Ischemic Edema Research Articles

Beneficial Effect of Prolonged Administration of Albumin on Ischemic Cerebral Edema and Infarction after Occlusion of Middle Cerebral Artery in Rats

This study compared the therapeutical effect of the prolonged administration of albumin, 2 g/kg body weight per day, with that of saline or dextran, 0.8 g/kg body weight per day, on cerebral ischemia, using an occlusion of the middle cerebral artery in the rat. Brain water, sodium, and potassium contents were measured 72 hours after middle cerebral artery occlusion. The volume of infarction was represented as volume index, which is a total of the infarction area measured in the five brain slices at 168 hours after middle cerebral artery occlusion. The postischemic administration of albumin at the dose tested elucidated an antiedema effect and reduced the infarction size after regional ischemia in rats. These results strongly support the idea that hemodilution therapy with colloids such as albumin has wide usage as a treatment of patients with ischemic cerebral stroke.

Neuroprotection following focal cerebral ischaemia with the NMDA antagonist dextromethorphan, has a favourable dose response profile.

Although N-methyl-D-Aspartate (NMDA) antagonists protect against focal cerebral ischaemia, there is concern that the high doses necessary for neuroprotection may cause unacceptable adverse effects. We studied the dose response characteristics of the clinically available NMDA antagonist dextromethorphan in a rabbit model of transient focal ischaemia. Thirty-three anaesthetized rabbits underwent occlusion of the left internal carotid and anterior cerebral arteries for 1 h followed by 4.5 h of reperfusion. One hour after the onset of ischaemia, they were treated with an i.v. infusion of varying doses of dextromethorphan or normal saline. Seventeen additional unanaesthetized, nonischaemic rabbits received similar infusions of dextromethorphan to correlate brain with blood levels and to evaluate adverse effects. Rabbits with plasma dextromethorphan levels 500-1500 ng ml-1 had a 64% reduction in ischaemic neuronal damage (p < 0.05); those with levels > 1500 ng ml-1 showed 92% attenuation of neuronal damage and 65% decrease in ischaemic oedema (p < 0.01). Drug levels suggest that dextromethorphan's neuroprotection is not mediated by its active metabolite dextrorphan. Unanaesthetized rabbits with plasma levels > 2500 ng ml-1 demonstrated severe gait ataxia. These results demonstrate that systemic treatment with dextromethorphan after 1 h of focal ischaemia can significantly protect against cerebral damage if adequate plasma and brain levels are achieved. Dextromethorphan was concentrated 7-30 x in brain compared with plasma, and brain levels were highly correlated with plasma levels (r = 0.89). Neuroprotective doses of dextromethorphan were tolerated with only transient side effects.

Relationship between postoperative anemia and cardiac morbidity in high-risk vascular patients in the intensive care unit.

To determine if postoperative anemia is associated with postoperative myocardial ischemia and morbid cardiac events Case control study. Postanesthesia care unit and surgical intensive care unit. A total of 27 high-risk patients undergoing infra-inguinal arterial bypass procedures. None. After informed consent, patients were continuously monitored by ambulatory electrocardiographic recorders from the evening before surgery up to 80 hrs during the postoperative period. Myocardial ischemia was defined as > or = 1 mm of horizontal or downsloping ST depression or > or = 2 mm ST segment elevation persisting for at least 60 secs on the ambulatory electrocardiogram. Morbid cardiac events were defined as: cardiac death, myocardial infarction, unstable angina, and ischemic pulmonary edema. Using a receiver operating characteristic curve, a hematocrit of 28% was determined to be the best threshold hematocrit value below which morbid cardiac events were most likely to occur. Statistical significance between hematocrit and cardiac outcome was determined by Fisher's exact test where appropriate. Thirteen of 27 patients had a hematocrit < 28%. Of these 13 patients, ten demonstrated postoperative myocardial ischemia and six sustained a morbid cardiac event. Of 14 patients with a hematocrit > or = 28%, two displayed myocardial ischemia and none sustained a morbid cardiac event. A hematocrit of < 28% was significantly associated with myocardial ischemia (p = .001) and morbid cardiac events (p = .0058). No significant differences in baseline heart rate and heart rate at the onset of myocardial ischemia were noted between the anemic and nonanemic patients. This study suggests that postoperative anemia may play a role in postoperative myocardial ischemia and cardiac morbidity.

