Multisystem organ failure in neurosurgical patients.
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Aged↗
Biomedical subjects
A Unterberg
Publications and source records attributed to A Unterberg.
Evidence against leukotrienes as mediators of brain edema.
Leukotrienes are powerful metabolites of arachidonic acid which are known to increase the permeability of peripheral blood vessels. These substances are found in brain tissue in association with cerebral ischemia, and in brain tumors. Therefore, it has been proposed that leukotrienes have a mediator function in brain edema. This hypothesis was subjected to further experimental analysis in this study, in which the authors investigated whether: 1) superfusion of the exposed brain surface with leukotrienes increases the permeability of extraparenchymal blood vessels in vivo; 2) intraparenchymal infusion of leukotrienes induces brain edema; and 3) pharmacological inhibition of leukotriene formation by BW755C, an inhibitor of leukotriene synthesis, reduces formation of brain edema from a standardized traumatic insult. The pial vessels of the parietal cortex of cats were examined by fluorescence microscopy during cerebral superfusion with the leukotrienes C4 (LTC4), D4 (LTD4), or E4 (LTE4) by using an open cranial window preparation. Intravenous Na(+)-fluorescein served as an in vivo blood-brain barrier (BBB) indicator. Superfusion of the pia with leukotrienes (up to 2 microM) did not open the barrier to fluorescein, but was associated with a significant constriction (up to 25%) of arterial and venous vessels. In experiments with slow infusion of leukotriene B4 (LTB4) or LTC4 into the white matter of feline brain, the tissue water content was subsequently determined in serial brain slices using the specific gravity method. Tissue water profiles obtained after a 15-microM infusion of either LTB4 or LTC4 were virtually identical with those of control animals infused with mock cerebrospinal fluid. Thus, neither LTB4 nor LTC4 led to an augmentation of infusion-induced brain edema. In a final series, a cold lesion of the left parietal cortex was induced in rabbits. Twenty-four hours later, swelling of the exposed hemisphere was quantified by gravimetrical comparison of its weight with that of the contralateral nontraumatized hemisphere. Eight animals received BW755C intravenously prior to and after trauma to inhibit formation of leukotrienes. Seven rabbits were infused with an equivalent volume of saline as a control study. The resulting hemispheric swelling was 7.7% +/- 0.6% (mean +/- standard error of the mean) 24 hours later in animals receiving BW755C and 7.8% +/- 1.2% in the control group, indicating that inhibition of leukotrienes was ineffective in preventing formation of vasogenic brain edema. The findings demonstrate that leukotrienes administered to the brain in concentrations occurring under pathological conditions do not open the BBB nor do they induce brain edema.(ABSTRACT TRUNCATED AT 400 WORDS)
4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
[Mediator substances of brain edema in cerebral ischemia].
Brain edema in focal or global cerebral ischemia is associated with formation and release of pathophysiologically active mediator compounds. Therapeutical methods which interfere with mediator compounds under these circumstances might improve specificity of treatment of ischemic brain edema and thereby effectivity. Ischemic brain edema has a vasogenic and cytotoxic component. Extravasation of edema fluid under these conditions can be attributed to ischemic damage of the elements of the blood-brain barrier, the cerebrovascular endothelium. The development of ischemic cell swelling involving nerve- and glial cell processes can not be viewed only as manifestation of cell damage resulting from e.g. energy failure but also as an attempt to maintain or reestablish homeostasis important for cell survival and nerve cell function. The acidosis-induced cell swelling is a case in point. Accumulation of H(+)-ions in the cell causes activation of ion exchange mechanisms to protect or normalize the intracellular pH, respectively. Consequently, Na(+)- and Cl-ions together with water accumulate in the cell as the final process underlying cell swelling. Further, the increased concentrations of glutamate and K(+)-ions found in ischemic brain tissue cause glial cell swelling secondary to an active accumulation of this material together with water in the intracellular compartment in an attempt to normalize the extracellular milieu. A therapeutical inhibition of those mechanisms underlying ischemic cell swelling would prevent reestablishment of the homeostasis and, thereby, enhance secondary tissue damage. A focal brain tissue necrosis, such as an ischemic infarct or traumatic contusion can be utilized to illustrate the pathophysiological significance of the formation and release of mediator compounds of secondary brain damage.(ABSTRACT TRUNCATED AT 250 WORDS)
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Prevention and treatment of secondary brain damage. Clinical aspects.
