High Volume Plasma Exchange in Acute Liver Failure: A Brief Review

Matthew D Rockstrom, MD¹

Jonathan D Rice, MD^1,2

Tomio Tran, MD³

Anna Neumeier, MD^1,4

¹Department of Medicine, University of Colorado School of Medicine, Aurora, CO USA

²Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO USA

³Department of Medicine, Division of Cardiology, University of Washington, Seattle, WA USA

⁴Department of Medicine, Division of Pulmonary Sciences and Critical Care, Denver Health and Hospital Authority, Denver, CO USA

Abstract

Acute liver failure (ALF) is characterized by acute liver injury, coagulopathy, and altered mental status. Acetaminophen overdose contributes to almost half the cases of ALF in the United States. In the era of liver transplantation, mortality associated with this condition has improved dramatically. However, many patients are not transplant candidates including many who present with overt suicide attempt from acetaminophen overdose. High volume plasma exchange (HVP) is a novel application of plasma exchange. Prior research has shown that HVP can correct the pathophysiologic derangements underlying ALF. A randomized control trial demonstrated improved transplant-free survival when HVP was added to standard medical therapy. In this case, we examine a patient who presented to the intensive care unit with ALF caused by intentional acetaminophen overdose. She was denied transplant due to overt suicide attempt, was treated with HVP, and made a rapid recovery, eventually discharged to inpatient psychiatry and then home.

Abbreviations: ALF: acute liver failure: CVVH: continuous veno-venous hemodialysis; DAMPs: damage associated molecular patterns; FFP: fresh frozen plasma; HVP: high volume plasma exchange; MODS: multisystem organ dysfunction; NAC: N-acetyl cysteine; NNT: Number needed to treat; SIRS: systemic inflammatory response syndrome; SMT: standard medical therapy; TNF-α: tumor necrosis factor alpha

Introduction

Acute liver failure (ALF) is a rare, life-threatening condition. Although survival has improved in the transplant era, mortality remains high without transplantation. Here we discuss a novel therapy for ALF patients which may provide improved transplant-free mortality.

Case Report

A 21-year-old woman arrived by ambulance, found to be obtunded and hypotensive in the field, with an empty bottle of acetaminophen and a suicide note. She had a history of depression, infrequent alcohol and marijuana use, and was otherwise healthy.

Upon presentation, she was afebrile (temperature 36.5°C), tachycardic (heart rate 155 beats-per-minute) and hypotensive requiring norepinephrine of 0.1 μg/kg/min to maintain mean arterial blood pressure above 65.  Due to grade IV encephalopathy, she was intubated.  Admission lab work is shown below (Table 1). Viral hepatitis and HIV serologies were negative and ultrasound demonstrated patent vasculature and normal liver parenchyma.

Table 1: Lab work on admission, hospital day 2, and following high-volume plasma exchange therapy.

BUN: blood urea nitrogen, AST: aspartate aminotransferase; ALT: alanine aminotransferase; INR: international normalized ratio; APAP: N-acetyl-para-aminophenol

N-acetyl cysteine (NAC) was administered and transplant evaluation was obtained. Despite meeting King’s College Criterion for transplantation, she was declined due to presentation for suicide attempt. She was managed supportively with vasopressors, continuous veno-venous hemodialysis (CVVH), and high-volume plasma exchange (HVP) at a rate of 8 liters of fresh frozen plasma (FFP) daily, receiving 24 liters total. After initiation of HVP, vasopressors were immediately weaned. The following day, her encephalopathy improved, and she followed simple commands. CVVH was discontinued on hospital day 4. She was extubated on hospital day 6 and was eventually discharged home.

Clinical Discussion

ALF is a life-threatening syndrome characterized by acute liver injury, encephalopathy, and coagulopathy. In the United States, the most common etiology is acetaminophen overdose, accounting for ~46% of cases (1). Standard medical therapy (SMT) is supportive, treating the underlying etiology and mitigating manifestations of multisystem organ dysfunction (MODS). The advent of transplantation dramatically improved the mortality associated with ALF but the benefit of transplant must be balanced with high-risk surgery, lifelong immunosuppression, and organ scarcity (2). Given these risks, patients undergo evaluation including psychologic evaluation which commonly excludes patients presenting with intentional acetaminophen overdose. Without transplantation, mortality for these patients remains high.

