Ischemic Anoxia Research Articles

Lead Poisoning in Cattle Held in a Military Training area

Background: Lead poisoning is one of the major toxic diseases of cattle. Contamination occurs with ingestion of products containing lead, especially batteries, or through contaminated pastures and water sources. Clinical signs are neurological and necropsy findings and histopathological changes may vary depending on the clinical presentation. Although the diseaseis widely reported in the literature, there are rare descriptions of intoxication in cattle raised in military training areas. This work describes the epidemiological, clinical and anatomopathological features of an outbreak of lead poisoning in cattle kept in a military artillery training camp.Case: Fifteen cattle out of a herd of sixty 4-6 year-old, mixed breed castrated males were affected. The cattle were held in a 100 ha of native pasture used for military artillery training. After three weeks in this area, the affected cattle had predominantly neurological clinical manifestations, characterized by somnolence, ambulatory incoordination, muscle tremors,bruxism, aimless walking, blindness and decubitus. The clinical course was 24-72 h. Eight of the 15 affected cattle died and two were necropsied. Necropsy finds were non-specific and the histological lesions of both necropsied cattle were restricted to the brain and kidneys. Laminar neuronal necrosis, neuropil vacuolization (spongiosis) and vascular endothelial hypertrophy were observed in the telencephalic cortex. Additionally there was astrocytic degeneration and neuronophagia.There was degeneration and necrosis of renal tubular epithelium and in one bovine there were intranuclear inclusion bodies in the renal epithelial cells; these inclusion bodies were highlighted using both modified Ziehl-Neelsen and periodic acid Schiff (PAS) stains. The levels of lead found in the kidneys and livers of the two necropsied cattle were respectively51.7 μg/g and 41.00 μg/g for one of the necropsied cattle; and 431μg/g and 39.0 μg/g for the other. After the diagnosis of intoxication, cattle were removed from the area and the remaining seven affected bovines recovered.Discussion: The diagnosis of lead poisoning in cattle in the current study was based on epidemiological, clinical, anatomopathological data and in the determination of lead levels in the kidney and liver. The association of these data provides an invaluable aid in confirming a presumptive diagnosis of lead poisoning. Pasturing on military artillery training fieldsis a rarely described form source of lead for the intoxication in bovine species. In such cases, cattle may ingest the lead directly from the soil or through contaminated pastures containing lead dust on the surface of the leaves. Histologically, laminar neuronal necrosis in the telencephalic cortex, associated with tubular necrosis and intranuclear inclusion bodies intubular epithelial cells, are characteristic features of the intoxication. These changes are usually associated with ischemic anoxia in the nervous system and alteration in nuclear function which interferes in gene expression in the kidney. Lead poisoning in cattle should be differentiated from other neurological conditions, especially rabies, hepatic encephalopathyand several causes of polioencephalomalacia. Areas of military artillery training are unfit for the development of agricultural exploitation activities, as they represent potential sources of contamination for livestock.Keywords: diseases of cattle, toxicology, heavy metal, polioencephalomalacia.