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Animals↗
The effect of various steroid treatment regimens on cold-induced brain swelling.
The role of steroid therapy in brain oedema following acute cerebral lesions is still unsolved. This study was conducted to compare the efficacy of dexamethasone and triamcinolone, and to analyze the influence of timing and duration of treatment on cold-induced brain swelling. In rabbits, a cryogenic lesion of the left parietal cortex was induced. 24, or 48 hrs after trauma, hemispheric swelling, water- and electrolyte-contents were measured. A first series of animals received dexamethasone, triamcinolone or saline for 24 hrs, starting treatment 10 min after trauma. In a second series, steroid treatment lasted 48 hrs and in a third series the animals were additionally pretreated for 24 hrs. Dexamethasone and triamcinolone slightly decreased posttraumatic hemispheric swelling, from 7.7% in controls to 7.0% in treated animals. There was no significant difference between dexamethasone and triamcinolone. Reduction of swelling was most pronounced in animals with 48 hrs treatment. Pretreatment with steroids was not superior to early posttraumatic treatment. On the other hand, dexamethasone and triamcinolone significantly decreased cerebral water content in the traumatized and contralateral hemisphere, as well as in non-traumatized animals. The unspecific reduction of water content by steroids in rabbits might explain the moderate therapeutical effect on brain swelling. This effect might be beneficial, nevertheless, with respect to an improvement of the intracranial compliance.
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Role of leukotrienes as mediator compounds in brain edema.
Leukotrienes accumulate in brain tissue after cerebral ischemia and in brain tumors. Thus, their release might contribute to the blood-brain barrier damage observed under these conditions and, hence, brain edema. The effect of these substances on the permeability of pial vessels and whether inhibition of LT synthesis reduces cold injury brain edema were studied. The pial vasculature of cats was studied by fluorescence microscopy. The cortex was superfused with LTC4, LTD4, or LTE4 via a cranial window. Na(+)-fluorescein was intravenously administered as blood-brain barrier indicator. LT concentrations up to 2 microM did not induce any leakage of the blood-brain barrier indicator into the parenchyma. However, all LTs tested constricted pial arteries and veins. Brain edema formation was studied in rabbits with cold injury. BW755C, an inhibitor of cyclooxygenase and lipoxygenase preventing formation of LTs, was given before and after trauma. Control animals received saline only. BW755C was ineffective in attenuating cold injury edema. Hemispheric swelling in control animals was 7.8 +/- 1.1%, and 7.7 +/- 0.4% in animals with treatment. LTs, even when administered to the brain in concentrations exceeding levels occurring under pathological conditions, did not induce barrier damage, nor did inhibition of LT synthesis attenuate formation of vasogenic edema. The results provide further evidence against LTs as mediator compounds of this process.
4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
Enhancement of infusion-induced brain edema by mediator compounds.
