The effects of indomethacin on intracranial pressure, cerebral blood flow and cerebral metabolism in patients with severe head injury and intracranial hypertension

Jensen, Katrine; Öhrström, J.; Cold, Georg E.; Astrup, Jens

doi:10.1007/bf01418518

Cited by 86 publications

(79 citation statements)

References 32 publications

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“…Other inhibitors of cyclooxygenase, such as aspirin and ibuprofen, will not result in cerebral vasoconstriction. 22 Alternative mechanisms include interference with the regulation of cerebrovascular tone mediated by extracellular pH, 23 a reduction of cerebral temperature, 24 as well as a direct non-prostaglandin-mediated vasoconstrictive effect. 25 Our study was not designed to dissect this complexity, although we did show evidence of decreased prostanoid formation without effects on body temperature.…”

Section: Discussionmentioning

confidence: 99%

Indomethacin Prevents the Development of Experimental Ammonia–Induced Brain Edema in Rats After Portacaval Anastomosis

Chung

2001

Hepatology

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Brain edema is a leading cause of death in fulminant hepatic failure (FHF). Patients with FHF who develop brain edema and intracranial hypertension exhibit an increase in cerebral blood flow (CBF). 1-3 Changes in cerebral perfusion have been documented with different techniques, are not related to alterations in systemic hemodynamics, 4 and contribute to intracranial hypertension by increasing cerebral blood volume. Although some subjects with FHF show a reduced CBF, 5,6 the majority of these patients do not exhibit brain edema. 1-2 An increase in cerebral perfusion has been described in experimental models of severe hyperammonemia. 7 Recent studies link elevated plasma ammonia levels to the development of cerebral herniation in FHF. 8,9 Insight into the importance of cerebral perfusion arises from work in an experimental model of brain edema, i.e., rats with portacaval anastomosis (PCA) infused with ammonium acetate. In this preparation, brain swelling and an increase in intracranial pressure (ICP) predictably develop after 3 hours of ammonia infusion in the absence of acute liver injury, allowing the performance of pathophysiologic studies in an otherwise stable model. 10 Using the radioactive microsphere technique, we have shown a selective increase in CBF at 3 hours of infusion, 11 without concomitant changes in systemic hemodynamics or flow to other regional beds. In this model, the increase in cerebral perfusion appears related to an intracerebral signal generated after the detoxification of ammonia to glutamine in astrocytes. Administration of methionine-sulfoximine, an irreversible inhibitor of glutamine synthetase, ameliorated the increase in CBF seen in this model. 12 The nature of the intracerebral signal has not been elucidated. Our initial postulate of increased nitric oxide synthesis in the brain 12,13 led to experiments using nonselective and selective inhibitors of nitric oxide synthase isoforms. Under these conditions, the rise in CBF was still present. 14 We proposed that the development of cerebral hyperemia is necessary for the appearance of cerebral swelling in this model. Mild hypothermia (33°C and 35°C) was shown to prevent the development of ammonia-induced brain edema 11 as well as forestall brain water accumulation in a model of FHF. 15 Clinical studies confirm the protective effect of hypothermia to 32°C in patients with FHF and severe intracranial hypertension. 3 The mechanisms by which hypothermia reduces ICP may be multiple, 16 but an effect on cerebral perfusion has been well documented in our experimental model 11 as well as in humans with FHF. 3 High values of CBF seen in both the experimental and human condition are normalized by hypothermia.We designed an experiment in which indomethacin, a known cerebral vasoconstrictor, 17 was coadministered to PCA rats receiving an ammonia infusion. The drug is a nonselective inhibitor of endothelial cyclooxygenase and has minimal penetration into the brain. 18 If a selective effect on cerebral blood flow influences the development of brain ...

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Section: Discussionmentioning

confidence: 99%

Indomethacin Prevents the Development of Experimental Ammonia–Induced Brain Edema in Rats After Portacaval Anastomosis

Chung

2001

Hepatology

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“…55 In a patient with spaceoccupying hemispheric infarction, indomethacin was effective in transiently reducing ICP and improving CPP after all other conventional therapies had failed, and repeated boluses continued to be effective. 56 However, a critical decline in cerebral blood flow with secondary ischemia may occur as a result of cerebral vasoconstriction.…”

Section: Bardutzky and Schwabmentioning

confidence: 99%

“…56 However, a critical decline in cerebral blood flow with secondary ischemia may occur as a result of cerebral vasoconstriction. 55 Given the lack of systemic clinical trials, indomethacin for the treatment of postischemic swelling remains experimental.…”