Central retinal artery occlusion and cerebral stroke

Sir, Aspects of the review by Varma and colleagues1 conspire to amplify the confusion that surrounds central retinal artery occlusion (CRAO). First, they report that a foveal cherry-red spot is present in 90% of eyes examined within 1 week of CRAO onset, whereas only 58% show concomitant macular opacification. Surely these ‘classic' CRAO signs must co-exist? Second, Varma and colleagues discuss ‘transient' CRAO, a small subgroup of eyes in the Iowa CRAO classification characterised by CRA reopening by the time of initial presentation and fluorescein angiography.2, 3 They state that ‘transient' CRAO is ‘analogous to a transient ischaemic attack affecting the eye' since ‘restoration of blood flow … results in symptom resolution'.1 This is not the case. The Iowa classification dispenses with terminological convention by labelling events as ‘transient' even though complete reversal of symptoms and signs is precluded by a duration of ischaemic anoxia exceeding 4 h (inner retina's maximum survival time).4 They also state that ‘transient' CRAO presents ‘greatly varied fundus findings'.1 This is not the case. If the duration of ‘transient' CRAO exceeds 4 h, the ‘classic' signs will persist for at least a week. Alternative presentations in the form of ‘scattered patches of retinal opacity'2, 3 usually signify ‘partial', not ‘transient', CRAO.5 Third, Varma and colleagues believe ‘only a rare subgroup of individuals have viable tissue' in the inner retina by 24 h from CRAO onset.1 This is not the case. Although the survival time of anoxic tissue in the posterior pole has been exceeded, this ‘core' of infarction will be surrounded by a zone of critically hypoxic but viable tissue (the ‘ischaemic penumbra'), just as in cerebral stroke. Unlike penumbral cerebral cortex, however, penumbral retina can persist indefinitely.5 Reperfusion of this tissue explains the recovery of the ERG b-wave after CRA unclamping following 4 h of CRAO.4 It can also account for the visual improvement frequently attributed to ‘natural history' in patients,1, 2, 3 provided neural connectivity is maintained between reoxygenated penumbra and optic nerve. However, if the CRA does not reopen and cilioretinal collaterals are not formed, the enduring penumbral state of the tissue will stimulate intraocular neovascularisation (developing in 15–20% of CRAO eyes).5

Neuropsychological profile of persons with anoxic brain injury: Differences regarding physiopathological mechanism

Primary objective: To determine the neuropsychological profile of persons with anoxic brain injury.Methods and procedures: A retrospective study on a population of persons with anoxic brain injury admitted to a Brain Injury Unit (Institut Guttmann, Spain) from 1995–2003. The sample was divided according to physiopathological mechanisms in two sub-groups: ischemic anoxia (21 cases) and hypoxemic anoxia (11 cases). Functions assessed included orientation, attention, language, visuo-perceptive and visuo-constructive processing and verbal memory.Results: Neuropsychological assessment showed diffuse cognitive impairment in all assessed functions. Episodes of ischemic anoxia caused more severe verbal memory and learning problems than episodes of hypoxemic anoxia.Conclusions: This study shows that memory problems are the most prominent and relevant impairment, although all other cognitive functions are also impaired, affecting both memory itself and general behaviour. Statistical analysis also provides preliminary evidence on the different profile of memory impairment whether cerebral anoxia had hypoxic or ischemic origin.

Anoxia tolerance and freeze tolerance in hatchling turtles

Freezing survival in hatchling turtles may be limited by ischemic anoxia in frozen tissues and the associated accumulation of lactate and reactive oxygen species (ROS). To determine whether mechanisms for coping with anoxia are also important in freeze tolerance, we examined the association between capacities for freezing survival and anoxia tolerance in hatchlings of seven species of turtles. Tolerance to freezing (-2.5 degrees C) was high in Emydoidea blandingii, Chrysemys picta, Terrapene ornata, and Malaclemys terrapin and low in Graptemys geographica, Chelydra serpentina, and Trachemys scripta. Hatchlings survived in a N(2) atmosphere at 4 degrees C for periods ranging from 17 d (M. terrapin) to 50 d (G. geographica), but survival time was not associated with freeze tolerance. Lactate accumulated during both stresses, but plasma levels in frozen/thawed turtles were well below those found in anoxia-exposed animals. Activity of the antioxidant enzyme catalase in liver increased markedly with anoxia exposure in most species, but increased with freezing/thawing only in species with low freeze tolerance. Our results suggest that whereas oxygen deprivation occurs during somatic freezing, freeze tolerance is not limited by anoxia tolerance in hatchling turtles.

Response of purine metabolism to hypoxia and ischemia.