The pathophysiology of ALF is not entirely understood but is largely driven by hepatic necrosis leading to hepatic metabolic dysfunction and release of intracellular contents. Intracellular damage associated molecular pattern (DAMPs) and Kupffer cell activation trigger the release of pro-inflammatory cytokines like tumor necrosis factor alpha (TNF-α), which result in systemic inflammatory response syndrome (SIRS) and vasodilation (3,4). Subsequent hepatic metabolic dysfunction is manifested by hyperbilirubinemia, hyperammonemia, coagulopathy, and hypoglycemia.

High volume plasma exchange (HVP) has shown promise as a new modality of treatment for patients with ALF. A new implementation of plasma-exchange therapy, patient plasma is exchanged with donor FFP. In one prospective, randomized control trial by Larsen et al, 15% of ideal body weight of FFP was exchanged daily for three days in addition to SMT. HVP plus SMT improved survival to discharge when compared to SMT alone (58.7 % versus 47.8%, respectively; number needed to treat (NNT) 9.2) (5). HVP plus SMT has been shown to reverse clinical parameters associated with ALF including INR, bilirubin, vasopressor requirements, reliance on renal replacement, hepatic encephalopathy (5-7). HVP was also shown to significantly attenuate DAMPs, including IL-6 and TNF-α, indicating an ability to attenuate the biochemical nidus of MODS (6,7). A systematic review of HVP found evidence of mortality benefit in HVP for both ALF and acute on chronic liver failure, though Larsen et al remains the only randomized prospective trial. Subsequently, HVP has become a level I, grade 1 recommendation in European guidelines for ALF (6).

There are limitations associated with HVP including utilization of FFP, concerns for precipitation volume overload, and worsening cerebral edema. Additionally, there is no clear optimal regimen for dose and duration of HVP. In a recent randomized control trial by Maiwall et al, standard volume plasma exchange was shown to improve transplant free survival using only 1.5 to 2 times calculated patient plasma volume (4).

Conclusion

In this case, a 21-year-old patient presented with ALF following acetaminophen overdose. Despite qualifying for transplantation, she was denied due to presentation for suicide attempt. She was treated with standard medical therapy and HVP and had rapid improvement in hemodynamics and mentation. While it is impossible to quantify the degree to which HVP contributed to her recovery, her clinical improvement was dramatic despite presentation with severe disease. HVP has been shown to reverse the pathophysiologic hallmarks of ALF, improve transplant-free mortality, and is now a level I recommendation according to European guidelines. More trials are necessary to determine the optimal dose and duration of this life saving modality.

References

1. Lee WM. Etiologies of acute liver failure. Semin Liver Dis. 2008 May;28(2):142-52. [CrossRef] [PubMed]
2. Lee WM, Squires RH Jr, Nyberg SL, Doo E, Hoofnagle JH. Acute liver failure: Summary of a workshop. Hepatology. 2008 Apr;47(4):1401-15. [CrossRef] [PubMed]
3. Chung RT, Stravitz RT, Fontana RJ, Schiodt FV, Mehal WZ, Reddy KR, Lee WM. Pathogenesis of liver injury in acute liver failure. Gastroenterology. 2012 Sep;143(3):e1-e7. [CrossRef] [PubMed]
4. Maiwall R, Bajpai M, Singh A, Agarwal T, Kumar G, Bharadwaj A, Nautiyal N, Tevethia H, Jagdish RK, Vijayaraghavan R, Choudhury A, Mathur RP, Hidam A, Pati NT, Sharma MK, Kumar A, Sarin SK. Standard-Volume Plasma Exchange Improves Outcomes in Patients With Acute Liver Failure: A Randomized Controlled Trial. Clin Gastroenterol Hepatol. 2021 Jan 29:S1542-3565(21)00086-0. [CrossRef] [PubMed]
5. Larsen FS, Schmidt LE, Bernsmeier C, et al. High-volume plasma exchange in patients with acute liver failure: An open randomised controlled trial. J Hepatol. 2016 Jan;64(1):69-78. [CrossRef] [PubMed]
6. Tan EX, Wang MX, Pang J, Lee GH. Plasma exchange in patients with acute and acute-on-chronic liver failure: A systematic review. World J Gastroenterol. 2020 Jan 14;26(2):219-245. [CrossRef] [PubMed]
7. Larsen FS, Ejlersen E, Hansen BA, Mogensen T, Tygstrup N, Secher NH. Systemic vascular resistance during high-volume plasmapheresis in patients with fulminant hepatic failure: relationship with oxygen consumption. Eur J Gastroenterol Hepatol. 1995 Sep;7(9):887-92. [PubMed]

