysis All clinical data were analyzed using the SPSS software for windows (version 7.5). All variables were expressed as mean (SD). Qualitative variables were compared between patients randomized to phenytoin and controls using the x2 test. Quantitative variables were compared using the student’s t-test. All P values were two sided and the level of significance was set at P ¼ 0:05: The study was designed to conform to the revised consort guidelines for randomized trials.
4. Results During the study period 47 patients with a diagnosis of ALF were evaluated for inclusion in the study. For 5 patients consent could not be obtained for treatment as per the study protocol. The remaining 42 patients were included in the study for the purpose of therapeutic trial.
4.2. Overall outcome Infection (diagnosed clinically, radiologically or on cultures) developed in 30 (71.4%) patients within the initial 72 h. Ten (23.8%) patients developed overt clinical seizures and all of them succumbed to their illness despite therapy. Mechanical ventilation was required in 22 (52.4%) patients. Of them, only one patient survived. The overall mortality rate was 69% (29/42). One or no poor prognostic variable was present in 22 patients, while 20 patients had two or more poor prognostic variables. These previously validated prognostic parameters were found to be predictive of outcome. Of the former group, only 11 (50%) died compared to 18 (90%) patients from the latter group ðP ¼ 0:01Þ: Because of randomized stratification, these two groups of patients with different prognostic variables were equally represented in the phenytoin treated and control groups (Table 1), thus eliminating any confounding influence on the outcome. Thirty one patients had cerebral edema at admission. Of them, 26 (83.9%) died. Eleven patients did not have cerebral edema at admission. Of them 3 (27.3%) died. This difference was highly significant ðP ¼ 0:00Þ: Presence of cerebral edema is one of the
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Table 1 Comparison of demographic, clinical and biochemical features of the two randomized groups Parameter
Group I: phenytoin Rx ðn ¼ 20Þ
Group II: controls ðn ¼ 22Þ
P-value
Age (years) Mean (SD) Median Range
25.6 (8.6) 25 14–44
28.6 (12.5) 25 15– 70
0.36
Sex Male Female
7 13
6 16
0.75
Pregnancy
6
6
PE interval (days) Mean (SD) Median Range
10.5 (7.0) 7.0 2–25
8.4 (6.3) 5.5 2–20
0.32
IE interval (days) Mean (SD) Median Range
7.5 (7.6) 3.5 0–25
5.4 (5.5) 3.0 0–20
0.31
Poor prognostic variables 0, 1 2, 3, 4
11 9
11 11
0.75
Coma grade at admission Grade 2 Grade 3 Grade 4
4 4 12
6 3 13
0.78
Cerebral edema at admission
12
10
0.35
Virologic markers IgM-anti HAV IgM-antiHBc IgM-anti HEV Isolated HBsAg Anti-HCV All markers negative
0 1 9 2 2 1
0 0 11 4 1 1
0.82 0.71 0.62 0.37
Bilirubin (mg/dl) Mean (SD) Median Range
15.9 (7.4) 14.9 5.3–35.8
17 (8.9) 15.0 6.7– 42
0.66
PT prolongation (s) Mean (SD) Median Range
28 (15.2) 24.5 2–48
27.2 (16) 26.1 4–60
0.87
Urea (mg/dl) Mean (SD) Median Range
18.6 (13.3) 14.0 12–70
22.7 (17.3) 14.0 14– 93
0.41
ALT (IU/l) Mean (SD) Median Range
1070.9 (1057.3) 734.5 245–4640
1078.5 (644.4) 938 175– 2505
0.98
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Table 1 (continued) Parameter
Group I: phenytoin Rx ðn ¼ 20Þ
Group II: controls ðn ¼ 22Þ
P-value
Albumin (mg/dl) Mean (SD) Median Range
2.8 (0.6) 2.7 2.0–3.5
2.6 (0.7) 2.5 1.3–4.4
0.46
Arterial ammonia (mmol/l) Mean (SD) Median Range
320.9 (217.3) 284.7 30.2–798
174.9 (248.8) 58.5 32.6 – 735
0.12
Serum sodium (mmol/l) Mean (SD) Median Range
139.6 (7.5) 139.0 123.0–158.0
136.6 (6.8) 136.0 124.0– 151.0
0.19
Serum creatinine (mg/dl) Mean (SD) Median Range
0.7 (0.3) 0.6 0.3–1.2
0.7 (0.6) 0.5 0.4–2.7
0.82
Blood glucose (mg/dl) Mean (SD) Median Range
238.6 (150.7) 159.5 102.0–481.0
246.7 (159.2) 198.5 86–582
0.90
Mean arterial pressure (mmHg) Mean (SD) Median Range
54.1 (8.6) 54.8 31.7–68.3
60.0 (10.4) 59.0 36.7–80.5
0.06
Oxygen saturation (%) Mean (SD) Median Range
97.1 (2.4) 97.6 90.6–99.9
