Orchestration of chromatin-based processes: mind the TRRAP.

Chromatin modifications at core histones including acetylation, methylation, phosphorylation and ubiquitination play an important role in diverse biological processes. Acetylation of specific lysine residues within the N terminus tails of core histones is arguably the most studied histone modification; however, its precise roles in different cellular processes and how it is disrupted in human diseases remain poorly understood. In the last decade, a number of histone acetyltransferases (HATs) enzymes responsible for histone acetylation, has been identified and functional studies have begun to unravel their biological functions. The activity of many HATs is dependent on HAT complexes, the multiprotein assemblies that contain one HAT catalytic subunit, adapter proteins, several other molecules of unknown function and a large protein called TRansformation/tRanscription domain-Associated Protein (TRRAP). As a common component of many HAT complexes, TRRAP appears to be responsible for the recruitment of these complexes to chromatin during transcription, replication and DNA repair. Recent studies have shed new light on the role of TRRAP in HAT complexes as well as mechanisms by which it mediates diverse cellular processes. Thus, TRRAP appears to be responsible for a concerted and context-dependent recruitment of HATs and coordination of distinct chromatin-based processes, suggesting that its deregulation may contribute to diseases. In this review, we summarize recent developments in our understanding of the function of TRRAP and TRRAP-containing HAT complexes in normal cellular processes and speculate on the mechanism underlying abnormal events that may lead to human diseases such as cancer.

First-line 5-fluorouracil/folinic acid, oxaliplatin and irinotecan (FOLFOXIRI) does not impair the feasibility and the activity of second line treatments in metastatic colorectal cancer.

BACKGROUND: We conducted two phase II trials evaluating the combination of 5-fluorouracil/folinic acid, oxaliplatin and irinotecan (FOLFOXIRI) as first-line treatment in 74 metastatic colorectal cancer patients. Results were very promising with an overall response rate of 71% and 72%, a median PFS of 10.4 and 10.8 months and an overall survival of 26.5 and 28.4 months, respectively. A concern about the use of all three active agents up-front is the possibility that this might limit, after progression, disease control with second-line treatments. Therefore, we conducted the present analysis to evaluate the outcome of second-line treatments in these 74 patients. METHODS: Among the 71 patients so far progressed 54 (76%) received second line chemotherapy (23: FOLFIRI, 17: FOLFOXIRI, five: 5-FU protracted infusion, three: FOLFOX, three: 5-FU+MMC, two: CPT-11, one: CPT-11+LOHP, one: raltitrexed). Seventeen patients (24%) did not receive second line treatments: 10 because of deterioration of performance status (PS), four because of patient refusal and three because of death. Patients' characteristics at the time of second-line treatment were: M/F 36 of 18 patients, median age 64 yrs (range 44-75), ECOG PS>or=1 21 (39%) patients, multiple sites of disease 33 (61%) patients. RESULTS: A median of 4.1 months of second-line chemotherapy per patient were administered (range 1-8). Overall response rate (52 out of 54 evaluable patients) was 33% and stable disease were 19 (37%). Median duration of response was 8.1 months. At a median follow up of 15.1 months from the start of salvage chemotherapy median PFS and overall survival were respectively 6.7 and 15.2 months. CONCLUSIONS: First-line FOLFOXIRI does not impair the possibility to obtain objective responses and delay tumor progression with second line treatments containing the same agents used in first-line.

MMTV-like sequences in human breast cancer: a fluorescent PCR/laser microdissection approach.