Cite as: Rockstrom MD, Rice JD, Tran T, Neumeier A. High Volume Plasma Exchange in Acute Liver Failure: A Brief Review. Southwest J Pulm Crit Care. 2021;22(5):102-5. doi: https://doi.org/10.13175/swjpcc009-21 PDF

November 2013 Critical Care Case of the Month: A Series of Unfortunate Infections

Kenneth K. Sakata, MD

Karen L. Sapienza, MD

Lewis J. Wesselius, MD 

Department of Pulmonary Medicine

Mayo Clinic Arizona

Scottsdale, AZ

History of Present Illness

A 22 year old man was admitted with fever for 2 weeks. He had a history of acute lymphocytic leukemia (ALL) and had received a stem cell transplant in (SCT) in May 2013.

PMH, SH, FH

Other than the ALL and STC transplant there was no significant PMH, SH, or FH. The STC was uneventful.

Physical Examination

T 38.6°C with a pulse of 110 beats/min. Otherwise the physical examination was unremarkable.

CT scan

A CT scan of the thorax was performed in a search for the source of the fever (Figure 1).

Figure 1. Admission thoracic CT scan showing an abnormality. The remainder of the CT scan was unremarkable.

Which of the following best describes the CT abnormality?

1. Chest wall abnormality in the left chest
2. Focal area of consolidation in the left lung
3. Focal area of consolidation in the right lung
4. Mass in the left lung
5. Mass in the right lung

Reference as: Sakata KK, Sapienza KL, Wesselius LJ. November 2013 pulmonary case of the month: a series of unfortunate infections. Southwest J Pulm Crit Care. 2013;7(5):280-8. doi: http://dx.doi.org/10.13175/swjpcc139-13 PDF

ARTERIAL AMMONIA LEVELS IN THE MANAGEMENT OF FULMINANT LIVER FAILURE

Robert Raschke

Steven Curry

Silke Remke

Ester Little

Richard Gerkin

Richard Manch

Alan Leibowitz

Banner Good Samaritan Regional Medical Center, Phoenix, AZ

Reference as:  Raschke R, Curry S, Remke S, Little E, Gerkin R, Manch R, Leibowitz A. Arterial ammonia levels in the management of fulminant liver failure. Southwest J Pulm Crit Care 2011;2:85-92. (Click here for PDF version)

Abstract

Previous studies have suggested that an arterial ammonia level greater than 150 mmol/L is highly sensitive for predicting subsequent development of cerebral edema in patients with fulminant liver failure. We performed a prospective cohort study to confirm this relationship. We enrolled 22 consecutive patients who presented to our transplant hepatology service with grade 3-4 encephalopathy associated with fulminant liver failure. All patients underwent placement of an intraparenchymal ICP monitor, and every 12 hourly arterial ammonia levels. The prevalence of intracranial hypertension (IHTN) in our population was 95% (21/22 patients), with 82 discrete episodes recorded. The sensitivity of arterial ammonia levels to predict the onset of IHTN was 62% (95% CI: 40.8 to 79.3) at a cut point of 150 mmol/L. Arterial ammonia levels preceding the first intracranial hypertension event were less than 150 mmol/L in 8 of 21 patients (39%). Fifty nine of 82 episodes of IHTN (73%) occurred when arterial ammonia levels were less than 150 mmol/L. We conclude that the arterial ammonia level is not useful in making decisions regarding management related to cerebral edema in patients with fulminant liver failure. In fact, since almost all our study patients with grade III or IV encephalopathy secondary to fulminant liver failure went on to develop intracranial hypertension, our study supports the contention that all such patients might benefit from ICP monitoring regardless of arterial ammonia levels.

Background

Cerebral edema is the most common cause of death in fulminant liver failure (FLF) (1,2), occurring in 80% of patients with advanced encephalopathy (3). Cerebral edema causes brain injury by compromising cerebral perfusion pressure and/or by causing cerebral herniation. Intracranial hypertension (IHTN) is the most reliable sign of cerebral edema, and is defined as an intracranial pressure (ICP) greater than 20 mmHg (4-6). Many authors have recommended ICP monitoring in FLF to guide management of cerebral edema (7,8) although this procedure entails significant hemorrhagic risk (9,10).

