Treatment of hemorrhagic hypotension with hypertonic saline/dextran: effects on brain surface oxygen tension in experimentally traumatized brain.
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Animals↗
Biomedical subjects
A Baethmann
Publications and source records attributed to A Baethmann.
Swelling of C6 glioma cells and astrocytes from glutamate, high K+ concentrations or acidosis.
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Acidosis, Lactic↗
[Therapy of hemorrhagic shock using small volumes of hypertonic-hyperoncotic NaCl-dextran solution--effects on the brain].
Infusion of small volumes of hypertonic/hyperoncotic solution (HHL: 7.2% NaCl/10% dextran 60) is highly effective in haemorrhagic shock. Cardiovascular function is restored in a matter of minutes by rapid mobilisation of extravasal fluid. However, little experience has been collected to date on the side effects on the brain by this new form of shock therapy. The present studies on HHL were conducted with particular reference to cerebral blood flow, cerebral oxygen supply, and intracranial pressure. Haemorrhagic shock with a drop in arterial blood pressure to 40 mmHg over a period of 30 min was induced in rabbits under alpha-chloralose anaesthesia by means of bloodletting. Subsequently, the hypertonic/hyperoncotic solution (HHL) was infused into the experimental animals within two minutes. The regional cerebral blood flow (H2-clearance) and the cerebral O2 supply were studied by determining the pO2 of the cerebral cortex in experimental animals without haemorrhagic shock but with infusion of HHL. Finally, separate single tests were conducted to analyse the effect of the infusion of HHL on the intracranial pressure after induction of a focal cold lesion of the brain in combination with the implantation of a rubber balloon in the epidural space as an intracranial space-occupying growth. Infusion of HHL during shock produced rapid normalisation of cardiac output, whereas in normovolaemic animals without shock it produced a temporary increase of this parameter.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Mechanisms of glial swelling induced by glutamate.
The mechanisms of glutamate-induced glial swelling have been studied using an in vitro model that permits detection of cell volume changes with high accuracy. The model allows for a close control of the extracellular environment to study in isolation the effect of defined extracellular alterations occurring in brain under pathophysiologic conditions. Glutamate was applied in concentrations between 50 microM and 10 mM to either C6 glioma cells or astrocytes from primary culture. Glutamate uptake was assessed by HPLC measurements of amino acids in the extracellular medium. Glutamate at all concentrations tested caused glial swelling, which, however, was moderate, with maximal average volume increases between 5.0 +/- 1.92 and 18.38 +/- 1.6% of control at 50 microM and 5 mM glutamate, respectively. Swelling was concentration dependent and correlated with glutamate uptake. After removal of all extracellular glutamate by glial uptake, cell volume spontaneously normalized. Pretreatment of the cells for 90 min with ouabain (1 mM) to abolish the extracellular/intracellular Na+ gradient, prevented glutamate-induced swelling. It is concluded that while glial cells readily accumulate glutamate from the extracellular environment to protect neurons from excitotoxic effects, swelling results from the increase of intracellular osmotic activity due to the uptake of Na+ and glutamate.
Animals↗
Treatment of hemorrhagic hypotension with hypertonic/hyperoncotic solutions: effects on regional cerebral blood flow and brain surface oxygen tension.
Hypertonic/hyperoncotic solutions (e.g. HHS: 7.2% NaCl/10% dextran-60) are highly effective to normalize cardiovascular function in hemorrhagic shock due to rapid mobilization of fluid from the extravascular compartment. Since experiences are limited with regard to potential side effects of this treatment on the central nervous system, the present studies were carried out under particular consideration of the cerebral blood flow and O2 supply. HHS was administered in albino rabbits subjected to alpha-chloralose anesthesia and artificial ventilation with and without hemorrhagic hypovolemia. Hemorrhagic hypovolemia of 30 min duration was induced by withdrawal of approximately one third of the circulating blood volume resulting in a decrease in arterial blood pressure to 40 mm Hg. HHS was studied in addition to normovolemic animals. Cardiac output was rapidly normalized by infusion of HHS in animals with hypovolemia, while it increased intermittently in normovolemic animals. In animals with hemorrhagic shock arterial blood pressure recovered by treatment to approximately 70% of normal, whereas blood pressure remained unchanged after infusion of HHS in normovolemic controls. Cerebral blood flow, which was assessed by H2 clearance at the brain surface, had a range of 43.0-50.3 ml/100 g/min under control conditions. It remained virtually unchanged during hemorrhagic hypovolemia and also after infusion of HHS in normovolemic animals. Treatment of shock by HHS was followed 90 or 120 min later by a moderate increase in regional cerebral blood flow to 61 ml/100 g/min. Local tissue PO2 at the brain surface was obtained by an O2 multiwire electrode in the vicinity of the H2 clearance measurements using a weightless suspension system to avoid compression of the brain surface. Infusion of HHS in normovolemic animals did not affect the O2 supply of the brain. Hemorrhagic hypovolemia which led to a left shift of the cerebral PO2 histogram was followed by gradual normalization after fluid resuscitation. The current findings taken together do not indicate adverse side effects of this efficient method of fluid resuscitation with regard to the cerebral blood and O2 supply. The results make worthwhile further investigations on HHS in the presence of a focal brain lesion causing brain edema to find out whether the HHS are useful also for the treatment of intracranial hypertension.
