The Effect of Indomethacin on Intracranial Pressure, Cerebral Perfusion and Extracellular Lactate and Glutamate Concentrations in Patients with Fulminant Hepatic Failure

Tofteng, Flemming; Larsen, Fin Stolze

doi:10.1097/01.wcb.0000125648.03213.1d

Cited by 111 publications

(49 citation statements)

References 32 publications

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“…102 Chung and colleagues also demonstrated that indomethacin can prevent the development of ammonia-induced brain edema in rats that have undergone portocaval anastamosis. 103 In a chronic portocaval-shunted rat model, Cauli and colleagues showed that the NSAID ibuprofen restored the ability of the rats to learn the Y-task maze, in addition to normalization of the function of the glutamate-nitric oxide cyclic guanosine monophosphate enzyme pathway in the cerebral cortex.…”

Section: Non-steroidal Anti-inflammatoriesmentioning

confidence: 98%

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

Aldridge

Tranah

Shawcross

2015

Journal of Clinical and Experimental Hepatology

235

190

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The syndrome we refer to as Hepatic Encephalopathy (HE) was first characterized by a team of Nobel Prize winning physiologists led by Pavlov and Nencki at the Imperial Institute of Experimental Medicine in Russia in the 1890's. This focused upon the key observation that performing a portocaval shunt, which bypassed nitrogen-rich blood away from the liver, induced elevated blood and brain ammonia concentrations in association with profound neurobehavioral changes. There exists however a spectrum of metabolic encephalopathies attributable to a variety (or even absence) of liver hepatocellular dysfunctions and it is this spectrum rather than a single disease entity that has come to be defined as HE. Differences in the underlying pathophysiology, treatment responses and outcomes can therefore be highly variable between acute and chronic HE. The term also fails to articulate quite how systemic the syndrome of HE can be and how it can be influenced by the gastrointestinal, renal, nervous, or immune systems without any change in background liver function. The pathogenesis of HE therefore encapsulates a complex network of interdependent organ systems which as yet remain poorly characterized. There is nonetheless a growing recognition that there is a complex but influential synergistic relationship between ammonia, inflammation (sterile and non-sterile) and oxidative stress in the pathogenesis HE which develops in an environment of functional immunoparesis in patients with liver dysfunction. Therapeutic strategies are thus moving further away from the traditional specialty of hepatology and more towards novel immune and inflammatory targets which will be discussed in this review. ( J CLIN EXP HEPATOL 2015;5:S7-S20) H epatic encephalopathy (HE) is the term used to encapsulate the broad spectrum of neuropsychiatric disturbances associated with both acute and chronic liver failure (ALF and CLF, respectively), as well as porto-systemic bypass in the absence of hepatocellular disease. The clinical manifestations of HE can be extremely heterogeneous in nature, with symptoms presenting anywhere on a continuum spanning from seemingly normal cognitive performance, right the way through to states of confusion, stupor and coma. In between these extremes, patients with HE may exhibit signs such as inattentiveness, blunted affect, impairment of memory or reversal of the sleep-wake cycle, as well as physical manifestations such as tremor, myoclonus, asterixis and deep tendon hyperreflexia.ALF is defined by the onset of coagulopathy alongside any degree of encephalopathy in patients with no evidence of pre-existing liver disease. 1 The presence of HE in those with ALF is prognostic, with up to a quarter of cases developing raised intracranial pressure. 2 Patients presenting with ALF are at risk of developing its cardinal, lifethreatening feature, cerebral edema. Left untreated, cerebral edema can rapidly progress to cause herniation of the uncus through the falx cerebri, leading to compression of the brainstem and, ultimately, death. H...

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Section: Non-steroidal Anti-inflammatoriesmentioning

confidence: 98%

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

Aldridge

Tranah

Shawcross

2015

Journal of Clinical and Experimental Hepatology

235

190

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“…In our data, however, the position of the γ-CH 2 Glx at 2.34 ppm in all ALF patients and controls indicates that the main component of the Glx peaks in the white and grey matter brain tissue of ALF patients and controls is glutamate. Considering that sharply elevated extracellular brain glutamate concentrations have [22], the possibility of part of the Glx signal representing extracellular rather than intracellular glutamate should be considered. We conclude that of the total of up to 6 mmol/l Glx observed in the brains of ALF patients (Table 2), up to 5% might have been extracellular glutamate.…”