The pathogenesis of cerebral edema in FLF is likely multifactorial, but substantial evidence supports a causal role for hyperammonemia. Elevated ammonia levels alter neurotransmitter synthesis, and interfere with mitochondrial function causing oxidative stress and neuronal apoptosis (4,5,6,11-16). Increased delivery of ammonia to astrocytes provides substrate for the accumulation of intracellular glutamine (17-18). The resulting osmotic effect causes astrocyte swelling and cerebral edema (6,7,19). Clinical studies have repeatedly shown that arterial ammonia levels around 150 mmol/L have a statistically significant association with the development of IHTN and cerebral edema in humans (8,20-22).

Clemmensen and colleagues (8) measured arterial ammonia levels at the onset of grade III encephalopathy in 44 patients with FLF. Fourteen of those patients subsequently developed cerebral herniation. The patients who developed cerebral herniation had significantly higher mean arterial ammonia levels (230 vs. 118 μmol/L P<0.001), and all had ammonia levels > 146 μmol/L. At this cut point, arterial ammonia had a sensitivity of 100%, a specificity of 73% and a PPV of 64% for the subsequent development of cerebral herniation (8).

The results of this study raised the possibility that arterial ammonia levels could be used to select FLF patients likely to benefit from ICP monitoring. If arterial ammonia levels above 146 μmol/L were highly sensitive for predicting the development of IHTN, patients with arterial ammonia levels below this threshold would not likely benefit from ICP monitoring, therefore the significant hemorrhagic risk of monitor placement could be avoided (20,23).

The primary aim of our study was to confirm this premise by reassessing the sensitivity of the arterial ammonia concentration for predicting the onset of intracranial hypertension (IHTN). We chose IHTN as our dependent variable since cerebral herniation is uncommonly seen in patients managed with our neuroprotective treatment protocol (24), and because intracranial hypertension can cause brain injury by compromising cerebral perfusion in the absence of herniation. The secondary aim of our study was to determine whether following serial arterial ammonia levels are valuable in predicting the timing of recurrent IHTN episodes before and after liver transplantation.

Methods

A prospective case series was approved by the Institutional Review Board at Banner Good Samaritan Regional Medical Center, a 650 bed community teaching hospital in Phoenix Arizona. The Transplant Hepatology service identified consecutive patients admitted with FLF, as defined by standard criteria (20) between May 2004 and September 2006. All patients underwent serial neurological examinations by an intensivist, and those who developed grade 3-4 encephalopathy were evaluated for study participation. Eligible patients’ families were asked to provide informed consent.

Serial arterial ammonia levels were obtained in study patients. An arterial catheter was placed and 5 cc of arterial blood was drawn into a sodium heparin-containing tube every 12 hours. These samples were transported to the chemistry laboratory on ice within 30 minutes. Quantitative plasma ammonia concentrations were performed using an enzymatic kinetic assay (Roche Diagnostics, Mannheim Germany). This assay has a reportable range of 5.87-587 mmol/L and a coefficient of variability of 2%.

An intraparenchymal ICP monitor (Codman MicroSensor^® - Codman/Johnson & Johnson Professional, Inc., Randolph, MA) was placed in the non-dominant frontal lobe under local anesthesia by a neurosurgeon. The ICP was monitored continuously thereafter. Hemostatic therapy and ICP management used in the study have been previously described (24). ICP monitors were removed post-transplantation when the patient could tolerate lowering of their head to zero degrees without precipitating IHTN. In patients who did not undergo transplantation, ICP monitors were removed upon clinical recovery or death.  

Our main independent variable was the arterial plasma ammonia level. Our main dependent variable was intracranial hypertension, defined as an ICP > 20 mmHg for > 20 mins.  We performed 3 separate sets of analyses to examine the relationship between arterial ammonia levels and IHTN: 1) we analyzed the arterial ammonia level that most closely preceded the onset of the first episode of IHTN in each patient; 2) we analyzed all arterial ammonia levels in relation to all episodes of IHTN; and 3) we analyzed all arterial ammonia levels in relation to all episodes of IHTN occurring post liver transplantation. The second and third analyses involved data values that were not independent of each other, therefore standard statistical techniques were not appropriate and time series analysis was performed. Statistical analyses were performed using SPSS 13.0 (SPSS Inc. Chicago IL.) Operating characteristics of arterial ammonia levels were calculated at a cut point of 150 mmol/L.  

Results

Twenty two patients were entered – their clinical characteristics at study entry are listed in Table 1.