There are three types of O2 supply disturbances leading to tissue hypoxia: ischemia, hypoxemia and anemia.1 Ischemia means critically reduced blood flow. Upon reduction of blood flow the oxygen concentration in venous blood is decreased leading to ischemic anoxia. During ischemia the washout of catabolic end-products is also decreased.KeywordsPurine MetabolismPurine Nucleoside PhosphorylaseHypoxia ToleranceHigh Energy PhosphateAdenosine ProductionThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Response of purine metabolism to hypoxia and ischemia

There are three types of O2 supply disturbances leading to tissue hypoxia: ischemia, hypoxemia and anemia.1 Ischemia means critically reduced blood flow. Upon reduction of blood flow the oxygen concentration in venous blood is decreased leading to ischemic anoxia. During ischemia the washout of catabolic end-products is also decreased.

Cerebral resuscitation after cardiac arrest: Research initiatives and future directions

At present, fewer than 10% of cardiopulmonary resuscitation (CPR) attempts prehospital or in hospitals outside special care units result in survival without brain damage. Minimizing response times and optimizing CPR performance would improve results. A breakthrough, however, can be expected to occur only when cerebral resuscitation research has achieved consistent conscious survival after normothermic cardiac arrest (no flow) times of not only five minutes but up to ten minutes. Most cerebral neurons and cardiac myocytes tolerate normothermic ischemic anoxia of up to 20 minutes. Particularly vulnerable neurons die, in part, because of the complex secondary post-reflow derangements in vital organs (the postresuscitation syndrome) which can be mitigated. Brain-orientation of CPR led to the cardiopulmonary-cerebral resuscitation (CPCR) system of basic, advanced, and prolonged life support. In large animal models with cardiac arrest of 10 to 15 minutes, external CPR, life support of at least three days, and outcome evaluation, the numbers of conscious survivors (although not with normal brain histology) have been increased with more effective reperfusion by open-chest CPR or emergency cardiopulmonary bypass, an early hypertensive bout, early post-arrest calcium entry blocker therapy, or mild cerebral hypothermia (34 C) immediately following cardiac arrest. More than ten drug treatments evaluated have not reproducibly mitigated brain damage in such animal models. Controlled clinical trials of novel CPCR treatments reveal feasibility and side effects but, in the absence of a breakthrough effect, may not discriminate between a treatment's ability to mitigate brain damage in selected cases and the absence of any treatment effect. More intensified, coordinated, multicenter cerebral resuscitation research is justified.

Modification of human tumour and normal tissue pH during hyperthermic and normothermic antiblastic regional isolation perfusion for malignant melanoma: a pilot study.

Human tumour and normal tissue pH were investigated during hyperthermic and normothermic antiblastic regional isolation perfusion and the effects of vascular occlusion, artificially induced hypoxia, hyperglycaemia, haemoglobin level of the perfusate and hyperthermia on tumour and normal tissue pH were evaluated. A pilot study was performed on 10 patients, with locally inoperable recurrent and primary malignant melanoma of the leg. The treatment consisted of a regional isolation perfusion with hyperthermia (120 min at 42-43 degrees C), at femoral level, followed by a normothermic regional isolation perfusion with Melphalan (60 min at 37-38 degrees C), at iliacal level, 7-10 can be distinguished: (1) first ischaemic anoxia period; (2) extracorporeal circulation, during which the leg is heated to the desired temperature, after which either hyperthermia or Melphalan is applied; (3) second ischaemic anoxia period. During the anoxia periods the large vessels that supply the leg are temporarily clamped and the effects on tissue pH can be investigated. During extracorporeal circulation, high-dose glucose can be administered to the isolated leg, to acutely decrease tumour tissue pH. Such a decrease is expected to sensitize tumours to hyperthermia, when applied immediately prior to or during heating. At the beginning of the treatment the mean tumour pH was significantly lower than normal tissue pH (7.14, with a mean tumour volume of 39.2 cm3, and 7.38, respectively; p < 0.01). During the perfusions with hyperthermia and Melphalan, tissue pH decreased by -0.41 units and -0.20 for tumour, and -0.11 units for normal tissue, respectively (all statistically significant). The two anoxia periods accounted for approximately half of the net decrease. During these periods tumour pH appeared to decrease more selectively, although there was great variation. The other investigated modalities, such as hyperglycaemia and hyperthermia, also decreased tissue pH, but to a lesser extent. However, a combination of more than one modality caused a larger decrease than a single one, but no preference for tumour could be detected. Before the second perfusion mean tumour pH was significantly increased by 0.14 units, and was no longer significantly different from normal tissue pH in the course of the regional isolation perfusion. This could be the reflection of the reduced tumour volume (by 30%, n.s.). Similar pH changes occurred during this Melphalan perfusion, but they were less pronounced since the total treatment time was shorter. Summarizing, tumour pH can be decreased more than normal tissue pH in the course of the regional isolation perfusion. In particular, vascular occlusion appeared to be tumour pH selective.(ABSTRACT TRUNCATED AT 400 WORDS)