Mediator compounds such as bradykinin, arachidonic acid, and LT are released in the brain in conditions causing cerebral swelling. The potential of these compounds to enhance this process was studied in the infusion-induced model of brain edema. Cats subjected to chloralose anesthesia were infused with 400 microliters of artificial CSF into the right and left frontal white matter within 2.5 hr. CSF infused into the left hemisphere contained either bradykinin (40 microM), arachidonic acid (3 mM), LTB4 (15 microM), or LTC4 (16 microM), respectively. Evans blue was administered as blood-brain barrier indicator. Water content of gray and white matter was microgravimetrically determined in serial coronal brain slices. Infusion of CSF only led to an increase in water content from 69 to between 75% and 79%. Addition of bradykinin effectively enhanced the infusion edema but did not open the barrier to Evans blue. Arachidonic acid even more effectively led to an increase in water content and opened the barrier to Evans blue, in addition. Infusion of LT (LTB4, as well as LTC4) was not found to increase further the infusion edema and did not open the blood-brain barrier to Evans blue. It is concluded that the infusion edema model is suitable for studying the edema-enhancing potential of mediator compounds. Marked enhancement of vasogenic brain edema by bradykinin or arachidonic acid again demonstrates a pathophysiological function of these compounds as mediators of secondary brain damage, although LT are unlikely to be specifically involved in vasogenic edema formation.
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Blood-brain barrier permeability and vascular reactivity to bradykinin after pretreatment with dexamethasone.
The role of kinins as mediator substances is increasingly recognized in cerebral ischemia and trauma. It has previously been shown that cerebral exposure to bradykinin, which causes brain edema, is associated with arteriolar dilatation and selective opening of the blood-brain barrier (BBB) to small molecular weight indicators, such as Na+-fluorescein. Since the evidence suggests that these effects results from an activation of the arachidonic acid cascade, particularly from formation of E- and I-type prostaglandins, therapeutical inhibition of the cerebral effect of bradykinin has been attempted by pretreatment of experimental animals with dexamethasone. The BBB function and changes of the pial vessel diameters were studied by fluorescence microscopy in cats in alpha-chloralose anesthesia during superfusion of the exposed cerebral cortex. After a control phase bradykinin was added to a cerebral superfusate in concentrations of 4 x 10(-8) M to 4 x 10(-3) M. Two additional groups of animals received dexamethasone in a dose of 1, or 5 mg/kg body wt., respectively, 5 h prior to the cerebral superfusion with bradykinin. Na+-fluorescein (mol wt.: 376) was infused intravenously as a BBB indicator. The BBB marker remained strictly confined to the intravascular compartment under control conditions. Pretreatment with dexamethasone did not prevent opening of the BBB by bradykinin, either at the low, or high dose. However, the low dose of dexamethasone blunted the vasodilatory response to bradykinin, whereas the high dose (5 mg/kg) was found to enhance the dilatory properties of bradykinin at concentrations of 4 x 10(-3) M.(ABSTRACT TRUNCATED AT 250 WORDS)
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The ultrastructural basis of interactions between leukocytes and endothelium.
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Animals↗
Effects of free radicals on permeability and vasomotor response of cerebral vessels.
To obtain further evidence on the role of free radicals as mediators of secondary brain damage, blood-brain barrier (BBB) function and vasomotor response of pial vessels were studied during cortical superfusion of a free radical-generating system of xanthine-oxidase (XO) and hypoxanthine (HX). Intravenously administered Na+-fluorescein (mol. wt. 376), or fluorescein isothiocyanate (FITC)-dextran (mol. wt. 62,000) served as low- and high-molecular weight BBB indicators. Since undialyzed XO considerably increased the osmolarity of artificial cerebrospinal fluid, XO was subjected to equilibrium dialysis, which did not affect enzyme activity. Cortical superfusion with either HX (4 mM) or dialyzed XO alone (0.5 U/ml; osmolarity, 310 mosmol/l) did not induce a vasomotor response. Cortical superfusion with the free radical-generating system under normotonic conditions (HX plus dialyzed XO), led to moderate arterial dilation only with a maximum of +13%. The venous diameters remained unaffected. Moderate extravasation of the low molecular weight indicator Na+-fluorescein was seen in only 33% of the experiments, leakage of FITC-dextran was never observed. To assess the role of hypertonicity of the superfusate, the same experiments were performed with undialyzed XO. When superfusing the cortex with undialyzed XO (0.5 U/ml; osmolarity, 420 mosmol/l), the pial arteries dilated to 146%-168% of normal. Similarly, simultaneous superfusion with undialyzed XO (0.25 U/ml) and HX (2 mM) elicited arterial dilatation to 161%-178% of normal. Even the pial veins were significantly dilated to 108% of normal. In this series a moderate extravasation of Na+-fluorescein occurred in 75%, with leakage of FITC-dextran in 25%.(ABSTRACT TRUNCATED AT 250 WORDS)
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Mediators of blood-brain barrier dysfunction and formation of vasogenic brain edema.