Animals↗
[Anesthesiologic efficacy of propanidid as a liposome dispersion. An experimental study with rats].
BACKGROUND: Propanidid, an ultra-short-acting i.v. anaesthetic agent, was widely used in the 1960s. Reports of anaphylactoid reactions in patients associated with release of histamine following administration of the drug, however, led to withdrawal of this useful anaesthetic. Since the adverse side effects of the former solution could be attributed to the solvent cremophor, attempts have recently been made to produce a propanidid solution without addition of the solvent. We report on comparative investigations employing a new liposomal solution (B. Braun, Melsungen, FRG) and the conventional cremophor preparation with regard to anaesthetic properties, haemodynamic side effects, and electroencephalographic effects (EEG). METHODS: Sprague-Dawley rats (n = 46) were implanted with venous and arterial lines and epidural EEG electrodes during chloral-hydrate anaesthesia. The following day, arterial blood pressure (ABP), heart rate (HR), and EEG were monitored in awake animals and then after induction of anaesthesia by a bolus of the respective propanidid preparation, followed by an infusion period of 15 min in six different experimental groups. Animals of groups L-60, L-90, L-120, or C-60, C-90, or C-120 groups received 60, 90, or 120 mg.100 g-1.h-1 of the liposomal (L) or cremophor (C) preparation. During anaesthesia, the corneal reflex and nociception to tail-clamping were also tested. At termination of the infusion, blood samples were drawn for determination of plasma propanidid concentrations. RESULTS: Both preparations were similarly effective in induction and maintenance of anaesthesia in a dose-dependent manner; both similarly lowered ABP and HR. The corneal reflex and nociceptive responses to tail clamping were also comparably suppressed. However, whereas the liposomal preparation was well tolerated at higher dose levels, the cremophor preparation caused considerable dose-dependent mortality of 11%, 86%, and 86% in animals in groups C-60, C-90, and C-120, respectively. Both preparations were found to induce a burst-suppression pattern in the EEG associated with clonic seizures, with a lower incidence with the liposomal preparation (22% and 50% in groups L-90 and L-120) as compared to the cremophor preparation (100% and 89% in groups C-90 and C-120). A remarkable variability in propanidid plasma concentrations was found at the end of the infusion period, although no differences were observed between both preparations. Discontinuation of infusion of propanidid resulted in rapid awakening (less than 5 min), irrespective of whether the liposomal or conventional preparation was employed. CONCLUSION: The present findings demonstrate largely identical anaesthetic potencies of a new liposomal solution as compared to the conventional cremophor preparation of propanidid. The liposomal preparation, however, was superior as far as tolerance and incidence of clonic seizures was concerned. The present findings should prompt further studies on the suitability of liposomal propanidid as a short-acting anaesthetic agent in patients.
Anesthesia, Intravenous↗
Atrial natriuretic peptide augments the blood-brain transfer of water but not leucine and glucose.
Recent evidence predicts an effect of atrial natriuretic peptide (ANP) on the blood-brain transfer of water. To test this prediction, we measured the blood-brain transfer of water, L-leucine, and D-glucose in 9 brain regions of male rats after intravenous injection of 10 pmol ANP. The peptide elicited an increase of the permeability-surface area (PaS) product of labeled water by 28-108% while the PaS products of leucine and glucose remained unchanged. Cerebral blood flow increased 15-48% while cardiac output and plasma volume in brain did not alter, indicating no change of capillary surface area (CSA). Regionally, the CSA varied from 63 cm2/g (striatum) to 97 cm2/g (colliculi) and the fraction of capillaries contributing to the total vascular volume varied from 29% (olfactory bulb/lobe) to 62% (striatum). The blood-brain barrier (BBB) permeability to water (5.7 micron/s) was an order of magnitude higher than to glucose (0.4 micron/s) or to leucine (0.3 micron/s).