Cytochemical studies of hydrogen peroxide generation in postischemic hepatocytes

Reoxygenation injury that occurs when blood circulation is restored to previously ischemic tissues is currently discussed as a pathophysiological entity distinct from the primary anoxic injury that develops during ischemia per se. To test the hypothesis that reoxygenation injury in hepatocytes is caused by a postischemic burst of reactive oxygen species (ROS), including superoxide radicals, O2-., and hydrogen peroxide, H2O2, we performed a cytochemical study exploiting the peroxidase activity within peroxisomes as a sensitive ultrastructural detector of intracellular H2O2 generation. The osmiophilic polymer formed when tissue peroxidase is incubated with 3,3'-diaminobenzidine (DAB) and H2O2 was used as a marker for endogenous H2O2 in rat liver slices in short-term organ culture subjected to a cycle of 60-min ischemic anoxia and 30-min reoxygenation in the presence of DAB without exogenous H2O2. Peroxisomal reaction product was quantitatively evaluated in transmission electron micrographs of systematically sampled hepatocytes. Mean densities of positive peroxisomes per 1,000 micron2 (+/- SE) in liver slices subjected to various treatments were as follows: continuous anoxia (negative control) 0 +/- 0; normoxia + exogenous H2O2 (positive control) 45 +/- 12; normoxia only 26 +/- 2; ischemia-reoxygenation 13 +/- 6; ischemia-reoxygenation + xanthine oxidase inhibitor, oxypurinol 5 +/- 3; ischemia-reoxygenation + peroxidase inhibitor, aminotriazole 7 +/- 3. Endogenous H2O2 can be detected in hepatocytes by electron microscopic cytochemistry and may in part derive from xanthine oxidase, but it is not substantially increased in the postischemic state. We conclude that hepatocytes do not exhibit a postischemic burst of reactive oxygen species that could cause reoxygenation injury.

Postresuscitation disease.

The postresuscitation disease is a specific pathophysiologic state of vital organ systems early after ischemic anoxia. This report summarizes reviews of past research and makes suggestions for future research concerning revival of the cerebral cortex after clinical death, CNS stimulation vs. sedation, postischemic coma and pain, near-death experiences, and extracerebral derangements. The stages of resuscitation when the CNS should be stimulated and those when it is preferable to depress the activity of not fully recovered higher centers remain to be clarified. Future research in reanimatology should include the chemical nature of endotoxins in terminal states. Adult respiratory distress syndrome (ARDS, shock lung), a component of the postresuscitation disease, occurs frequently after cardiac arrest or in sepsis and cannot be fully prevented by artificial ventilation. Prevention of ARDS should also be studied.

Effects of carotid artery compression test on regional cerebral blood volume, hemoglobin oxygen saturation and cytochrome-C-oxidase redox level in cerebrovascular patients.

The effects on the EEG tracings of a short lasting digital occlusion of the carotid artery in the neck has long since been used as a functional test in the clinical assessment on cerebrovascular patients. The occurance of EEG slowing during this manoeuvre is the expression of a cerebral ischemic anoxia and probably of a defective collateral circulation.

Brain injury by ischemic anoxia: Hypothesis extension — A tale of two ions?

The understanding of the pathophysiology of cerebral ischemic anoxia depends on elucidation of cellular neuronal changes during this event and under conditions of cardiopulmonary resuscitation. Current knowledge of these metabolic developments is reviewed, and a hypothesis of the role of iron in this situation is presented.