97.9 (1.5) 98.4 94.0–99.9
0.25
validated poor prognostic variables among our patients with ALF. The admission-to-death interval ranged from 1 to 20 days with a mean (SD) of 6.0 (4.7) days. Twenty-one of the 29 patients who died had a postmortem liver biopsy, and in all of them the histological features were suggestive of acute hepatitis with massive or sub-massive necrosis. Patients with $ 2 poor prognostic signs at admission have a predicted mortality of 80% in our setting and would be the candidates for transplantation. In the phenytoin treated group 9 of 20 patients met transplant criteria of whom 7 died. In the control group 11 of 22 patients met transplant criteria of whom all 11 died. Thus the proportion of patients who met the criteria for transplantation and their mortality was similar in both the groups (P ¼ 0:99 and 0.19, respectively). Liver transplantation facilities were however unavailable, and all the patients were managed conservatively till recovery or demise. An etiological evaluation was available in 33 patients. HEV infection was found in 20 (47.6%) and acute HBV
infection in 2 (4.8%) patients. Presence of isolated HBsAg and Anti-HCV antibodies were detected in 6 (14.3%) and 3 (7.1%) patients, respectively. All available markers were negative in 9 (27.3%) patients. None of the patients had a history suggestive of drug toxicity, mushroom poisoning or alcohol use. Hence the study group was etiologically homogenous. Twenty patients were randomized to phenytoin therapy and 22 patients served as controls (Fig. 1). At the time of enrollment into the trial, the two groups were matched with respect to age, sex, pre-encephalopathy and icterusencephalopathy intervals, blood biochemistry, arterial ammonia levels, etiology, coma grade at admission and presence or absence of cerebral edema at admission (Table 1) Need for mechanical ventilation. Elective mechanical ventilation was instituted in 10 (50%) phenytoin treated patients and 12 (54.6%) control patients ðP ¼ 0:77Þ: Occurrence of seizures. Clinical seizures occurred in 5 (25%) patients who were already on phenytoin and in 5
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Fig. 1. Patient progress through the trial.
(22.7%) controls ðP ¼ 0:86Þ: Focal seizures did not occur in any patient, and none had any focal neurological deficit on evaluation in the interictal period. All the patients who developed seizures ðn ¼ 10Þ died. At admission, cerebral edema was present in 9 of the 10 patients who developed seizures, and in 22 of the 32 patients who did not ðP ¼ 0:25Þ: Among the former 10 patients who developed seizures, 9 were admitted in grade 3 or 4 coma, while 23 of the latter 32 patients who did not develop seizures were in grade 3 or 4 coma at admission ðP ¼ 0:40Þ: Hence the proportion of patients presenting with cerebral edema and deeper coma grades was similar among those who developed seizures and those who did not. Occurrence of cerebral edema. At presentation 12 (60%) patients in the phenytoin treated group and 10 (56%) in the control group had cerebral edema ðP ¼ 0:35Þ: Four of 8 (50%) patients without cerebral edema receiving phenytoin and 5 of 12 (45%) patients without cerebral edema among controls developed cerebral edema during their illness. Therefore phenytoin use did not avert the subsequent development of cerebral edema. Change in the grade of coma. The depth of coma remained unchanged or worsened during initial 72 h of hospitalization in 16 and 15 patients in the phenytoin treated
and control groups, respectively. Improvement was seen in only 4 phenytoin treated patients and 7 control patients ðP ¼ 0:55Þ: Mortality. The mortality rate among phenytoin treated patients was 70% (14/20) compared to 68.2% (15/22) in control patients ðP ¼ 0:89Þ: The time interval from admission to death was also similar, being 4.9 (SD 3.0) days and 7.1 (SD 5.8) days in phenytoin treated and control groups, respectively, ðP ¼ 0:21Þ: The above outcome measures are summarized in Table 2.