Animals↗
On the blood-brain barrier to peptides: specific binding of atrial natriuretic peptide in vivo and in vitro.
Using the intracarotid bolus injection technique, a saturable binding of [125I]atrial natriuretic peptide (ANP) was found in 8 blood-brain barrier (BBB)-protected rat brain regions as well as in the pineal gland, choroid plexus, neurointermediate and anterior lobes of the pituitary, i.e. structures lacking a BBB. The presence of specific ANP binding on the BBB, here shown for the first time by an in vivo approach, was evidenced concomitantly in vitro by incubation of isolated microvessels. A single-class high affinity binding without regional differences was obtained with Kd = 0.23 nM and Bmax = 120 fmol/mg protein. From that a density of 1,400 binding sites per endothelial cell was calculated, thought to be localized predominantly in the luminal membranes. In the in vivo study, the portion of the extracted peptide that, under the conditions used, may have crossed the BBB by passive diffusion amounted to less than 0.4% of the labeled ANP administered. ANP itself did not change the tightness of the BBB to the non-diffusible reference molecule [14C]inulin. In the BBB-free areas, ANP enhanced the inulin space by nearly 50%.
Animals↗
Glial ion transport and volume control.
K(+)-induced glial swelling results from an intricate interaction of transport and diffusion processes and metabolic stimulation, with many open questions remaining. Our concept of the major mechanisms involved can be summarized as follows: high extracellular K+ causes a burst-like stimulation of Na+/K+ ATPase and, hence, increases the metabolic demands. Lactate is produced; the cell is slightly acidified. To maintain a normal intracellular pH, the Na+/K+ antiporter extrudes protons and supplies Na+ for further Na+/K+ exchange. In addition, K+ ions enter the cell via membrane channels or furosemide-inhibitable transport. K+, Cl-, and lactate- ions accumulate as the osmotic basis for cell swelling. Later, cell volume normalizes slowly, a process involving lactate export and other, so far unidentified mechanisms. Taken together, the temporary swelling of glia at high K+ concentrations is the result of a homeostatic function, for the maintenance of a constant extracellular potassium concentration. Ion control ranges over volume control. In pathophysiologic states the loss of cell volume regulation may become a clinical problem, if cerebral swelling leads to an increase in intracranial pressure. It should be kept in mind, however, that elevation of the extracellular K+ concentration is not the only cause of glial swelling. Tissue acidosis, the release of neurotransmitters, especially glutamate, or free fatty acids are other mediator mechanisms initiating the swelling of glial elements. Only under controlled in vitro conditions can the individual significance of these factors be evaluated on a quantitative basis. Therapeutic approaches should be selected very carefully in order to maintain homeostatic mechanisms that are of utmost importance, especially after an insult to the brain.
Biological Transport↗
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)
Animals↗
Prevention and treatment of secondary brain damage. Clinical aspects.
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Animals↗
The brain in shock. Secondary disturbances of cerebral function.
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Animals↗
Pathophysiology of acute brain damage following epilepsy.
The possible pathophysiological mechanisms, both intrinsic and systemic, leading to acute brain damage following epilepsy are reviewed. In particular involvement of changes in blood brain barrier, alterations of acid base regulation in the brain, release of a variety of mediator compounds, such as arachidonic acid and glutamate, intracellular influx of calcium ions, and the inhibition of protein synthesis are discussed. Finally, pathophysiology of brain damage following epilepsy is compared with that following ischaemia and hypoglycaemia.
Acid-Base Equilibrium↗
Effects of antineutrophil serum (ANS) on posttraumatic brain oedema in rats.
The role of white blood cells in acute central nervous system disorders, such as stroke or traumatic injury is poorly understood. In this experimental study the effect of neutropenia on posttraumatic brain oedema was investigated. Polyclonal antiserum against polymorphonuclear leukocytes was used to induce neutropenia. Control animals received normal serum or no treatment at all. Hemispheric swelling and brain water content after cryo-injury to the exposed left cerebral hemisphere was gravimetrically assessed, and by the wet weight-dry weight method. Administration of anti-neutrophil serum led to a significant reduction of circulating neutrophils. In untreated animals or in rats receiving normal serum, hemispheric swelling of the brain was 7.26 +/- 0.35% or 8.52 +/- 0.26%, respectively. Neutropenia induced by anti-neutrophil serum resulted in a significant increase in hemispheric swelling to 11.44 +/- 0.84% (p less than 0.001). It may be noted, however, that the enhancement of brain swelling by neutropenia was not obvious when comparing the water contents of the affected hemispheres of animals subjected to cold injury with and without anti-neutrophil serum. The enhancement of brain oedema by neutropenia suggests a protective function of neutrophils against extravasation in the presence of a broken blood-brain barrier.