PH changes on the surface of brain and in cisternal fluid in dogs in cardiac arrest.

We measured brain surface pH and cisternal cerebrospinal fluid (CSF) acid-base variables in Na-pentobarbital anesthetized dogs during KCl induced cardiac arrest. Electrocardiographically, an agonal rhythm occurred within seconds, presumably resulting in rapid fall in cerebral blood flow. The mean arterial blood pressure fell from 125 +/- 22 (mean +/- 1 SD) to 35 +/- 28 mm Hg at 30 seconds and to 19 +/- 3 mm Hg at 60 seconds after KCl injection. The mean brain surface pH (n = 8) dropped abruptly from 7.30 to 6.80 within 3 minutes after induction of cardiac arrest. Changes in cisternal CSF pH, however, occurred slowly with the mean pH falling from 7.33 to 7.27 at 4 minutes and to 6.99 at 10 minutes after induction of cardiac arrest. The fall in cisternal CSF pH was due to a rise in CSF concentration of organic acids as well as a rise in CSF Pco2; the mean cisternal CSF [HCO3-] fell 3.6 mEq/l while the mean cisternal CSF lactate concentration and the mean CSF Pco2 rose, respectively, 2.1 mEq/l and 37.8 mm Hg 10 minutes after induction of cardiac arrest. We conclude that during acute ischemic anoxia gross pH disequilibria develop between brain extracellular fluid and cisternal CSF; analyses of the latter fluid provide unreliable information about brain metabolic status and its acid-base balance even up to ten minutes after induction of cardiac arrest.

Brain Ischemic Anoxia

THE DEVELOPMENT of effective therapy to preserve normal neurological function in patients surviving a cardiac arrest hinges on our growing understanding of the pathophysiology of ischemic anoxia. It is worthwhile, then, to review our new understanding of these mechanisms, as well as the laboratory search for therapies to protect neurons injured by cardiac arrest. The early doctrine that four to six minutes of ischemic anoxia leads to irreversible brain injury was based on work done in the 1940s with dogs subjected to breathing 100% nitrogen.^1,2However, it became apparent from work by Ames and Guarian³and Hossman and Kleihues⁴that the neurons themselves have substantial intrinsic resistance to complete ischemic anoxia. The evidence suggests that CNS neurons can tolerate between 20 and 60 minutes of complete ischemic anoxia without irreversible injury. Following these severe insults, neurons regain the ability to synthesize protein, produce adenosine triphosphate (ATP), and

Effect of nizofenone on pyramidal response, electrocorticogram and regional cerebral blood flow following recirculation after complete global brain ischemia in cats

Effect of nizofenone on pyramidal response (PR), electrocorticogram (ECoG) and regional cerebral blood flow (rCBF) following recirculation after complete global brain ischemia was compared with that of pentobarbital in gallamine-immobilized cats. The basilar artery and the branches of both carotid arteries (superior thyroid artery, dorsal muscular branch, internal carotid artery, occipital artery and ascending pharyngeal artery) were all ligated. The cats were subjected to complete brain ischemia by occluding both common carotid arteries for 45 min, followed by 180 min recirculation. rCBF of the cortex (suprasylvian gyrus) and the internal capsule was monitored by the hydrogen clearance method. Blood gases were regulated within a range determined previously in freely-moving cats throughout the experiment. Nizofenone (1 mg/kg, i.v.) facilitated the recovery of PR and ECoG, and it inhibited the phenomenon of secondary suppression evidenced by interruption and reversion of the recovery process. rCBF showed good recovery throughout the recirculation period. Pentobarbital (20 mg/kg, i.v.) facilitated the recovery of PR during the early period of recirculation, but secondary suppression of PR, associated with the decline of rCBF, was evident. These results suggest that the ameliorative effect of nizofenone on the recovery of neuronal functions is due to its ability to protect neurons against ischemic anoxia and to prevent interruption of postischemic circulation, and also the good recovery of rCBF is due to its ability to protect vasculature against ischemic anoxia.