The hypothesis that a retrovirus homologous to the mouse mammary tumour virus (MMTV) is involved in human breast cancer aetiology has fascinated scientists from many years, but it has never been convincingly demonstrated. Renewed interest in this hypothesis developed when an MMTV env gene-like sequence was found in 38% of human breast cancer tissues. Whereas some subsequent studies confirmed these findings, others did not. The main reasons for this discrepancy, among others, are the different sensitivities and technical details of current molecular approaches to the detection of these sequences. This study is an attempt to find sensitive and reproducible conditions capable of detecting MMTV env-like sequence in human samples. To this end, we first developed a fluorescence nested-PCR (FN-PCR) method that was able to detect very low copies of the viral genome, and then screened a panel of 45 frozen breast cancer samples obtained by laser microdissection. The MMTV env gene-like sequence was found in 15 (33%) of the human breast cancers analysed, whereas the same sequence was detectable neither in normal tissues nor in other types of tumour. Sequence analysis revealed 96% homology with the MMTV genome, but no other significant similarities with the human genome. The combined use of frozen material, microdissected cell populations and FN-PCR provides a novel, sensitive, robust, non-radioactive and fast methodology for the molecular detection of human-MTV. This approach might be successfully used in large molecular studies that aim to investigate the hypothesis of a retroviral aetiology of human breast cancer.

Molecular staging of the sentinel lymph node in melanoma patients: correlation with clinical outcome.

BACKGROUND: This study was designed to determine the debated prognostic significance of reverse transcriptase-polymerase chain reaction (RT-PCR) positivity in melanoma patients' sentinel lymph node (SLN) negative by conventional histopathology (PATH). PATIENTS AND METHODS: Patients with primary stage I-II cutaneous melanoma underwent radioguided sentinel lymphadenectomy. Their SLNs were assessed for tyrosinase (Tyr) and melanoma antigens recognized by T-cells (MART-1) mRNA expression using RT-PCR, in parallel with hematoxylin and eosin staining and immunohistochemistry. Tyr and MART-1 expression in the SLNs were correlated with PATH assay results, standard prognostic factors, time to progression and overall survival. RESULTS: Twenty-three of the 124 patients (18.5%) had positive SLNs by both PATH and RT-PCR (PATH+/PCR+). Sixteen patients (13%) were negative by PATH and positive by RT-PCR (PATH-/PCR+). Eighty-five patients (68.5%) had SLNs that were negative by both PATH and RT-PCR (PATH-/PCR-). At a median follow-up of 30 months, recurrence rates among the three cohorts were statistically different (PATH+/PCR+, 60%; PATH-/PCR+, 31%; PATH-/PCR-, 9.4%). Seven of 23 (30%) and two of 16 (12.5%) patients died in the PATH+/PCR+ and PATH-/PCR+ SLN groups, respectively, whereas no patient died in the PATH-/PCR- SLN group. CONCLUSIONS: RT-PCR is more sensitive than PATH to detect SLN metastases and it is a reliable predictor of disease relapse in stage I-II melanoma patients.

[Continuous fiberoptic monitoring of oxygen saturation in cerebral veins in severe craniocerebral trauma--experiences and results]. / Kontinuierliche fiberoptische Uberwachung der hirnvenösen Sauerstoffsättigung bei schwerem Schädel-Hirn-Trauma--Erfahrungen und Ergebnisse.

