RESUMEN
The effect of the combination of two drugs, i.e. lidoflazine (a calcium antagonist), and deferoxamine (an iron chelator) was evaluated following 15 min global brain ischaemia (GBI) and reperfusion in dogs in a randomized blind study. GBI was produced by complete cardiac arrest of 15 min duration. Histopathological analysis performed on in situ fixed brains 40 h post-resuscitation revealed diffuse microhaemorrhages in the control group. These were noted rarely in the treatment group, the mean value of foci of microhaemorrhages/20 low power fields (LPF) being 5.2 in the treatment group versus 28 in the control group (p less than 0.001). Diffuse coagulative necrosis of neurons (ischaemic cell change) in the cerebral cortex, especially lamina 3, hippocampus, striatum, brain stem and cerebellum was present in all cases. Quantitation of the degree of cellular damage obtained by counting the number of anoxic neurons (in consistent regions of the brain) with the use of an image analysis system, revealed no significant difference between the 2 groups. The mean percentages of the ischaemic neurons in the control group in the various areas studied were: parietal cortex, 22.25; hippocampus, 50.37 and cerebellum (Purkinje cells), 66.75; and in the treatment group 25.3, 55.04 and 70.6 respectively. Thus, the lidoflazine-deferoxamine regimen significantly reduced the incidence of microhaemorrhages in the brain, but it did not have any protective effect against anoxic neuronal injury 40 h post-ischaemia in this experimental model of GBI of 15 min duration.
Asunto(s)
Bloqueadores de los Canales de Calcio/uso terapéutico , Deferoxamina/uso terapéutico , Hierro/metabolismo , Ataque Isquémico Transitorio/tratamiento farmacológico , Lidoflazina/uso terapéutico , Piperazinas/uso terapéutico , Animales , Perros , Quimioterapia Combinada , Ataque Isquémico Transitorio/metabolismo , Ataque Isquémico Transitorio/patologíaRESUMEN
Recent evidence suggests that ultimate neurologic injury following cardiac arrest and resuscitation may be largely determined by biochemical events occurring during reperfusion. To test this hypothesis and further characterize the time course of some of these events, we examined tissue samples from the parietal cortex for their total content of calcium (Ca), magnesium (Mg), iron (Fe), sodium (Na), and potassium (K) after 10 minutes, two hours, four hours, and eight hours of reperfusion following a 15-minute cardiac arrest in dogs. After 10 minutes of reperfusion, there were relatively small, but significant, increases in the total tissue content of Ca and Na, as compared to nonischemic controls. All values had returned to normal at two hours and remained normal at four hours of reperfusion. However, at eight hours of reperfusion, Ca and Na content approximately doubled and K content was reduced by half. There were no significant changes at any time in the tissue content of Fe or Mg. We conclude that with between four and eight hours of reperfusion following a 15-minute cardiac arrest, a major defect occurs in many cells of the cortex with respect to their ability to control ionic balances of Ca, Na, and K. This might be explained either by failure of the energy-dependent ionic pumps or by more generalized damage to the membrane permeability barrier by a process such as lipid peroxidation.
Asunto(s)
Paro Cardíaco/terapia , Lóbulo Parietal/metabolismo , Resucitación , Animales , Calcio/metabolismo , Perros , Hierro/metabolismo , Magnesio/metabolismo , Potasio/metabolismo , Sodio/metabolismoRESUMEN
A time course of tissue ionic changes, and their relation to ultrastructural findings during reperfusion following a 15-min global ischemic brain insult was studied in a dog model. Parietal cortex was analyzed for Ca, Na, K, Mg and Fe in controls and after 10 min, 2, 4, and 8 h of reperfusion. After 8 h of reperfusion, the mean values (mumol/g tissue wet wt.) for Ca (control = 1.43, 8 h = 2.76) and Na (control 60.4, 8 h = 107.4) doubled and K (control = 90.4, 8 h = 48.5) decreased to half that of the control. Ultrastructural studies and subcellular localization of calcium in parietal cortex of in situ-fixed brains after 8 h showed cortical neurons with clumping of nuclear chromatin, dilatation of endoplasmic reticulum and disruption of plasma membranes. Large amounts of electron-dense precipitates of calcium were present within dilated astrocytic processes, synaptic vesicles, cytoplasm of edematous dendrites and mitochondria. Cortical neurons from postischemic dogs without reperfusion showed only slight chromatin clumping and edema of astrocytic processes, but no calcium accumulation. The large ionic shifts noted between 4 and 8 h of reperfusion, indicate a progressive inability of the cells to maintain normal transmembrane gradients of these ions and may reflect a membrane destructive process, as demonstrated ultrastructurally at 8 h. Enhanced calcium entry into the neuron during reperfusion appears to be a part of the cytotoxic mechanism leading to neuronal necrosis.