Tissue lactic acidosis and ischemic brain damage

Current evidence suggests that the brain has considerable potential to tolerate prolonged periods of complete ischemic anoxia. Moreover, the brain may be less damaged by complete ischemic anoxia than by severe incomplete ischemia. The accumulation of lactic acid in the brain during severe incomplete ischemia approaches three times the levels seen with complete ischemic anoxia, and this phenomenon is implicated in exacerbated biochemical and structural injury.

Earliest irreversible changes during ischemia

The ability to synthesize new protein was used as a marker of irreversible neuronal injury in experiments with isolated rabbit retinas exposed to various types of ischemic insult. The retinal neurons were able to fully recover their protein synthetic capacity after 20 min of complete ischemic anoxia, but not after 30 min. There was better toleration to either isolated substrate deprivation or complete anoxia than to both together. Increasing extracellular Mg 2+ prolonged toleration to complete ischemic-anoxia. Removing Ca 2+ completely from the extracellular fluid exacerbated injury. Moreover, increasing extracellular volume improved toleration to the combined insult. This experiment suggests that injured neurons may elaborate cytotoxic compounds into the extracellular fluid. This suggestion was confirmed by further experiments demonstrating exacerbation of injury following minimum insults when the retina was incubated with other already extensively damaged tissue.

Dynamics of Brain Resuscitation After Ischemic Anoxia

The belief that even a few minutes of anoxia result in irreversible brain damage has been put into serious question, so that the possibility of brain resuscitation has taken on a new significance. A major focus for both laboratory and clinical investigation is the development of techniques to protect neurons during the critical reperfusion period after restoration of cerebral blood flow.

Effect of anoxia and hypoxia on brain lipid metabolism.

Lipid metabolism in rat brain was investigated in mild hypoxia (5-7% O2 in nitrogen), which is associated with no apparent change in energy metabolism, and in severe anoxic conditions (ischemic anoxia), which are associated with a rapid decrease in ATP and oxygen content in brain. When brain slices were incubated with labeled glucose or acetate, the amount of labeled CO2 produced was no different in experimental and control conditions, but the incorporation of radioactivity into brain lipids was decreased in all hypoxic and anoxic conditions. Interestingly, the incorporation of label from [14C]glucose into phosphatidylinositols was specifically inhibited by both hypoxic conditions but not by conditions associated with anoxia. The incorporation of the same labeled precursor, i.e., [14C]glucose, into fatty acids was elevated in ischemic anoxia but reduced after mild hypoxia. Because of the obvious differences in oxygen utilization in brain in anoxic and hypoxic conditions, we believe that the observed disturbances in lipid metabolism may be due to factors other than those that arise from oxygen deficiency alone.

Determination of the osmotic potential for swelling of cat brain in vitro

The osmotic potential for swelling of the brain was determined using feline cerebral tissue blocks as osmometers in deoxygenated Ringer's solution media containing various concentrations of the impermeant solute, polyethylene glycol 6000. The degree of swelling was determined gravimetrically. Curves showing the relationship between the volume change and glycol concentration were almost linear except for a slight S-shape deviation at about the zero-change level. The critical concentration at which the tissue blocks in Ringer's solution exhibited no volume change was 72 g/liter, from which the osmotic potential was estimated as 578 mm Hg. This high osmotic potential was attained within 30 min of anoxia, and maintained 12 h with a subsequent gradual decay. Analysis of concentration changes in small ions and proteins in the media during incubation of the tissue blocks revealed that the increased osmotic potential accompanied influxes of Na + and Cl − into the tissue blocks and effluxes of K + and proteins. The concentration changes in K + and proteins showed a statistically significant correlation. On the basis of quantitative analyses of these results, it is considered that the increased osmotic potential was caused not only by changes in the membrane permeability of the cells but also by physicochemical changes in intracellular proteins. After ischemic anoxia of the brain in situ, the huge osmotic potential of approximately 600 mm Hg inherent in the tissue would become apparent as an imbibing force for the development of brain edema and swelling.