AIM: Monitoring of jugular-venous O2-saturation (SjO2) enables the assessment of cerebral oxygen supply and the rapid detection of cerebral desaturation in patients with severe head injury. Furthermore, it may help to optimize circulation, ventilation, and intracranial hypertension therapy in these patients. This study was performed to evaluate the reliability of SjO2-monitoring as well as to measure cerebral O2-extraction and the frequency of episodes of cerebral desaturation after traumatic brain injury. METHODS: In 16 patients with severe head injury (GCS 3-8), SjO2 (fibreoptic system), arterial blood pressure, and intracranial pressure were continuously recorded after admission of the patients to the intensive care unit. Fluctuations of SjO2 (> 10% within 30 min), which were not included by therapeutic measures, were classified by off-line analysis as irregular-isolated or irregular-combined, if accompanied by similar fluctuations of ICP and arterial blood pressure. Recordings which were unreliable due to technical reasons, mainly because of wall adherence of the tip of the fibreoptic catheter, were evaluated separately. Episodes of cerebral desaturations (SjO2 < 50%) were assessed with regard to their frequency, duration (5-10/> 10 min) and underlying mechanisms. Cerebral O2-extraction was calculated as the difference between arterial and cerebrovenous O2-saturation and averaged for each day after trauma. RESULTS: Mean time of measurement for each patient was 194 hrs, a total of 3106 hrs were recorded. The correlation coefficient between in-vivo and in-vitro measured SjO2 was r = 0.62 (n = 367, p < 0.001). Reliable and artifact-free measurements of SjO2 were obtained only during 58.3% of all hours. Irregular-isolated fluctuations of the SjO2 occurred in 22.2% of the hours, and technical problems in 14.5%. Erroneous readings due to irregular-combined fluctuations of the jugular-venous O2-saturation were detected in 5.0% of the time periods. A total number of 66 episodes of cerebral desaturation (SjO2 < 50%) were found in all 16 patients, 41 of them had a duration of more than 10 minutes. Cerebral hypoxia was attributed to low cerebral perfusion pressure in 35% and hypocapnia in 17%. Global cerebral O2-extraction was significantly elevated at the day of injury compared to days 1-5 after trauma (37.4% vs. 28.9%-31.9%, p < 0.05). CONCLUSIONS: Monitoring of SjO2 in severe head injury provides an estimate of cerebral oxygen supply and may improve the assessment of therapeutic measures in these patients. The high incidence of erroneous readings of the SjO2 is a major drawback of this method. Initially after trauma, a high extraction of oxygen was found, followed by a marked decrease in the subsequent days, presumably reflecting an early, decreased cerebral blood flow and a hyperaemic flow pattern thereafter. Continuous measurements of SjO2 may contribute to advanced, organ-specific cerebral monitoring in severe craniocerebral trauma. The reliability of data, however, should be considerably improved for common clinical use.

Enteral versus parenteral nutrition: effects on gastrointestinal function and metabolism.

The effects of total parenteral nutrition (TPN) versus enteral nutrition (TEN) were studied in 34 patients following major neurosurgery. Measurements were made of resting energy expenditure (REE), urea production rate (UPR), visceral proteins, parameters of liver and pancreas function, as well as gastrointestinal absorption. To predict nutritional status, nutritional index (NI) was calculated. UPR revealed no significant differences between the groups. After 12 days of TEN, however, synthesis of visceral proteins increased significantly. In addition, NI improved after TEN (p < 0.05), whereas it remained unchanged after TPN. Thrombocyte and lymphocyte counts rose predominately during enteral nutrition. Only in the TEN group was REE increased by 18% and Glasgow Coma Scale (GCS) enhanced from Day 6 on. Exogenous insulin demand was enhanced in the parenterally fed group, and bilirubin (p < 0.05), amylase (p < 0.05), and lipase (p < 0.01) rose significantly, as did gamma-glutamyl-transferase (p < 0.0005) and alkaline phosphatase (p < 0.0005). After 12 d of TPN, vitamin A absorption was significantly attenuated, indicating reduced fat absorption compared to TEN. Carbohydrate absorption did not show significant changes between the groups. Only during TPN did mean values of xylose absorption remain below the normal range. Therefore, enteral nutrition following neurosurgical procedures is associated with an accelerated normalization of nutritional status and an improved substrate tolerance. TEN opposes early postoperative absorption disturbances of the small intestine.

Cerebral lactate production in relation to intracranial pressure, cranial computed tomography findings, and outcome in patients with severe head injury.