5. Discussion The present study attempted to evaluate the clinical utility of prophylactic anti seizure therapy in the management of patients with ALF. As liver transplantation was not available to interrupt the course of the illness, the effect of such an intervention on mortality could be objectively studied. None of our patients was paralyzed or on regular sedation. Bedside EEG monitoring was not available and neuroimaging was not possible in these very ill patients. However seizures in these patients never had a focal onset,
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Table 2 Comparison of outcome of the two groups Outcome parameter
Group I: phenytoin Rx ðn ¼ 20Þ
Group II: controls ðn ¼ 22Þ
P-value
Need for ventilation Clinical seizures D Comaa Cerebral edema D Cerebral edemab Mortality Admission to death (days)
10 (50%) 5 (25%) 4 16 (80%) 3 14 (70%) 4.9 (SD 3)
12 (54.6%) 5 (22.7%) 7 15 (68.2%) 8 15 (68.2%) 7.1 (SD 5.8)
0.77 0.86 0.55 0.38 0.15 0.89 0.21
a b
Improvement in coma grade over initial 72 h. Resolution of cerebral edema over initial 72 h.
and focal neurological deficit was not documented in any patient during the interictal period. Phenytoin use did not influence the development or resolution of cerebral edema among those admitted without cerebral edema. Hence phenytoin is unlikely to have controlled sub-clinical seizures if they are a major contributing factor for development of cerebral edema. This fact is further supported by the fact that intravenous phenytoin did not influence overt seizure activity as well (Table 2). Interestingly, cerebral edema and grade 3 or 4 encephalopathy was present at admission in a similar proportion of patients who later developed seizures and those who did not. Hence the likelihood of seizures could not be predicted when the patient presented. However all patients who developed seizures had overt cerebral edema, and all died within 24 h of seizure onset despite intensive therapy. There could have been other variables including renal failure, hyponatremia, hypoglycemia, hypoxemia, low MAP or drug toxicity that might aggravate cerebral edema and seizures and mask any beneficial effect of phenytoin. However none of our patients had renal failure. As described previously renal failure among our patients with ALF is infrequent [7]. These above parameters were similar between both the groups and were closely monitored and corrected energetically and quickly. The potential for neurotoxic side effects of cloxacillin and ranitidine increase only in the presence of advanced renal failure and acute hepatic dysfunction does not effect the pharmacokinetic or pharmacodynamics of these drugs [13 – 15]. We could not find any reported case of suspected or proved neurotoxicity related to cloxacillin use in the literature. In addition both these drugs were used in all the patients in both arms thus removing any confounding variable. One notable feature of the seizures was their recalcitrance. Repeated doses of diazepam were required for initial seizure control. Patients in the control group who developed seizures were also initiated on phenytoin. Oxygen saturation, blood glucose and electrolytes were rechecked in all patients who developed seizures. Five patients each in the control group and phenytoin group developed seizures.
Furthermore, phenytoin was also found ineffective for treating seizures once they occurred. We did not find prophylactic phenytoin therapy to be useful in preventing the development of cerebral edema, need for mechanical ventilation or deterioration in coma grade. Fourteen patients who were randomized to phenytoin therapy died compared to 15 control patients ðP ¼ 0:89Þ: The time interval from admission to death was also similar. Hence no reduction in the mortality rate was achieved with phenytoin use. It can be argued that the majority of patients in this study had florid cerebral edema and advanced encephalopathy at admission and hence phenytoin use might have been ‘too late’ to alter the outcome. However this fact underscores the point that most patients with ALF in our country present late to the hospital and phenytoin is not useful for them. The question whether earlier use could be helpful remains unanswered but seems unlikely. The data available for seizure activity in ALF is surprisingly sparse in the world literature [4,16 – 21] although an increase in seizure activity may be expected in this hyperammonemic state. We found that the arterial ammonia levels are markedly elevated in all patients with ALF at admission with the mean level around 6 times higher than the upper limit of normal. However we could not demonstrate any difference in the arterial ammonia levels between those who developed seizures and those who did not, possibly because of inadequate patient numbers. Ellis et al. reported in an uncontrolled study that subclinical seizure activity reduced from 32% among controls to 15% among phenytoin treated patients—a difference which was not significant. Pupillary abnormalities and/or raised ICP were however seen less frequently in the phenytoin treated group. There was no reduction in mortality. Since a number of patients were transplanted it is difficult to draw conclusions about the actual impact of phenytoin treatment from this study [5]. Recommendations for routine electroencephalographic monitoring of comatose ALF patients and prophylactic phenytoin use have appeared in standard Hepatology textbooks subsequent to this study [22,23]. However unless overt benefit in the form of prevention of cerebral edema and improvement in survival is clearly documented with prophylactic phenytoin use, its effect on
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sub-clinical seizure activity or amelioration of cerebral edema in autopsy studies may not be clinically relevant. We conclude that prophylactic anti seizure therapy does not alter the outcome of patients with ALF and should not be used routinely in comatose patients. It does not prevent cerebral edema and mortality, because seizures occur in the setting of advanced cerebral edema, rather than the reverse. Future therapies should be directed at optimizing the treatment of cerebral edema, thereby preventing seizures. Further larger trials in this direction are warranted.