Animals↗
Effect of stimulation of leukocyte chemotaxis by fMLP on white blood cell behaviour in the microcirculation of rat brain.
The role of white blood cells in acute cerebral disorders such as ischemia or stroke is still unclear. Therefore, in the present study we investigated the effects of the leukotaxin n-formyl-methionyl-leucyl-phenylalanine (fMLP) on white blood cell endothelial-cell interactions in the rat brain surface microcirculation. An improved closed cranial window technique was applied. Superfusion of fMLP in rising concentrations (10(-8) - 10(-5) M) was seen to induce rolling and adherence of leukocytes to teh endothelium of small venules. Rolling was more effectively stimulated than firm attachment. fMLP-induced vasodilation was more pronounced in arterioles than in venules. In this study it has been shown that the hydrophilic fMLP is effectively stimulating neutrophil chemotaxis across the blood-brain barrier. Further, the closed cranial window preparation is useful to analyze quantitatively properties of activated leukocytes, which may be pertinent in injury to the blood-brain barrier and induction of microcirculatory disturbances.
Animals↗
Effects of lactacidosis on volume and viability of glial cells.
The effect of lactacidosis was analyzed in vitro by employment of C 6 glioma cells and astrocytes from primary culture. The cells were suspended in an incubation chamber under continuous control of pH, temperature and pO2. Cell swelling and viability were quantified by flow cytometry using propidium iodide for staining of dead cells. After a control period, the pH of the suspension medium was titrated to levels between pH 6.8 down to 4.2 by addition of isotonic lactic acid. Acidification below pH 6.8 led to an immediate swelling of C 6 glioma cells as well as of astrocytes. The degree of cell swelling was related to the decrease in pH and the duration of exposure. For instance, lactacidosis of 60 min at pH 6.2 resulted in an increase of glial volume to 124.5 +/- 4.6%, while pH 4.2 in an increase to 190.9 +/- 8.4%. Cell viability remained unchanged down to pH 6.2. At pH 5.6 and below viability decreased in relation to the severity of acidosis. When sulfuric acid was used, the extent of cell swelling at pH 5.6 was only 50% of what was found by addition of lactic acid, whereas cell viability was not differently affected. The results demonstrate a specific efficacy of lactic acid to induce glial swelling, which might be due to a cellular accumulation of the compound.
Acidosis, Lactic↗
Effects of anaesthetic agents on cerebral blood flow and brain oedema from a focal lesion in rabbit brain.
Anaesthetic agents reduce cerebral metabolism and may impair coupling of cerebral blood flow and metabolism. We analyzed the effects of isoflurane (I) (1 MAC), fentanyl (F), thiopental (T) (32.5 mg/kg x hr) and alpha-chloralose (C) on rCBF and brain oedema formation after a focal cerebral injury (cold lesion) in rabbits (n = 6 per group). In the isoflurane group, angiotensin II (0.15 microgram/kg x min) was given to maintain blood pressure. rCBF of cerebral cortex was measured 3 times per hr by H2-clearance with needle electrodes placed at different distances to the lesion during 6 hrs after induction of trauma. Thereafter, samples of white matter were obtained near the focal lesions and from corresponding areas of the contralateral hemisphere for measurement of specific gravity (SG) by a linear density column (Percoll R). Blood pressure was 78, 86, 72, and 88 mmHg for groups I, F, T, and C, respectively. After induction of the lesion, hyperemia of approximately 1 hr was observed in all groups. This was most pronounced distant to the lesion. Close to the lesion rCBF remained unchanged in groups C and T, but fell significantly below control in I and F. The blood flow response distant to the trauma was characterized by a moderate increase (C), or no alteration (T), while isoflurane animals had a pronounced secondary hyperemia for about 3 hrs. With fentanyl, however, rCBF was markedly reduced in this area. SG of white matter close to the lesion decreased significantly to values of 1.032 g/cm3 (I, F, T), or 1.031 (C), indicative of oedema. Specific gravity was 1.034 in the contralateral hemisphere (control).(ABSTRACT TRUNCATED AT 250 WORDS)
Anesthetics↗