Section: Bardutzky and Schwabmentioning

confidence: 99%

Antiedema Therapy in Ischemic Stroke

Bardutzky

Schwab

2007

Stroke

176

103

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Abstract-Life-threatening, space-occupying brain edema occurs in up to 10% of patients with supratentorial infarcts and is traditionally associated with a high mortality rate of up to 80%. Management of these patients is currently being changed to an earlier and more aggressive treatment regimen. Early surgical decompression has recently been proven effective to reduce mortality and increase the number of patients with a favorable outcome in randomized controlled trials and is now the "antiedema" therapy of first choice for patients with large middle cerebral artery infarction aged 60 years or younger. Several medical treatment strategies have been proposed to control brain edema and reduce intracranial pressure, including different osmotherapeutics, hyperventilation, tromethamine, hypothermia, and barbiturate coma. None of these treatments is supported by level 1 evidence of efficacy in clinical trials, and some of them may even be detrimental. Preliminary results on hypothermia for space-occupying hemispheric infarction are encouraging, but far from definitive. (Stroke. 2007;38:3084-3094.)

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“…The only tomographic study on living animals (Schumann et al, 1996), found no change of the global CMR O 2 but interestingly (see below) a small and significant increase of CMR O 2 in thalamus and pons. In adult humans, the effect of indomethacin on CMR O 2 was assessed only by the arterio-venous difference (Wennmalm et al, 1981;Jensen et al, 1991;Dahl et al, 1996;Bundgaard et al, 1996) and no significant change was observed in any of these studies. However, a study of preterm infants with near-infrared-spectroscopy of cytochrome oxidase indicated reduced oxygenation (Benders et al, 1995).…”

Section: Effect Of Indomethacin On Cmr Omentioning

confidence: 99%

“…We then tested the properties of the extended model equation by calculating the magnitude of the equation parameters, which would accurately predict the values of oxygen consumption measured in the course of drug-induced lowering of CBF. We used indomethacin, which lowers blood flow, probably by nonselectively inhibiting cyclooxygenase-1 (COX-1) and -2 (Jensen et al, 1991(Jensen et al, , 1993Dahl et al, 1996;Imberti et al, 1997;Zonta et al, 2003), although other mechanisms have also been proposed (Wang et al, 1993;Parfenova et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Cerebral Metabolic Response to Low Blood Flow: Possible Role of Cytochrome Oxidase Inhibition

Gjedde

Johannsen

Cold

et al. 2005

J Cereb Blood Flow Metab

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The reactions of cerebral metabolism to imposed changes of cerebral blood flow (CBF) are poorly understood. A common explanation of the mismatched CBF and oxygen consumption (CMR O 2 ) during neuronal excitation holds that blood flow rises more than oxygen consumption to compensate for an absent oxygen reserve in brain mitochondria. The claim conversely implies that oxygen consumption must decline when blood flow declines. As the prevailing rate of reaction of oxygen with cytochrome c oxidase is linked to the tension of oxygen, the claim fails to explain how oxygen consumption is maintained during moderate reductions of CBF imposed by hyperventilation (hypocapnia) or cyclooxygenase (COX) inhibition. To resolve this contradiction, we extended the previously published oxygen delivery model with a term allowing for the adjustment of the affinity of cytochrome c oxidase to a prevailing oxygen tension. The extended model predicted constant oxygen consumption at moderately reduced blood flow. We determined the change of affinity of cytochrome c oxidase in the extended model by measuring CBF in seven, and CMR O 2 in five, young healthy volunteers before and during COX inhbition with indomethacin. The average CBF declined 35%, while neither regional nor average CMR O 2 changed significantly. The adjustment of cytochrome c oxidase affinity to the declining oxygen delivery could be ascribed to a hypothetical factor with several properties in common with nitric oxide.

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The effects of indomethacin on intracranial pressure, cerebral blood flow and cerebral metabolism in patients with severe head injury and intracranial hypertension

Cited by 86 publications

References 32 publications

Indomethacin Prevents the Development of Experimental Ammonia–Induced Brain Edema in Rats After Portacaval Anastomosis

Indomethacin Prevents the Development of Experimental Ammonia–Induced Brain Edema in Rats After Portacaval Anastomosis

Antiedema Therapy in Ischemic Stroke

Cerebral Metabolic Response to Low Blood Flow: Possible Role of Cytochrome Oxidase Inhibition

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