Acute liver failure (ALF), the abrupt loss of liver function in a patient without previous liver disease, remains a highly mortal condition. Patients with ALF often succumb to their liver injury after the development of cerebral edema, resulting in intracranial hypertension and brain herniation. While the management of cerebral edema in ALF always includes the administration of osmotically active agents, osmotherapy often reduces intracranial pressure (ICP) insufficiently, such that herniation may be delayed but not prevented. Therapeutic hypothermia, the intentional reduction of body core temperature, has been increasingly used to treat cerebral edema in patients with traumatic and hypoxic brain injury. Data in animal models of ALF also suggest that hypothermia is effective in the prevention and treatment of cerebral edema, and case reports in humans have suggested that hypothermia is an effective bridge to orthotopic liver transplantation. A randomized, controlled trial comparing the management of ALF patients under normothermic and hypothermic conditions is a logical extension of these preliminary observations. Herein, we consider the many difficulties which will be encountered in the design of such a trial in patients with ALF at high risk of developing cerebral edema.
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Trey C, Davidson CS. The management of fulminant hepatic failure. Prog Liver Dis. 1970;3:282–98.
Lee WM. Acute liver failure in the United States. Semin Liver Dis. 2003;23(3):217–26.
Makin AJ, Wendon J, Williams R. A 7-year experience of severe acetaminophen-induced hepatotoxicity (1987–1993). Gastroenterology. 1995;109(6):1907–16.
Williams R, Wendon J. Indications for orthotopic liver transplantation in fulminant liver failure. Hepatology. 1994;20(1 Pt 2):S5–10.
Clemmesen 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(3):648–53.
Bernal W, Hall C, Karvellas CJ, Auzinger G, Sizer E, Wendon J. Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure. Hepatology. 2007;46(6):1844–52.
Ware AJ, D’Agostino AN, Combes B. Cerebral edema: a major complication of massive hepatic necrosis. Gastroenterology. 1971;61(6):877–84.
Lidofsky SD, Bass NM, Prager MC, Washington DE, Read AE, Wright TL, et al. Intracranial pressure monitoring and liver transplantation for fulminant hepatic failure. Hepatology. 1992;16(1):1–7.
O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989;97(2):439–45.
O’Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet. 1993;342(8866):273–5.
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(4 Pt 1):734–9.
Vaquero J, Polson J, Chung C, Helenowski I, Schiodt FV, Reisch J, et al. Infection and the progression of hepatic encephalopathy in acute liver failure. Gastroenterology. 2003;125(3):755–64.
Canalese J, Gimson AE, Davis C, Mellon PJ, Davis M, Williams R. Controlled trial of dexamethasone and mannitol for the cerebral oedema of fulminant hepatic failure. Gut. 1982;23(7):625–9.
Hanid MA, Davies M, Mellon PJ, Silk DB, Strunin L, McCabe JJ, et al. Clinical monitoring of intracranial pressure in fulminant hepatic failure. Gut. 1980;21(10):866–9.
Murphy N, Auzinger G, Bernel W, Wendon J. The effect of hypertonic sodium chloride on intracranial pressure in patients with acute liver failure. Hepatology. 2004;39(2):464–70.
Forbes A, Alexander GJ, O’Grady JG, Keays R, Gullan R, Dawling S, et al. Thiopental infusion in the treatment of intracranial hypertension complicating fulminant hepatic failure. Hepatology. 1989;10(3):306–10.
Tofteng F, Larsen FS. The effect of indomethacin on intracranial pressure, cerebral perfusion and extracellular lactate and glutamate concentrations in patients with fulminant hepatic failure. J Cereb Blood Flow Metab. 2004;24(7):798–804.
Clemmesen JO, Hansen BA, Larsen FS. Indomethacin normalizes intracranial pressure in acute liver failure: a twenty-three-year-old woman treated with indomethacin. Hepatology. 1997;26(6):1423–5.
Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557–63.
The Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549–56.
Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005;353(15):1574–84.
Marion DW, Penrod LE, Kelsey SF, Obrist WD, Kochanek PM, Palmer AM, et al. Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med. 1997;336(8):540–6.
Henderson WR, Dhingra VK, Chittock DR, Fenwick JC, Ronco JJ. Hypothermia in the management of traumatic brain injury. A systematic review and meta-analysis. Intensive Care Med. 2003;29(10):1637–44.
Traber P, DalCanto M, Ganger D, Blei AT. Effect of body temperature on brain edema and encephalopathy in the rat after hepatic devascularization. Gastroenterology. 1989;96(3):885–91.
Cordoba J, Crespin J, Gottstein J, Blei AT. Mild hypothermia modifies ammonia-induced brain edema in rats after portacaval anastomosis. Gastroenterology. 1999;116(3):686–93.
Rose C, Michalak A, Pannunzio M, Chatauret N, Rambaldi A, Butterworth RF. Mild hypothermia delays the onset of coma and prevents brain edema and extracellular brain glutamate accumulation in rats with acute liver failure. Hepatology. 2000;31(4):872–7.
Vaquero J, Blei AT. Mild hypothermia for acute liver failure: a review of mechanisms of action. J Clin Gastroenterol. 2005;39(4 Suppl 2):S147–57.
Vaquero J, Butterworth RF. Mild hypothermia for the treatment of acute liver failure—what are we waiting for? Nat Clin Pract Gastroenterol Hepatol. 2007;4(10):528–9.
Jalan R, Damink SW, Deutz NE, Lee A, Hayes PC. Moderate hypothermia for uncontrolled intracranial hypertension in acute liver failure. Lancet. 1999;354(9185):1164–8.