Severe head injury is frequently associated with focal or global disturbances of cerebral blood flow and metabolism. Routine monitoring of intracranial pressure (ICP) and cerebral perfusion pressure (CPP) in these patients does not provide information about critically reduced local or global cerebral blood flow. Measurements of cerebral lactate difference, Lactate-Oxygen-Index (LOI) and cerebral oxygen extraction were evaluated for advanced monitoring by comparing these parameters with ICP, cranial computed tomography (CCT) findings, and outcome in a group of severely head-injured patients. In 21 patients with severe brain trauma (GCS < or = 8), arterial as well as jugular venous lactate levels and oxygen saturation were measured in vitro every 6 h after admission of patients to the intensive care unit (ICU) throughout the acute course of treatment. Arterial blood pressure, blood gases, and ICP were assessed by standard monitoring measurements. CCT was performed initially after admission of the patients to the hospital, during the acute period in the ICU, if indicated, and 10 to 14 days after trauma. Outcome was classified according to the Glasgow outcome scale (GOS) at six months after injury. Data were averaged in each patient for every day after trauma and over the entire monitoring period. Resulting values were tested for correlation by regression analysis. Additionally, the data of the group of patients with normal to minimally elevated mean ICP (ICP < 20 mmHg, n = 12) were compared to those of the patients with increased mean ICP (ICP > 20 mmHg, n = 9). The cerebral lactate difference in all patients on the day of trauma was significantly increased as compared to the later period (0.20 vs. 0.11-0.07 mmol/l, p < 0.05), but was not different with high or normal to minimally elevated ICP. In patients with intracranial hypertension, the cerebral lactate difference remained significantly increased from the first to the fifth day after injury, whereas it normalized in this period in the group with normal to minimally elevated ICP. Averaged over the acute course, patients with increased ICP had significantly higher mean lactate differences (0.18 +/- 0.16 vs. 0.067 +/- 0.025 mmol/l, p = 0.001) and higher mean LOIs (0.072 +/- 0.071 vs. 0.028 +/- 0.013, p = 0.011). There was a significant correlation of increased mean cerebral lactate difference to poor outcome (r = 0.46, p = 0.035). Cerebral oxygen extraction in all patients tended to increase on the day of trauma (36.7% vs. 29.2% to 31.5% during the subsequent course), but this difference was not significant. The initial degree of brain swelling, classified by CCT according to Marshall et al. (1991), showed no correlation with cerebral lactate differences, ICP, O2-extraction, or outcome. Neither was there a correlation of cerebral oxygen extraction to ICP nor to outcome. In conclusion, the severity of brain trauma and outcome of patients was reflected by increased cerebral lactate production. Unchanged values of global cerebral oxygen extraction suggest that the regulatory mechanisms of brain oxygen supply were not impaired by trauma. Measurements of cerebral lactate differences and brain oxygen extraction may contribute to advanced monitoring in severe head injury.

Correlation of jugular venous oxygen saturation to spontaneous fluctuations of cerebral perfusion pressure in patients with severe head injury.

Continuous measurements of mean arterial pressure (MAP), ICP, and jugular venous oxygen saturation (SjO2) were performed in 11 patients with severe head injury (GCS 3-7) to assess the dependence of SjO2 from the cerebral perfusion pressure (CPP), trying to establish an indirect measure of cerebrovascular autoregulation. Changes in CPP resulting from spontaneous fluctuations in MAP or ICP induced highly significant alterations in SjO2 in the range of 0.14-0.56% SjO2 mmHg-1 CPP in all patients and all periods after trauma. The analysis of the distribution of the SjO2:CPP-ratios showed the highest frequency of values in the range of 0.0-0.25% SjO2 mmHg-1 CPP in 9 of the 11 patients. Within the first 2 days after trauma, a more pronounced dependency of SjO2 from changes in CPP was found, but this was not statistically significant. No predictable relationship of the SjO2:CPP-ratio to the level of ICP could be demonstrated in the patients. Because changes in SjO2 induced by alterations in CPP were found in all patients and throughout the acute phase of severe head injury, these changes more probably reflect physiological alterations in CBF with varying perfusion pressure rather than impaired autoregulation after head trauma. Although assessment of cerebral autoregulation by estimation of the SjO2:CPP-ratio offers new possibilities for monitoring of these patients, the high frequency of erroneous readings or irregular fluctuations of the SjO2-signal from the fibreoptic catheter limits the usefulness of the SjO2-dependency from CPP for practical use in the intensive care unit.