[11]
[12]
[13] [14]
References [15] [1] Flannery DB, Hsia YE, Wolf B. Current status of hyperammonia syndromes. Hepatology 1982;2:495–506. [2] Strauss GI, Knudson GM, Kondrup J, Moller K, Larsen FS. Cerebral metabolism of ammonia and amino acids in patients with fulminant hepatic failure. Gastroenterology 2001;121:1109–1119. [3] Clemmensen JO, Larsen FS, Kondrup J, Hansen BA, Ott P. Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology 1999;29:648 –653. [4] Blei AT. Medical therapy of brain edema in fulminant hepatic failure. Hepatology 2000;32:666– 669. [5] Ellis AT, Wendon JA, William R. Subclinical seizure activity and prophylactic phenytoin infusion in acute liver failure: a controlled clinical trial. Hepatology 2000;32:536–541. [6] Tandon BN, Bernauau J, O’Grady J, Gupta SD, Krish RE, Liaw YF, et al. Recommendations of the International Association for the study of the liver subcommittee on nomenclature of acute and subacute liver failure. J Gastroenterol Hepatol 1999;14:403–404. [7] Acharya SK, Dasarathy S, Kumer TL, Sushma S, Uma Prasanna KS, Tandon A, et al. Fulminant hepatitis in a tropical population: clinical course, cause and early predictors of outcome. Hepatology 1996;23: 1448–1455. [8] Riegler JL, Lake JR. Fulminant hepatic failure. Med Clin North Am 1993;77(1057):83. [9] Ede RJ, Williams R. Hepatic encephalopathy and cerebral edema. Semin Liver Dis 1986;6:107–118. [10] Nanda SK, Yalchinkaya K, Panigrahi AK, Acharya SK, Jameel S,
[16]
[17]
[18]
[19]
[20]
[21] [22]
[23]
Panda SK. Etiological role of hepatitis E virus in sporadic fulminant hepatitis. J Med Virol 1994;42:133 –137. Jameel S, Durgapal H, Habibullah CM, Khuroo MS, Panda SK. Enteric non A, non B hepatitis: epidemics, animal transmission, and hepatitis E virus detection by the polymerase chain reaction. J Med Virol 1992;37:263 –270. Cha T, Kolberg J, Irvene B, Stempien M, Beall E, Yano M, et al. Use of a signature nucleotide sequence of hepatitis C virus for detection of viral RNA in human serum and plasma. J Clin Microbiol 1991;29: 2528–2534. Grondahl TO, Langmoen IA. Epileptogenic effect of antibiotic drugs. J Neurosurg 1993;78:938 –943. De Sarro A, Ammendola D, Zappala M, Grasso S, De Sarro GB. Relationship between structure and convulsant properties of some beta lactam antibiotics following intracerebroventricular microinjection in rats. Antimicrob Agents Chemother 1995;39:232–237. Shimokawa M, Yamamoto K, Kawakami J, Sawada Y, Iga T. Effect of hepatic or renal dysfunction on neurotoxic convulsion induced by ranitidine in mice. Pharm Res 1994;11:1519–1523. Gazzard BG, Portmann B, Murray-Lyon IM, Williams R. Cause of death in fulminant hepatic failure and relationship to quantitative histological assessment of parenchymal damage. Q J Med 1975;176: 615 –626. Schiodt FV, Bondesen S, Petersen I, Ott P, Tygstrup N. Admission levels of serum Gc-globulin: predictive value in fulminant hepatic failure. Hepatology 1996;23:713–718. Papaevangelou G, Tassopoulos N, Roumeliotou-Karnayannis A, Richardson C. Etiology of fulminant viral hepatitis in Greece. Hepatology 1986;6:648–665. Bernuau J, Goudeau A, Poynard T, Dubios F, Lesage G, Yvonnet B, et al. Multivariate analysis of prognostic factors in fulminant hepatitis B. Hepatology 1986;6:648–665. Gimson AES, O’Grady J, Ede RJ, Portmann B, Williams R. Late onset hepatic failure: clinical, serological and histological features. Hepatology 1986;6:288 –294. Rakela J. Etiology and prognosis in fulminant hepatitis. Acute hepatic failure study group. Gastroenterology 1979;77:A33. Williams R, Riordan JR. Fulminant hepatic failure. In: Schiff ER, Sorrel MF, Maddrey WC, editors. Diseases of the liver, 9th ed. Philadelphia, PA: Lippincott; 2003. p. 941 –970. Yee HF, Lidofsky SD. Acute liver failure. In: Feldman M, Friedman LS, Sleisenger MH, editors. Gastrointestinal and liver disease, 7th ed. London: Saunders; 2002. p. 1567–1576.