Section: Glutamate/glutamine (Glx)mentioning

confidence: 99%

Quantitative multivoxel 1H MR spectroscopy of the brain in children with acute liver failure

et al. 2008

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Acute liver failure (ALF)-related encephalopathy was previously characterized by MR spectroscopy of single voxels containing both grey and white matter brain tissue. Quantitative multivoxel MRS was used here to compare grey and white matter brain tissue concentrations of glutamate/glutamine (Glx) and lactate in ALF and associate the results with other liver function parameters. Five pediatric patients with ALF-related encephalopathy and five controls, examined after successful liver transplantation, were examined by brain MRI/MRS. ALF patients had higher Glx and lactate concentrations in brain white matter than controls (Glx + 125%: P<0.01; lactate + 33%, P<0.05) and higher Glx in grey matter (Glx + 125%: P< 0.01). Within the group of ALF patients positive correlations were found between grey or white matter lactate concentration and serum ammonia (P<0.05), and negative correlations between grey or white matter Glx and venous pH (P<0.001). This is the first study presenting evidence of high Glx levels in both white and grey matter brain tissue in ALF-related encephalopathy. The elevations in CNS Glx and lactate concentrations appear to relate to hepatic detoxification (ammonia, venous pH), rather than to liver parenchymal integrity (aspartate aminotransferase, alanine aminotransferase) or biliary cholestasis (bilirubin, γ-glutamyl transpeptidase, alkaline phosphatase).

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“…Hyperventilation results in precapillary vasoconstriction (37) and while not recommended as a prophylactic measure, it is especially useful to control surges of ICP, a "pressure wave" that requires immediate medical therapy. A similar use can be assigned to indomethacin, a cerebral vasoconstrictor (38); the effects of the drug on the gastric mucosa and renal circulation preclude a prophylactic role.…”

Section: C) Therapeutic Optionsmentioning

confidence: 99%

Brain edema in acute liver failure: Can it be prevented? Can it be treated?

Blei

2007

Journal of Hepatology

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Acute liver failure; Brain edema; intracranial pressure; Cerebral blood flowThe management of cerebral edema in Acute Liver Failure (ALF) is still imperfect, reflecting the limited tools to control brain swelling in this disease as well as in other neurological conditions (1). A better understanding of the unique mechanisms responsible for brain edema in ALF has emerged over the last years (2). Data arising from studies in experimental animals and in humans allow a more rational approach to the prevention and treatment of this serious complication of ALF. A. THE PATHOGENESIS OF BRAIN EDEMA IN ALFA net increase in water content defines the presence of brain edema. In the setting of an intact blood-brain barrier, water moves into brain via 3 possible routes: Via diffusion through the lipid bilayer of plasma membranes, via co-transport with organic and inorganic ions and through specialized water channels, aquaporins (2). Of special interest is aquaporin 4, the predominant aquaporin in brain. Mainly localized to cerebral endothelial cells and astrocyte foot processes that surround them, aquaporin-4 may play an important role in the pathogenesis of cytotoxic brain edema. Brain edema as a result of water intoxication is markedly reduced in aquaporin-4-deficient mice (reviewed in 3).For many years, an accepted tenet has been the presence of an intact blood-brain barrier and a cytotoxic etiology to explain brain edema in ALF. This concept has been recently challenged (4) with the possibility of a "leaky" rather than a bona fide rupture of the barrier. Effects on endothelial tight-junction proteins could be present, a change potentially explained by the action of endotoxin and/or pro-inflammatory cytokines on cellular permeability (5). Still, cytotoxic mechanisms need to be considered as a major pathogenic factor. In a recent study, all 7 patients with ALF and deep encephalopathy showed evidence of cytotoxic edema using diffusion-weighted MRI of the brain (6).Figure 1 depicts current views of the complex pathogenesis of brain edema in ALF. Astrocyte swelling is initiated by the accumulation of glutamine, the result of the detoxification of ammonia. As a result of swelling, ions (such as K + ) and other osmolytes Correspondence: Andres T Blei, MD, Northwestern University Feinberg School of Medicine, Division of Hepatology, 303 E Chicago Avenue -Searle 10-574, Chicago, IL 60611, e-mail: a-blei@northwestern.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (including myo-inositol, glutamate and taurine) are released. Ammonia-induced effects in vitro include an increase in aquapor...

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The Effect of Indomethacin on Intracranial Pressure, Cerebral Perfusion and Extracellular Lactate and Glutamate Concentrations in Patients with Fulminant Hepatic Failure

Cited by 111 publications

References 32 publications

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

Quantitative multivoxel 1H MR spectroscopy of the brain in children with acute liver failure

Brain edema in acute liver failure: Can it be prevented? Can it be treated?

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