Cerebral protection against ischemia by locomotor activity in gerbils. Underlying mechanisms.

BACKGROUND AND PURPOSE: A previous communication of this laboratory demonstrated reduced mortality and neuronal damage by spontaneous locomotor activity preceding forebrain ischemia in Mongolian gerbils. The present experiments seek to elucidate potential mechanisms of protection by measurement of cerebral blood flow, cerebral tissue conductance as an indicator of ischemic cell swelling, and the cerebral release of eicosanoids. METHODS: Gerbils were maintained either in conventional cages (nonrunners) or with free access to running wheels (runners) for 2 weeks preceding 15 minutes of forebrain ischemia. During ischemia and 2.5 hours of reperfusion, cerebral tissue conductance was determined with a two-electrode system. Simultaneously, prostaglandin D2, prostaglandin F2 alpha, and thromboxane B2 were measured in ventriculocisternal perfusate. In additional animals cerebral blood flow was assessed by hydrogen clearance. RESULTS: Decreases in tissue conductance during ischemia were similar in nonrunners (56 +/- 3%) and runners (62 +/- 3%) but normalized more rapidly in runners during reperfusion. In both groups reperfusion was accompanied by marked increases of perfusate prostaglandin D2, prostaglandin F2 alpha, and thromboxane B2. In nonrunners, however, thromboxane B2 was already elevated during ischemia (147 +/- 9%, P < .01) and remained elevated longer during recirculation (P < .05). Postischemic perfusion maxima were higher in runners (70.8 +/- 7.4 versus 47.0 +/- 5.0 mL/100 g per minute, P < .05) and were observed sooner (27.4 +/- 6.9 versus 62.2 +/- 12.3 minutes, P < .05). Both groups displayed delayed hypoperfusion of a similar magnitude (runners, 29.0 +/- 2.4 mL/100 g per minute; nonrunners, 30.1 +/- 2.4 mL/100 g per minute). CONCLUSIONS: Protection by preischemic locomotor activity may involve enhanced postischemic reperfusion, leading to more rapid normalization of conductance and thus of cell volume. Enhanced reperfusion may be the consequence of attenuated thromboxane liberation during and after ischemia.

Influence of isoflurane, fentanyl, thiopental, and alpha-chloralose on formation of brain edema resulting from a focal cryogenic lesion.

The objective of this study was to analyze the effects of various anesthetics on the formation of brain edema resulting from a focal cryogenic lesion. Thirty rabbits (six per group) were anesthetized with isoflurane (1 minimum alveolar anesthetic concentration [MAC] 2.1 vol%), fentanyl (bolus 5 micrograms/kg; infusion rate 1.0-0.5 micrograms.kg-1.min-1), thiopental (32.5 mg.kg-1.h-1), or alpha-chloralose (50 mg/kg). Control animals (sham operation, no lesion) received alpha-chloralose (50 mg/kg). Regional cerebral blood flow (rCBF) in perifocal brain tissue was measured by H2-clearance. Animals anesthetized with isoflurane required support of arterial pressure by angiotensin II (0.15 micrograms.kg-1.min-1). Six hours after trauma the animals were killed. Formation of brain edema was studied by specific gravity of cortical gray matter, white matter, hippocampus, caudate nucleus, putamen, and thalamus. Brain tissue samples were collected at multiple sites close to and distant from the lesion. Mean arterial pressure, arterial PCO2 and PO2, hematocrit, body temperature, and blood glucose were not different between groups during the posttraumatic course (except for an increased arterial pressure with alpha-chloralose compared to thiopental 4-6 h after trauma). The specific gravity of cortical gray matter was significantly reduced up to a distance of 6 mm from the center of the lesion in animals anesthetized with isoflurane, thiopental, or alpha-chloralose and up to 9 mm in animals given fentanyl.(ABSTRACT TRUNCATED AT 250 WORDS)

A novel, remote-controlled suspension device for brain tissue PO2 measurements with multiwire surface electrodes.