Table 1:  Patient Characteristics:
Mean age:	32.7 years (S.D. 10.3 yrs, range 15-56)
Gender:	17/22 (77%) female
Etiology:	acetaminophen toxicity (12 patients) hepatitis A (3) hepatitis B (1) anticonvulsant hypersensitivity syndrome (1) sulfa hypersensitivity syndrome (1) Wilson’s disease (1) Cryptogenic (3)
Encephalopathy grade:	8 patients (36%) Grade III 14 patients (64%) Grade IV

Our 22 patients cumulatively underwent 3252 hours of ICP monitoring. Mean monitor duration was 147.8 +/- 143.3 hours. Monitors were left after liver transplantation in nine patients for 85.6 +/- 60.6 hours.

The prevalence of IHTN in our population was 95% (21/22 patients). Eighty-two discrete episodes of intracranial hypertension occurred. 62 occurred prior to, 4 during, and 16 after liver transplantation. The peak ICP during IHTN events was 33 +/- 13 mmHg (mean +/- S.D.) and the median duration was 60 minutes.

Relationship between arterial ammonia levels and the first episode of IHTN: The mean arterial ammonia level preceding the first intracranial hypertension event in each patient was 185 +/- 67 mmol/L (range: 96 – 337 mmol/L). The sensitivity of arterial ammonia levels to predict the onset of IHTN was 62% (95% CI: 40.8 to 79.3) at a cut point of 150 mmol/L. Arterial ammonia levels preceding the first intracranial hypertension event were less than 150 mmol/L in 8 of 21 patients (39%). We could not accurately calculate specificity or area under the receiver operator curve (AUROC) since only one patient did not develop IHTN.  

Relationship between arterial ammonia levels and all episodes of IHTN: The mean arterial ammonia levels just prior to each of the individual 82 episodes of IHTN were 122 +/- 80 mmol/L (range: 15 – 270 mmol/L). Fifty nine of 82 episodes of IHTN (73%) occurred when arterial ammonia levels were less than 150 mmol/L.

Relationship between arterial ammonia levels and all episodes of IHTN occurring post liver transplantation: Nine patients underwent liver transplantation. Seventy-nine ammonia levels were obtained post-liver transplantation in these patients. Four transplant recipients experienced 16 post-operative IHTN events. The mean arterial ammonia just prior to each of these events was 70 +/- 48 mmol/L (range: 15 – 161 mmol/L). The sensitivity of the arterial ammonia level preceding each IHTN event was 13% and the specificity was 100% at a cut point of 150 mmol/L. Arterial ammonia levels were statistically lower in post-transplant IHTN episodes than in pre-transplant episodes (P<0.001).

Discussion

Our study showed that almost all patients with grade III or IV encephalopathy secondary to fulminant liver failure will develop intracranial hypertension – this supports the possible benefit of intracranial pressure monitoring in all such patients regardless of arterial ammonia levels. Although the high prevalence of IHTN in our study population prevented us from calculating the specificity of arterial ammonia levels, sensitivity is the key characteristic of this test in terms of our research question. Our study shows that arterial ammonia levels > 150 mmol/L are not sensitive for subsequent development of IHTN, and therefore should not be used to identify a subset of patients unlikely to benefit from ICP monitoring.

Our study did not confirm the clinical utility of arterial ammonia levels in predicting neurological injury in patients with FLF, as suggested by Clemmensen et al (8). This could be because the clinical event of interest in the two studies differed – Clemmensen focused on cerebral herniation, and we measured IHTN directly. Cerebral herniation occurred in 14 of Clemmensens’ 44 patients, but it was not observed in our patients. Our study utilized a management protocol specifically designed to prevent cerebral herniation (24). It is unknown how many of our patients with IHTN would have gone on to herniate if IHTN had not been detected and aggressively treated.           

Several other studies have examined the predictive value of arterial ammonia levels for cerebral edema and IHTN in patients with acute liver failure. Bernal and colleagues studied 165 patients with acute liver failure and grade 3-4 encephalopathy and found that arterial ammonia on admission was higher in those who later developed IHTN (121 vs 109 mmol/L p<0.05 (20). However, the sensitivity of an ammonia cut-point of 150 mmol/L was only 40%, and the positive predictive value (probability that a patient with ammonia > 150 mmol/L would develop IHTN) was only 16%.   

Bhatia and colleagues studied 80 patients with ALF, 58 of whom had grade 3-4 encephalopathy (21). They calculated an optimal cut-point for arterial ammonia for predicting mortality was 124 mmol/L by ROC analysis. Patients with ammonia levels above this cutpoint had a higher frequency of cerebral edema (47% vs. 22% P=0.02). Sensitivity and positive predictive values can be calculated from data presented in their paper, and are 71% and 48% respectively.  

