Neurocritical Care

, Volume 9, Issue 1, pp 90–96 | Cite as

Therapeutic Hypothermia for Acute Liver Failure: Toward a Randomized, Controlled Trial in Patients with Advanced Hepatic Encephalopathy

  • R. Todd Stravitz
  • William M. Lee
  • Andreas H. Kramer
  • David J. Kramer
  • Linda Hynan
  • Andres T. Blei
Review

Abstract

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.

Keywords

Cerebral edema Hypothermia Acute liver failure 

References

  1. 1.
    Trey C, Davidson CS. The management of fulminant hepatic failure. Prog Liver Dis. 1970;3:282–98.PubMedGoogle Scholar
  2. 2.
    Lee WM. Acute liver failure in the United States. Semin Liver Dis. 2003;23(3):217–26.PubMedCrossRefGoogle Scholar
  3. 3.
    Makin AJ, Wendon J, Williams R. A 7-year experience of severe acetaminophen-induced hepatotoxicity (1987–1993). Gastroenterology. 1995;109(6):1907–16.PubMedCrossRefGoogle Scholar
  4. 4.
    Williams R, Wendon J. Indications for orthotopic liver transplantation in fulminant liver failure. Hepatology. 1994;20(1 Pt 2):S5–10.PubMedGoogle Scholar
  5. 5.
    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.PubMedCrossRefGoogle Scholar
  6. 6.
    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.PubMedCrossRefGoogle Scholar
  7. 7.
    Ware AJ, D’Agostino AN, Combes B. Cerebral edema: a major complication of massive hepatic necrosis. Gastroenterology. 1971;61(6):877–84.PubMedGoogle Scholar
  8. 8.
    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.PubMedCrossRefGoogle Scholar
  9. 9.
    O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989;97(2):439–45.PubMedGoogle Scholar
  10. 10.
    O’Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet. 1993;342(8866):273–5.PubMedCrossRefGoogle Scholar
  11. 11.
    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.PubMedCrossRefGoogle Scholar
  12. 12.
    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.PubMedCrossRefGoogle Scholar
  13. 13.
    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.PubMedCrossRefGoogle Scholar
  14. 14.
    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.PubMedCrossRefGoogle Scholar
  15. 15.
    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.PubMedCrossRefGoogle Scholar
  16. 16.
    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.PubMedCrossRefGoogle Scholar
  17. 17.
    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.PubMedCrossRefGoogle Scholar
  18. 18.
    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.PubMedCrossRefGoogle Scholar
  19. 19.
    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.PubMedCrossRefGoogle Scholar
  20. 20.
    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.Google Scholar
  21. 21.
    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.PubMedCrossRefGoogle Scholar
  22. 22.
    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.PubMedCrossRefGoogle Scholar
  23. 23.
    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.PubMedCrossRefGoogle Scholar
  24. 24.
    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.PubMedGoogle Scholar
  25. 25.
    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.PubMedCrossRefGoogle Scholar
  26. 26.
    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.PubMedCrossRefGoogle Scholar
  27. 27.
    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.PubMedCrossRefGoogle Scholar
  28. 28.
    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.PubMedCrossRefGoogle Scholar
  29. 29.
    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.PubMedCrossRefGoogle Scholar
  30. 30.
    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.PubMedCrossRefGoogle Scholar
  31. 31.
    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.PubMedCrossRefGoogle Scholar
  32. 32.
    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.PubMedCrossRefGoogle Scholar
  33. 33.
    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.PubMedCrossRefGoogle Scholar
  34. 34.
    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.PubMedGoogle Scholar
  35. 35.
    Williams R. Classification, etiology, and considerations of outcome in acute liver failure. Semin Liver Dis. 1996;16(4):343–8.PubMedGoogle Scholar
  36. 36.
    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.PubMedCrossRefGoogle Scholar
  37. 37.
    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.PubMedCrossRefGoogle Scholar
  38. 38.
    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.PubMedCrossRefGoogle Scholar
  39. 39.
    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.PubMedCrossRefGoogle Scholar
  40. 40.
    Bernal W. Changing patterns of causation and the use of transplantation in the United kingdom. Semin Liver Dis. 2003;23(3):227–37.PubMedCrossRefGoogle Scholar
  41. 41.
    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.PubMedCrossRefGoogle Scholar
  42. 42.
    Blei AT, Olafsson S, Webster S, Levy R. Complications of intracranial pressure monitoring in fulminant hepatic failure. Lancet. 1993;341(8838):157–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Axelrod YK, Diringer MN. Temperature management in acute neurologic disorders. Crit Care Clin. 2006;22(4):767–85.PubMedCrossRefGoogle Scholar
  44. 44.
    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.PubMedCrossRefGoogle Scholar
  45. 45.
    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.PubMedCrossRefGoogle Scholar
  46. 46.
    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.PubMedCrossRefGoogle Scholar
  47. 47.
    Munoz SJ. Hypothermia may impair hepatic regeneration in acute liver failure. Gastroenterology. 2005;128(4):1143–4.PubMedCrossRefGoogle Scholar
  48. 48.
    Jalan R. Intracranial hypertension in acute liver failure: pathophysiological basis of rational management. Semin Liver Dis. 2003;23(3):271–82.PubMedCrossRefGoogle Scholar
  49. 49.
    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.PubMedGoogle Scholar
  50. 50.
    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.PubMedCrossRefGoogle Scholar
  51. 51.
    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.PubMedCrossRefGoogle Scholar
  52. 52.
    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.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2008

Authors and Affiliations

  • R. Todd Stravitz
    • 1
  • William M. Lee
    • 2
  • Andreas H. Kramer
    • 3
  • David J. Kramer
    • 4
  • Linda Hynan
    • 2
  • Andres T. Blei
    • 5
  1. 1.Section of Hepatology, Hume-Lee Transplant CenterVirginia Commonwealth UniversityRichmondUSA
  2. 2.Southwestern Medical CenterUniversity of TexasDallasUSA
  3. 3.University of CalgaryCalgaryCanada
  4. 4.Mayo Clinic-JacksonvilleJacksonvilleUSA
  5. 5.Northwestern UniversityChicagoUSA

Personalised recommendations