A new device was developed for rapid assessment of PO2 values in viable tissue, such as the brain, using a multiwire surface electrode. The instrument utilizes a phonograph-like construction with weightless suspension of the electrode which thus minimizes surface pressure and allows for compensation of brain movements. The new and original component of the present device is the motor-driven, servo-controlled rotation of the PO2 electrode around its vertical axis. This enables PO2 measurements from precisely defined locations. From values measured on rabbit brain surface a PO2 histogram was constructed. The mean PO2 and distribution histogram were similar to those obtained with a needle electrode. The novel device, therefore, enables accurate and fast tissue PO2 measurements with minimal risk of brain damage.

7.2% NaCl/10% dextran 60 versus 20% mannitol for treatment of intracranial hypertension.

Severe head injury is frequently associated with extracranial injuries causing hemorrhagic hypotension. Volume replacement with isotonic fluids not only is therapeutically of limited efficacy but may aggravate posttraumatic brain edema. On the other side, hypertonic/hyperoncotic saline/dextran solution (HHS) shown to restore cardiovascular function in hemorrhagic shock instantaneously, was found to decrease intracranial pressure in experimental head injury. Currently the therapeutic efficacy of HHS and mannitol on ICP was compared at 24 hrs after a focal cerebral lesion and inflation of an epidural balloon in rabbits. Both solutions given at an equimolar dose rapidly lowered the ICP. After the first injection, ICP reduction was longer maintained with mannitol (189 +/- 27 min) as compared to HHS (98 +/- 14 min), while no difference in duration of lowering ICP was found after the second injection. Due to its blood pressure effects, HHS afforded a higher cerebral perfusion pressure than mannitol. In animals with HHS, the water content of the traumatized hemisphere was increased while the contralateral hemisphere was dehydrated. With mannitol, no differences in water content were found between the injured and uninjured hemisphere. The efficiency of HHS in hemorrhagic shock and intracranial hypertension render the fluid mixture particularly promising in patients with polytrauma in combination with head injury.

Effects of isoflurane, fentanyl, or thiopental anesthesia on regional cerebral blood flow and brain surface PO2 in the presence of a focal lesion in rabbits.

These studies were conducted to determine the effect of anesthetic drugs on tissue perfusion and O2 supply in the brain with focal cerebral edema. Using an open cranium preparation, we studied the effects of isoflurane (I; 1 minimum alveolar anesthetic concentration), of fentanyl (F; 0.5-1 microgram.kg-1 x min-1), or of thiopental (T; 32.5 mg.kg-1 x h-1) on regional cerebral blood flow (rCBF) and regional brain tissue PO2 in albino rabbits (n = 6 per group) with a focal brain lesion (cold injury). The doses of anesthetics were sufficient to suppress nociception. rCBF (H2 clearance) and tissue PO2 (multiwire surface electrode) were studied adjacent to and distant from the lesion. Cerebral hyperemia developed immediately after trauma in all groups, although the flow increase did not attain statistical significance. rCBF was subsequently reduced by about 25% in the vicinity of the lesion. Distant from the trauma, a continuing hyperemia (+30%) was later observed in animals with isoflurane, whereas rCBF was decreased then by 10%-20% in animals with fentanyl, or was unchanged with thiopental. Brain tissue PO2 was increased with isoflurane in areas distant from the lesion, but decreased with fentanyl. However, with thiopental, the PO2 level had already been lowered before trauma with a subsequent tendency toward normalization. The heterogeneity of the tissue PO2 in fentanyl anesthesia, as well as the increased frequency of hypoxic PO2 values with thiopental, might have resulted from microcirculatory disturbances. Thus, although isoflurane seemed to facilitate hyperemia with an increased O2 supply to the brain, fentanyl tended to induce the opposite response. Although these properties suggest the potential to manipulate perfusion and O2 supply in cerebral ischemia or hyperemia after head injury, the effects of such measures on intracranial pressure, neurologic status, and outcome have yet to be proven.

