Liver failure

Pretransplant Neurological Presentation and Severe Posttransplant Brain Injury in Patients With Acute Liver Failure

Authors: Tan WF, Steadman RH, Farmer DG, Hong JC, Busuttil RW, Apinyachon W, Xia VW.

BACKGROUND: Alterations in the central nervous system in patients with acute liver failure (ALF) present unique challenges in the perioperative period. In this retrospective study, we examined pretransplant neurological presentation and the incidence, clinical presentation, and risk factors associated with severe posttransplant brain injury (BI) in ALF patients undergoing orthotopic liver transplantation (OLT).
METHODS: After institutional review board approval, ALF patients who underwent OLT between 2004 and 2010 at our center were reviewed. Pretransplant neurological presentation and severe posttransplant BI were examined. Risk factors for the latter were identified.
RESULTS: During the study period, 90 (67 adults and 23 children) ALF patients underwent primary OLT. Preoperatively, all patients developed encephalopathy, 6 had seizure activity, 32 had radiological evidence of cerebral edema, and 11 had severe cerebral edema. After OLT, 7 patients developed severe posttransplant BI. Of these 7 patients, 4 had brain death, and 3 had irreversible injury that precluded them from living independently. Severe pretransplant cerebral edema and a higher posttransplant international normalized ratio (odds ratios and 95% confidence intervals: 50.2, 5.8-433.5 and 3.1, 1.1-8.8 , respectively) were risk factors associated with severe posttransplant BI.
CONCLUSIONS: Pretransplant neurological complications were prevalent, and severe posttransplant BI occurred at a rate of 7.8% and was significantly associated with severe pretransplant cerebral edema and postoperative international normalized ratio. Our findings support the use of pretransplant computed tomography. If severe pretransplant cerebral edema is confirmed, efforts should be made to aggressively control intracranial pressure and select a proper donor to minimize the risk of severe posttransplant BI and futile transplantation.

The Values of Cerebrovascular Pressure Reactivity and Brain Tissue Oxygen Pressure Reactivity in Experimental Anhepatic Liver Failure

Authors: Grözinger G, Schenk M, Morgalla MH, Thiel C, Thiel K, Schuhmann MU.

BACKGROUND: We investigated in a porcine model of anhepatic acute liver failure (ALF), the value of two parameters describing cerebrovascular autoregulatory capacity, pressure reactivity index (PRx) and brain tissue oxygen pressure reactivity (ORx), regarding their power to predict the development of intracranial hypertension.
METHODS: In six pigs, hepatectomy was performed. Only one animal was sham operated. All animals received neuromonitoring including arterial blood pressure, intracranial pressure (ICP), and brain tissue partial oxygen pressure (P(br)O(2)). The average time of neuromonitoring was 31.0 h. Cerebral perfusion pressures (CPP), cerebrovascular pressure reactivity index (PRx) and brain tissue oxygen reactivity index (ORx) were calculated.
RESULTS: Perioperative disturbance of AR improved within 4 h after surgery. From 6 to 16 h post hepatectomy, ICP did slowly increase by 4 mmHg from baseline; CPP remained stable around 40 mmHg. PRx and ORx, however, indicated in this period a progressive loss of AR, reflected in a decrease of P(br)O(2) despite unchanged CPP. Beyond 16 h, ICP rose quickly. At CPP levels below 35 mmHg, P(br)O(2) fell to ischemic levels.
CONCLUSIONS: The loss of cerebrovascular autoregulatory capacity, indicated by a rise of PRx and ORx precedes the final crisis of uncontrollable intracranial hypertension in this animal model by hours. During this phase cerebral blood flow, as reflected in tissue oxygenation, deteriorates despite unchanged CPP. Monitoring of AR during ALF therefore seems to carry the power to identify a risk for development of critical CBF and intracranial hypertension.

Correlation of the intracranial pressure to the central venous pressure in the late phase of acute liver failure in a porcine model

Authors: Scheuermann K, Thiel C, Thiel K, Klingert W, Hawerkamp E, Scheppach J, Königsrainer A, Morgalla MH, Leckie P, Proven A, Jalan R, Davies N, Schuhmann MU, Schenk M.

Volume loading is a common method used to ensure adequate circulation. However, in the late phase of acute liver failure complications that often lead to death are cerebral swelling and brainstem edema, which are considered to result from increasing intracranial pressure (ICP). In former studies cerebral venous pressure (CVP) and ICP were reported to be independent entities. Acute liver failure was induced in 25 German land race pigs by acetaminophen intoxication. CVP and ICP were measured continuously. Hydroxyethyl starch solution and noradrenalin were administered to stabilize the circulation at a mean arterial pressure above 60mmHg. There is an increasing correlation in quantity and quality between the CVP and ICP in the last 24 h before exitus. Beginning with a slope of 0.24 (ICP against CVP) and a low correlation coefficient of 0.08. 24h before exitus, this situation remained stable until 16 h to exitus (m = 0.22, r = 0.1). The correlation increased from 16 to 8 h prior to exitus to a slope of m = 0.5 and a correlation of r = 0.3 and remained until exitus. In late acute liver failure it seems therefore clinically reasonable to keep circulation within an adequate range by the use of noradrenalin and to avoid fluid overload.