Asunto(s)
Isquemia Encefálica/patología , Cationes/análisis , Corteza Cerebral/ultraestructura , Animales , Isquemia Encefálica/metabolismo , Calcio/análisis , Corteza Cerebral/análisis , Perros , Hierro/análisis , Magnesio/análisis , Potasio/análisis , Sodio/análisisRESUMEN
Brain injury after cardiac arrest and resuscitation may occur, in part, by oxygen radical mechanisms. The availability of a transition metal, such as iron, is essential for in vitro initiation of this type of reaction. The brain has significant stores of iron bound in large proteins. We conducted this study to determine whether iron availability is enhanced in the canine brain following resuscitation from 15 minutes of cardiac arrest, and whether this iron is associated with the appearance of products of radical-mediated lipid peroxidation (LP) after two hours of reperfusion. Examination of the data by the method of multivariate analysis revealed significant increases in the low molecular weight species (LMWS) iron (300% of nonischemic controls, P less than .01), malondialdehyde (MDA), a lipid peroxidation degradation product (145% of nonischemic controls, P less than .01), and conjugated dienes (CD) (204% of nonischemic controls, P = .07). Therapy with deferoxamine (50 mg/kg IV immediately post resuscitation) produced a reduction in MDA and CD to levels statistically indistinguishable from nonischemic controls. We conclude that brain tissue iron is delocalized from normal storage forms to a LMWS pool after two hours of reperfusion following resuscitation from a 15-minute cardiac arrest, and that this is associated with increased products of LP. The increase in LP products is blocked by treatment with deferoxamine.
Asunto(s)
Encéfalo/metabolismo , Paro Cardíaco/metabolismo , Hierro/metabolismo , Peróxidos Lipídicos/metabolismo , Análisis de Varianza , Animales , Encéfalo/irrigación sanguínea , Deferoxamina/metabolismo , Perros , Infusiones Parenterales , Malondialdehído/metabolismo , Modelos Biológicos , ResucitaciónRESUMEN
We hypothesize that brain injury from cardiac arrest occurs during reperfusion and is in part mediated by iron-dependent lipid peroxidation. We conducted a study to examine the time course of brain iron delocalization and lipid peroxidation in an animal model of cardiac arrest and resuscitation. Assays for brain tissue iron in low-molecular-weight species (LMWS iron) used the o-phenanthroline test on an ultrafiltered (molecular weight less than 30,000) tissue sample; malondialdehyde (MDA), a product of lipid peroxidation, in brain tissue was assayed by the thiobarbituric acid test (TBA). Samples of the parietal cortex from 11 nonischemic control dogs (Group 1) had LMWS iron levels of 9.6 +/- 4.9 nmol/100 mg tissue and MDA levels of 7.7 +/- 2.0 nmol/100 mg tissue. Samples from the parietal cortex taken from five dogs after 15 minutes of cardiac arrest (Group 2) had LMWS iron levels of 9.3 +/- 3.1 nmol/100 mg tissue and MDA levels of 6.1 +/- 1.0 nmol/100 mg tissue. Samples from the parietal cortex taken from five dogs after 45 minutes of cardiac arrest (Group 3) had LMWS iron levels of 6.7 +/- 3.3 nmol/100 mg tissue and MDA levels of 5.6 +/- 0.4 nmol/100 mg tissue. There was no significant difference among the three groups for either LMWS iron or MDA. Five dogs were subjected to 15 minutes of cardiac arrest and definitive resuscitation by internal cardiac massage and defibrillation (Group 4). Following resuscitation the chest was closed and the dogs were given intensive care for two hours.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Encéfalo/metabolismo , Paro Cardíaco/metabolismo , Hierro/metabolismo , Resucitación , Animales , Isquemia Encefálica/etiología , Isquemia Encefálica/metabolismo , Membrana Celular/metabolismo , Supervivencia Celular , Perros , Urgencias Médicas , Paro Cardíaco/complicaciones , Peróxidos Lipídicos/metabolismo , Malondialdehído/metabolismoRESUMEN
Regional cerebral cortical blood flow (rCCBF) in 15 large dogs was determined using the double thermistor dilution method during standard closed-chest massage (CCM), CCM with an epinephrine infusion at 30 micrograms/kg/min (CCM + Epi), and open-chest cardiac massage (OCCM). As a percentage of prearrest flow values, the rCCBF was 9.8% with CCM, 35% with CCM + Epi, and 156% with OCCM. The rCCBF was reduced significantly with CCM (P less than .005) and CCM + Epi (P less than .01). OCCM generated flows indistinguishable from prearrest values. The use of high-dose epinephrine significantly increased the rCCBF during CCM. The implications for intact neurologic resuscitation of these reductions in rCCBF with CCM are important.
Asunto(s)
Corteza Cerebral/irrigación sanguínea , Resucitación , Animales , Corteza Cerebral/efectos de los fármacos , Perros , Epinefrina/farmacología , Masaje Cardíaco/métodosRESUMEN
Perfusion of the cerebral cortex during closed chest CPR in dogs, generating systolic pressures of 60 to 70 mmHg, is only 10% of pre-arrest blood flow. In contrast, internal cardiac massage produces normal cortical perfusion rates. Following a 20-min perfusion arrest, during pressure controlled reperfusion, cortical flow rates decay to less than 20% normal after 90 min of reperfusion. This appears to be due to increasing cerebral vascular resistance, and is not due to rising intracranial pressure. The post-arrest cortical hypoperfusion syndrome is prolonged with cortical flow remaining below 20% normal up to 18 hr post arrest. The use of a variety of calcium antagonists, including flunarizine, lidoflazine, verapamil, and Mg2+, immediately post-resuscitation maintains cerebral vascular resistance and cortical perfusion at normal levels. A prospective blind trial of the calcium antagonist lidoflazine following a 15-min cardiac arrest in dogs and resuscitation by internal massage, demonstrates amelioration of neurologic deficit in the early postresuscitation period.