Our results confirm those of Bernal and Bhatia in that all 3 studies showed that the operating characteristics of the arterial ammonia test are insufficient for triaging ALF patients in regards to invasive ICP monitoring. But our study has several important differences. IHTN or cerebral edema was detected in only 29% of Bernal’s patients and 35% of Bhatia’s. Both studies relied heavily on physical examination to diagnose these outcomes despite evidence that it lacks the sensitivity to do so (1,3,25-27). Our study utilized the gold standard (ICP monitoring) in all our patients. We found a much higher prevalence of IHTN – 95% in patients with grade 3-4 encephalopathy. This high prevalence explains the higher positive predictive value in our study, and suggests that previous studies may have suffered from significant underdetection of IHTN and cerebral edema.

Our study is also unique in that we performed repeated measures of arterial ammonia. This was important in terms of our hypothesis that patients’ risk for IHTN might change over time in response to treatments such as lactulose, continuous renal replacement therapy, and liver transplantation. Unfortunately, we found that repeated measures of arterial ammonia were no more clinically useful than the single levels used in previous studies.

Our study has several important limitations. Our limited sample size produced wide confidence intervals about our estimation of sensitivity. Our study only included patients with advanced encephalopathy - it’s possible that arterial ammonia levels might demonstrate improved prognostic significance earlier in the course of FLF. We did not attempt to analyze the effect of cumulative ammonia exposure over time.

 Our findings, and those of previous investigators, suggest that other factors besides peak ammonia levels are important in the pathogenesis of FLF-induced cerebral edema. Two other proposed causative factors are pathological alterations in cerebral blood flow (28-32) and systemic inflammatory response (30,33-34). The interplay of all three factors may be critical to the pathogenesis of cerebral edema in FLF and this might explain why simple measurement of serum ammonia is not sufficient to predict IHTN.

   Further work is needed to elucidate the pathogenesis of IHTN in FLF and identify variables that predict which patients will develop this life-threatening complication. Until then, we suggest that all patients with grade 3 or 4 encephalopathy secondary to FLF are at high risk. Our study shows that arterial ammonia levels in these patients cannot be relied upon to accurately triage patients in regards to their risk for IHTN. Thus, it is not helpful in determining which patients might benefit from ICP monitoring, nor determining when ICP monitoring can safely be discontinued.

Conclusions

An arterial ammonia level of 150 mmol/L is poorly sensitive for determining which patients with ALF will develop IHTN and should not be used to determine which patients are likely to benefit from ICP monitoring. The prevalence of IHTN in FLF patients with grade 3-4 encephalopathy is so high that no other predictive test is likely to be of added value. Although arterial ammonia levels are correlated with episodes of IHTN, most individual IHTN episodes occur when arterial ammonia levels are < 150 mmol/L. After successful transplantation IHTN events can continue to occur even as ammonia levels enter the normal range.

References

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28. Wendon JA, Harrison PM, Keays R, Williams R. Cerebral blood flow and metabolism in fulminant liver failure. Hepatology. 1994;19:1407-13.

29. Sari A, Yamashita S, Ohosita S, Ogasahara H, Yamada K, Yonei A, Yokota K. Cerebrovascular reactivity to CO₂ in patients with hepatic or septic encephalopathy. Resuscitation. 1990;19:125-34

30. Jalan r, Olde Damink SWM, Hayes PC, Deutz NEP, Lee A. Pathogenesis of intracranial hypertension in acute liver failure: Inflammation, ammonia and cerebral blood flow. Journal of Hepatology. 2004;41:613-20.

31. Kramer D, Aggarwal M, Darby J, Obrist W, Rosenbloom A, Murray G, Linden P, et al. Management options in fulminant hepatic failure. Transplant Proc. 1991;23:1895-8.

32. Jalan R, Olde Damink SWM, Deutz NEP, Hayes PC, Lee A. Restoration of cerebral blood flow autoregulation and reactivity to carbon dioxide in acute liver failure by moderate hypothermia. Hepatology. 2001;34:50-4.

33. Rolando N, Wade J, Davalos M, Wendon J, Philpott-Howard J, Williams R. The systemic inflammatory response syndrome in acute liver failure. Hepatology. 2000;32:734-9

34. Vaquero J, Polson J, Chung C, Helenowski I, Schiodt FV, Reisch J, Lee W, Blei AT, and the U.S. Acute Liver Failure Study Group. Infection and the progression of hepatic encephalopathy in acute liver failure. Gastroenterology.2003;125:755-64.