Neurological complications of acute liver failure: Pathophysiological basis of current management and emerging therapies

Authors: Mpabanzi L, Jalan R. (Department of Surgery, Maastricht University Medical Centre, and NUTRIM School of Nutrition, Toxicology and Metabolism, Maastricht University, P.O. Box 5800, Maastricht, The Netherlands; Hepato-Pancreato-Biliary and Liver Transplant Surgery, Royal Free Hospital, University College London, Pond Street, London NW3 2QG, United Kingdom.)

One of the major causes of mortality in patients with acute liver failure (ALF) is the development of hepatic encephalopathy (HE) which is associated with increased intracranial pressure (ICP). High ammonia levels, increased cerebral blood flow and increased inflammatory response have been identified as major contributors to the development of HE and the related brain swelling. The general principles of the management of patients with ALF are straightforward. They include identifying the insult causing hepatic injury, providing organ systems support to optimize the patient's physical condition, anticipation and prevention of development of complications. Increasing insights into the pathophysiological mechanisms of ALF are contributing to better therapies. For instance, the evident role of cerebral hyperemia in the pathogenesis of increased ICP has led to a re-evaluation of established therapies such as hyperventilation, N-acetylcysteine, thiopentone sodium and propofol. The role of systemic inflammatory response in the pathogenesis of increased ICP has also gained importance supporting the concept that antibiotics given prophylactically reduce the risk of developing sepsis during the course of illness. Moderate hypothermia has also been established as a therapy able to reduce ICP in patients with uncontrolled intracranial hypertension and to prevent increases in ICP during orthopic liver transplantation. Ornithine phenylacetate, a new drug in the treatment of liver failure, and liver replacement therapies are still being investigated both experimentally and clinically. Despite many advances in the understanding of the pathophysiological basis and the management of intracranial hypertension in ALF, more clinical trials should be conducted to determine the best therapeutic management for this difficult clinical event.

The neurological manifestations of acute liver failure

Authors: Shawcross DL, Wendon JA.

Acute liver failure is a disorder which impacts on multiple organ systems and results from hepatocellular necrosis in a patient with no previous history of chronic liver disease. It typically culminates in the development of liver dysfunction, coagulopathy and encephalopathy, and is associated with high mortality in poor prognostic groups. In acute liver failure, some patients may develop cerebral edema and increased intracranial pressure although recent data suggest that intracranial hypertension is less frequent than previously described, complicating 29% of acute cases who have proceeded to grade 3/4 coma. Neurological manifestations are primarily underpinned by the development of brain edema. The onset of encephalopathy can be rapid and dramatic with the development of asterixis, delirium, hyperreflexia, clonus, seizures, extensor posturing and coma. Ammonia plays a definitive role in the development of cytotoxic brain edema. Patients with acute liver failure have a marked propensity to develop renal insufficiency and hence impaired ammonia excretion. The incidence of both bacterial and fungal infection occurs in approximately one third of patients. The relationship between inflammation, as opposed to infection, and progression of encephalopathy is similar to that observed in chronic liver disease. Intracranial pressure monitoring is valuable in identifying surges in intracranial hypertension requiring intervention. Insertion of an intracranial bolt should be considered only in the subgroup of patients who have progressed to grade 4 coma. Risk factors for developing intracranial hypertension are those with hyperacute and acute etiologies, progression to grade 3/4 hepatic encephalopathy, those who develop pupillary abnormalities (dilated pupils, sluggishly responsive to light) or seizures, have systemic inflammation, an arterial ammonia >150μmol/L, hyponatremia, and those in receipt of vasopressor support. Strategies employed in patients with established encephalopathy (grade 3/4) aim to maintain freedom from infection/inflammatory milieu, provide adequate sedation, and correct hypo-osmolality.

Moderate hypothermia with intracranial pressure monitoring as a therapeutic paradigm for the management of acute liver failure: a systematic review

Authors: Dmello D, Cruz-Flores S, Matuschak GM.

OBJECTIVE: To systematically review the literature and present data on the safety and efficacy of induced moderate hypothermia combined with ICP monitoring in critically ill patients with acute liver failure.

DESIGN: We conducted a retrospective observational search of MEDLINE database using both OVID and PubMed with the following MeSH terms, "Hypothermia, Induced," "Brain Edema," "Intracranial Hypertension" (ICH), "Liver failure, Acute" and "Liver Failure, Fulminant." We limited our search to case series involving at least three human subjects and all other clinical trials. Baseline ICP, cerebral perfusion pressure (CPP) and cerebral blood flow (CBF) as well as the response of these variables to hypothermia were recorded when available. Additional clinical and demographic data were also recorded.

RESULTS: Five case series were identified. Pre-existing coagulopathy from liver failure was reversed by various modalities in all studies prior to insertion of ICP monitors. Induction of moderate hypothermia combined with ICP monitoring consistently improved ICP, CPP and CBF in four trials; one trial demonstrated the feasibility and effectiveness of moderate induced hypothermia as part of a protocolized strategy for the management of ICH.

CONCLUSIONS: Limited data exist concerning the safety and efficacy of moderate hypothermia and ICP monitoring for the treatment of ICH in acute liver failure. The available evidence shows that induction of moderate hypothermia in this clinical setting is feasible and possibly efficacious. Well-designed prospective clinical trials are warranted in this challenging context, given the potential of providing a bridge to liver transplantation or even clinical recovery.


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