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Arachidonic Acid↗
Mediators of brain edema and secondary brain damage.
Progress is our understanding of the roles of vasogenic and cytotoxic brain edema in secondary brain damage can be expected from studies of the ability of biochemical factors to open the blood-brain barrier, derange the microcirculation, and cause cell swelling and necrosis. Mediator compounds are considered to form or to become released in an area of primarily damaged brain (necrosis) and to enter the cerebral parenchyma through the broken blood-brain barrier from the intravascular space. Many biochemical factors must be considered. We suggested three criteria for determining the roles of mediators: a) they must inflict brain tissue damage, b) they must occur in pathologic concentrations or in compartments not normally present, and c) specific inhibition should attenuate secondary brain damage. These requirements are met by the kallikrein-kinin system and by glutamate. In the case of arachidonic acid and its many metabolites, the concept is difficult to test because fatty acids may be active only if not bound to proteins, and therapeutic inhibition might be difficult. A variety of mediators may enhance each other in a cascade manner by various initiating reactions that might be amenable for pharmacologic inhibition.
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Studies of pial vascular permeability.
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Animals↗
Permeability and vasomotor response of cerebral vessels during exposure to arachidonic acid.
Release of arachidonic acid (AA) in brain tissue is found in various cerebral insults. Blood-brain barrier function and vasomotor response were studied during cerebral administration of the fatty acid to obtain further evidence on its role as mediator of secondary brain damage under pathological conditions. Na+-fluorescein or fluorescein isothiocyanate (FITC)-dextran were i.v. administered as low- and high-molecular weight blood-brain barrier indicators. Cortical superfusion of arachidonic acid led to moderate constriction of ca. 90% of normal of pial arteries of 60-220 micron phi, whereas the venous diameters remained unaffected. On the other hand, AA caused opening of the blood-brain barrier not only for Na+-fluorescein but also for FITC-dextran (mol.wt. 62,000). Extravasation of Na+-fluorescein started at AA concentrations of 3 X 10(-5) M. Concentrations of 3 X 10(-4) to 3 X 10(-3) M always sufficed to induce barrier opening for fluorescein, whereas 3 X 10(-3) M was required for FITC-dextran. Leakage of the blood-brain barrier indicators started around venules. Pretreatment with indomethacin, or with BW 755 C, a dual inhibitor of both the cyclo- and lipoxygenase pathway did not prevent barrier opening by arachidonate for Na+-fluorescein. However, in the presence of indomethacin higher concentrations of AA were required to open the barrier for Na+-fluorescein, whereas BW 755 C did not influence the dose-effect relationship of AA and barrier opening observed in untreated animals. The latter findings imply that the pathophysiological effects induced by AA are likely to be attributed to the acid itself, rather than to its metabolites, a conclusion which might be in conflict with earlier observations reported in the literature. Electron microscopy revealed marked alterations of the venous endothelium, such as an attachment and eventual penetration of polymorphonuclear granulocytes through the endothelial barrier, while the small arteries and arterioles were unaffected. The findings may indicate that opening of the barrier by AA is mediated by granulocytes and/or their products. Taken together, our findings support the concept that release of AA in primarily damaged brain tissue enhances secondary processes, such as a failure of the blood-brain barrier function. The limited potency or even ineffectiveness, respectively, of indomethacin or BW 755 C provides evidence for a direct involvement of the fatty acid rather than of its metabolic degradation products. Therefore, therapeutic prevention of AA formation under these circumstances might be superior to mere inhibition of its metabolism.