Jalan R, Olde Damink SW, Deutz NE, 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(1):50–4.
Jalan R, Olde Damink SW, Deutz NE, Davies NA, Garden OJ, Madhavan KK, et al. Moderate hypothermia prevents cerebral hyperemia and increase in intracranial pressure in patients undergoing liver transplantation for acute liver failure. Transplantation. 2003;75(12):2034–9.
Caldwell SH, Hoffman M, Lisman T, Macik BG, Northup PG, Reddy KR, et al. Coagulation disorders and hemostasis in liver disease: pathophysiology and critical assessment of current management. Hepatology. 2006;44(4):1039–46.
Vaquero J, Belanger M, James L, Herrero R, Desjardins P, Cote J, et al. Mild hypothermia attenuates liver injury and improves survival in mice with acetaminophen toxicity. Gastroenterology. 2007;132(1):372–83.
Stravitz RT, Kramer AH, Davern T, Shaikh AO, Caldwell SH, Mehta RL, et al. Intensive care of patients with acute liver failure: recommendations of the U.S. Acute Liver Failure Study Group. Crit Care Med. 2007;35(11):2498–508.
Williams R. Classification, etiology, and considerations of outcome in acute liver failure. Semin Liver Dis. 1996;16(4):343–8.
Schmidt LE, Larsen FS. MELD score as a predictor of liver failure and death in patients with acetaminophen-induced liver injury. Hepatology. 2007;45(3):789–96.
Schiodt FV, Ostapowicz G, Murray N, Satyanarana R, Zaman A, Munoz S, et al. Alpha-fetoprotein and prognosis in acute liver failure. Liver Transpl. 2006;12(12):1776–81.
Pereira LM, Langley PG, Hayllar KM, Tredger JM, Williams R. Coagulation factor V and VIII/V ratio as predictors of outcome in paracetamol induced fulminant hepatic failure: relation to other prognostic indicators. Gut. 1992;33(1):98–102.
Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005;42(6):1364–72.
Bernal W. Changing patterns of causation and the use of transplantation in the United kingdom. Semin Liver Dis. 2003;23(3):227–37.
Vaquero J, Fontana RJ, Larson AM, Bass NM, Davern TJ, Shakil AO, et al. Complications and use of intracranial pressure monitoring in patients with acute liver failure and severe encephalopathy. Liver Transpl. 2005;11(12):1581–9.
Blei AT, Olafsson S, Webster S, Levy R. Complications of intracranial pressure monitoring in fulminant hepatic failure. Lancet. 1993;341(8838):157–8.
Axelrod YK, Diringer MN. Temperature management in acute neurologic disorders. Crit Care Clin. 2006;22(4):767–85.
Jalan R, Olde Damink SW, Deutz NE, Hayes PC, Lee A. Moderate hypothermia in patients with acute liver failure and uncontrolled intracranial hypertension. Gastroenterology. 2004;127(5):1338–46.
Clifton GL, Miller ER, Choi SC, Levin HS, McCauley S, Smith KR Jr, et al. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med. 2001;344(8):556–63.
Polderman KH. Application of therapeutic hypothermia in the intensive care unit. Opportunities and pitfalls of a promising treatment modality—Part 2: practical aspects and side effects. Intensive Care Med. 2004;30(5):757–69.
Munoz SJ. Hypothermia may impair hepatic regeneration in acute liver failure. Gastroenterology. 2005;128(4):1143–4.
Jalan R. Intracranial hypertension in acute liver failure: pathophysiological basis of rational management. Semin Liver Dis. 2003;23(3):271–82.
Shiozaki T, Kato A, Taneda M, Hayakata T, Hashiguchi N, Tanaka H, et al. Little benefit from mild hypothermia therapy for severely head injured patients with low intracranial pressure. J Neurosurg. 1999;91(2):185–91.
Munoz SJ, Moritz MJ, Bell R, Northrup B, Martin P, Radomski J. Factors associated with severe intracranial hypertension in candidates for emergency liver transplantation. Transplantation. 1993;55(5):1071–4.
Diringer MN, Reaven NL, Funk SE, Uman GC. Elevated body temperature independently contributes to increased length of stay in neurologic intensive care unit patients. Crit Care Med. 2004;32(7):1489–95.
Clifton GL, Choi SC, Miller ER, Levin HS, Smith KR Jr, Muizelaar JP, et al. Intercenter variance in clinical trials of head trauma–experience of the National Acute Brain Injury Study: hypothermia. J Neurosurg. 2001;95(5):751–5.
This work was presented at the fifth annual meeting of the Neurocritical Care Society, Las Vegas, NV, on November 1, 2007, at a satellite symposium entitled “Management of Coagulopathy and Intracranial Hypertension in Acute Liver Failure: Is There a Role for Hypothermia?” The symposium was sponsored by the Neurocritical Care Society with generous funding from Novo Nordisk.
The authors wish to dedicate this work to our friend, teacher, and colleague, Dr. Andres Blei, who inspired the work as part of his life-long study of hepatic encephalopathy and acute liver failure. We also wish to acknowledge the thoughtful input of Drs. Fin Larsen, Julia Wendon, Nick Murphy, and William Bernal.
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Stravitz, R.T., Lee, W.M., Kramer, A.H. et al. Therapeutic Hypothermia for Acute Liver Failure: Toward a Randomized, Controlled Trial in Patients with Advanced Hepatic Encephalopathy. Neurocrit Care 9, 90–96 (2008). https://doi.org/10.1007/s12028-008-9090-y
- Cerebral edema
- Acute liver failure