[Hypertonic solutions in treatment of intracranial pressure]. / Hypertone Lösungen zur Behandlung des intrakraniellen Drucks.

Administration of hypertonic solutions is the method of choice for acute treatment of intracranial hypertension. Recording of the intracranial pressure during treatment facilitates adjustment of the dosis to the actual ICP-response, avoiding thereby administration of an excessive osmotic load as a basis to prolong therapeutical efficacy. The mechanisms underlying reduction of the intracranial pressure by hypertonic solutions are still controversially discussed. Dehydration of normal probably also of edematous brain parenchyma and constriction of cerebral resistance vessels as an autoregulatory response causing reduction of the intracranial blood volume are the most likely options. Administration of hypertonic/hyperoncotic solutions has regained attention on account of its unmatched therapeutical efficacy to reestablish normal conditions in severe hemorrhagic shock. Administration of, e.g. 7.2% NaCl/10% Dextran 60 in an amount equivalent of only 10% of the shed blood volume is immediately normalizing cardiac output and improving the microcirculation in peripheral organs. These therapeutical properties are relevant in head injury, since inflicted patients quite often are suffering from peripheral trauma and consequently from hemorrhagic shock. No evidence has been obtained in a variety of experimental studies that hypertonic/hyperoncotic solutions have adverse effects on the brain in the presence of a cerebral lesion. To the contrary, the fluid mixture has been found to lower the increased intracranial pressure. Administration of hypertonic/hyperoncotic solutions appears therefore appropriate in acute cerebral insults from head injury and impending circulatory failure from shock in order to inhibit development of secondary brain damage.

Relationship of cerebral blood flow disturbances with brain oedema formation.

Brain oedema is an important factor which compromises maintenance of the cerebral blood flow. Conversely, primary blood flow disturbances are leading to brain oedema. The mechanisms underlying blood flow impairment by brain oedema are associated with an increased regional tissue pressure in proportion to the degree of water accumulation in the parenchyma. The release of vasoactive mediator compounds might be considered in addition. Primary disturbances of the cerebral blood flow, such as focal or global cerebral ischaemia are leading to an increased cerebral water content. A decrease of the cerebral blood flow to ca. 40% of normal or below has been found to result in the development of brain oedema. This flow threshold is in the neighbourhood of the ischaemic flow level causing irreversible tissue damage. Whereas in focal ischaemia oedema formation is a function of the severity of the flow decrease, it is a pathophysiological hallmark of early postischaemic recirculation in global cerebral ischaemia. Nevertheless, during complete interruption of cerebral blood flow translocation of interstitial fluid into the intracellular compartment occurs as manifestation of ischaemic cell swelling. Cell swelling under these conditions may, however, not necessarily indicate cell damage, but more likely a compensatory response attributable to the uptake of excitotoxic transmitters such as glutamate, and of K(+)-ions which are excessively released at the onset of ischaemia into the extracellular space. Purpose of the swelling process, thus, is clearance of extracellular fluid from this material to re-establish homeostasis.(ABSTRACT TRUNCATED AT 250 WORDS)

[Therapy of hemorrhagic shock using small volumes of hypertonic-hyperoncotic NaCl-dextran solution--effects on the brain]. / Therapie des hämorrhagischen Schocks mit kleinen Volumina hyperton-hyperonkotischer NaCl-Dextranlösung--Auswirkungen auf das Gehirn.

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)

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.

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)