4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
The kallikrein-kinin system as mediator in vasogenic brain edema. Part 3: Inhibition of the kallikrein-kinin system in traumatic brain swelling.
Evidence has previously been provided that administration of kinins to the cerebrum causes edema and opening of the blood-brain barrier. It has further been shown that these highly active compounds are formed in the brain under pathophysiological conditions. Their formation was enhanced when cerebral blood flow became compromised by an increase in intracranial pressure. Final evidence, however, was not available as to whether specific inhibition of the kallikrein-kinin (KK) system has a therapeutic function in acute head injury. The authors have demonstrated in rabbits that inhibition of the activating enzyme kallikrein by aprotinin or by aprotinin plus soybean trypsin inhibitor (SBTI), which interfere with plasma and tissue kallikrein, is associated with a decrease in formation of posttraumatic swelling after a standardized cold lesion to the brain. Saline-treated control animals with cerebral cold-induced injury had an increase in hemispheric weight 24 hours later of 13.0% +/- 0.8% (standard error of the mean) in the damaged hemisphere compared to the contralateral nondamaged hemisphere. Administration of aprotinin or aprotinin plus SBTI led to a significant reduction of hemispheric swelling of 10.1% +/- 0.7% or 10.4% +/- 0.7%, respectively. In animals receiving SBTI only, hemispheric swelling evolving from cold injury was not significantly reduced. Therapeutic reduction of brain edema by aprotinin cannot be attributed to a nonspecific effect on the blood pressure, which in the experimental groups remained almost normal as compared to the control animals. Failure of SBTI to influence posttraumatic brain swelling may have resulted from disturbances in intravascular coagulation. Measurements of aprotinin in plasma and tissue demonstrate that the inhibitor doses employed are within an effective therapeutic range. Attenuation of brain edema by specific inhibition of the KK system provides evidence for a mediator role of kinins in vasogenic edema. Clinical trials with inhibitors of the KK system in acute forms of traumatic lesions associated with vasogenic edema appear worthwhile.
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Intravital fluorescence microscopy for the study of blood-brain-barrier function.
Vascular diameters and blood-brain-barrier (BBB) function were investigated in the parietal cortex of cats using an open skull window technique and intravital fluorescence microscopy. The cortical surface was superfused with artificial cerebrospinal fluid containing: bradykinin (BK), Na+-arachidonate (AA), or xanthine-oxidase (XO). Na+-fluorescein (MW: 376), fluorescein-isothiocyanate-labelled (FITC) albumin (MW: 67 000), or FITC-dextran (MW: 19 400-62 000) were given intravenously as blood-brain-barrier indicators of different molecular size. In control experiments, the effect of continuous exposure of the preparation to the light source used for fluorescence excitation was studied. Dependent on the molecular size of the tracer and light intensity, continuous light exposure led to extravasation and disturbances of the microcirculation in small veins. When Na+-fluorescein was employed as barrier indicator at a magnification of X 40, at least 55 min of continuous illumination were required to induce extravasation. Brief, i.e. 0.5-15 s and discontinuous illumination for taking microphotographs amounting to less than 20 min in total did not induce extravasation in control experiments of 3.5 h. Opening of the blood-brain-barrier was studied during superfusion with a hypertonic solution (2000 mOsmol 1(-1)). The results obtained with bradykinin, Na+-arachidonate, or xanthine-oxidase indicate that opening of the barrier can occur independently from a corresponding vasodilating reaction. BK, or AA led to initial venular leakage as a result of an increase of selective, or global barrier permeability. On the other hand, XO did not induce extravasation, although cerebral vessels were markedly dilated. Taken together, the experimental model presented is suitable to simultaneously analyze dynamic changes of the permeability of cerebral vessels in-vivo with excellent spatial resolution and of the cerebral vasomotor behaviour under physiological and pathological conditions.
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Effects of bradykinin on permeability and diameter of pial vessels in vivo.
The effect of bradykinin on the permeability and vasomotor response of pial vessels has been studied to enhance our understanding of the pathophysiological role of the kallikrein-kinin system in cerebral tissue. Intravital fluorescence microscopy of the pia arachnoidea was conducted using Na+-fluorescein, FITC-dextran, and FITC-albumin as low and high molecular weight blood-brain barrier indicators. Massive arterial dilatation evolved immediately upon administration of bradykinin by superfusion of the exposed cerebral surface. An increase of the arterial diameter by 40% was the maximal response found at bradykinin concentrations of 4 x 10(-5) M. Arterial dilatation became attenuated with continuous superfusion of the preparation with bradykinin. In pial veins, a moderate reduction of the vessel diameter was observed, however, only after prolonged superfusion of the preparation. Bradykinin led to selective opening of the blood-brain barrier for Na+-fluorescein at superfusate concentrations of greater than or equal to 4 x 10(-7) M, but not for FITC-dextran or FITC-albumin. Topical administration of l-isoproterenol (10(-4) M) was found to prevent extravasation of Na+-fluorescein in the presence of bradykinin concentrations of 4 x 10(-6) M. Protection of the blood-brain barrier by isoproterenol was not observed when higher concentrations of bradykinin were employed. Intracarotid infusion of bradykinin were employed. Intracarotid infusion of bradykinin led also to a selective opening of the blood-brain barrier for Na+-fluorescein, but not for FITC-dextran or FITC-albumin. In contrast to superfusion, this route of administration did not induce changes of the vasomotor behavior of the arteries or veins. Additional experiments with B1-agonists and -antagonists suggest that bradykinin causes the openings of the blood-brain barrier th rough an interaction with B2-receptors on endothelial cells, and arterial dilatation via interaction with B2-receptors on vascular smooth muscle cells. Our findings support the concept that the release of kinins in the brain during an acute cerebral lesion mediates secondary damaging processes by the enhancement of blood-brain barrier dysfunction.
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The kallikrein-kinin system as mediator in vasogenic brain edema. Part 1: Cerebral exposure to bradykinin and plasma.
Plasma and bradykinin were perfused into the ventricular system of mongrel dogs to investigate whether either or both induce brain edema. Formation of cerebral edema was determined by measurement of cerebral water and electrolytes in periventricular white matter, cerebral cortex, and caudate nucleus. The response of cerebral tissue to exposure to bradykinin or to plasma, as a carrier of kininogens, was analyzed by assessment of the perfusate composition after ventricle passage. The authors report that cerebral administration of bradykinin induces cerebral edema. Ventricular perfusion with plasma also led to an increase of cerebral water content which was restricted to the white matter, but involved all brain tissue areas, if bradykinin was used. Ventricular perfusion with plasma was associated with consumption of the kinin precursor (kininogens) indicative of formation of kinins. Significant consumption of the precursor was found in five out of nine animals subjected to plasma perfusion of the ventricular system. In these animals a close correlation between the increase of white matter water content and kininogen-consumption as a measure of kinin-formation was obtained. Marked kinin-degrading activity was observed during ventricular perfusion with bradykinin as concluded from a considerable decrease of bradykinin concentration in the cisternal effluent compared to the inflowing perfusate concentration. Ventricular perfusion with plasma was associated with a decrease of K+ clearance capacity with continued duration, and in two animals with a release of glutamate into the plasma perfusate, suggesting an involvement of cytotoxic mechanisms. These findings provide support for the hypothesis of a mediator function of the kallikrein-kinin (KK) system in vasogenic brain edema. The next question that needs to be answered to complete the picture--does spontaneous activation of the KK system occur in conditions leading to vasogenic edema?--is studied in a subsequent report.
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