Progressive Brain Compression

Continuous recording of vital physiological variables and sequential MR imaging were performed simultaneously during continuous expansion of an epidural rubber balloon over the left hemisphere in anaesthetised dogs. Balloon expansion led to a progressive and slightly nonlinear rise in intracranial CSF pressures and a fall in local perfusion pressures. Changes in systemic arterial pressure, pulse rate, and respiration rate usually appeared at a balloon volume of 4% to 5% of the intracranial volume (reaction volume), together with a marked transtentorial pressure gradient and MR imaging changes consistent with tentorial herniation. Respiratory arrest occurred at a balloon volume of approximately 10% of the intracranial volume (apnoea volume), which was associated with occlusion of the cisterna magna, consistent with some degree of foramen magnum herniation. Increase in tissue water was observed beginning at approximately the reaction volume, presumably due to ischaemic oedema, due to the fall in perfusion pressures.

Protective effects of tetrahydroneopterin against free radical-induced injury

The therapeutic potency of 5,6,7,8-tetrahydroneopterin (NPH4) was investigated in ischemic paw edema, Adriamycin® (ADR)-induced cardiotoxicity, and endotoxin [lipopolysaccharide (LPS)]- and carbon tetrachloride (CCl 4)-induced hepatotoxicity in mice. Ischemic paw edema was completely suppressed by pre-administration of NPH4. ADR-induced cardiotoxicity and LPS-induced hepatotoxicity were significantly decreased by post-administration of NPH4. Furthermore, NPH4 ameliorated ccl 4-induced hepatotoxicity. These results suggest that NPH4 may be useful for the treatment of free radical, especially Superoxide radical, -related tissue injury.

Evaluation of Poly(vinyl alcohol) for Protein Tailoring: Improvements in Pharmacokinetic Properties of Superoxide Dismutase

Conjugation of poly(vinyl alcohol) (PVA) containing a thiol group to superoxide dismutase (SOD) was performed by using N-(∈-maleimido caproyloxy)succinimide (EMCS) as a coupling agent. Various chemical charac teristics and pharmacokinetic parameters were evaluated. Two different molec ular weight PVA-SOD conjugates were prepared. Both retained at least 92% of the native SOD activity whereas the plasma half-life increased from 4.8 min for the native SOD to 3.0 and 7.8 h for the low and high molecular weight PVA conjugates, respectively. Tissue distribution studies revealed that in travenously administered PVA-SOD had a high concentration primarily in the circulation, followed by the kidney, the lung, the liver, and the spleen. Un modified SOD was rapidly excreted via the urine, with the exception of high retention in the kidney (36% of the injected dose). PVA-SOD was also rapidly ex creted in the urine, which suggests that the kidney is the main route of excre tion of the derivatives. PVA-SOD exhibited a lower antigenicity and immuno genicity and an enhanced therapeutic effect against ischemic edema of the mouse foot pad compared with the native form. PVA with a thiol functional group appears to be useful for the preparation of protein drug-polymer conju gates, with significant diminution of immunogenicity but retention of almost full biological activity attributable to both mild conjugation conditions and selective reaction.

Effects of Recanalization and Collateral Blood Supply on Infarct Extent and Brain Edema after Middle Cerebral Artery Occlusion

A series of 53 patients with angiographically proven middle cerebral artery (MCA) trunk occlusions treated with intravenous (in 46) or intra-arterial (in 7) recombinant tissue plasminogen activator (rt-PA) and heparin anticoagulation was studied with serial computed tomography to find out whether recanalization promotes ischemic brain edema and hemorrhagic transformation. Partial or complete recanalization of the MCA trunk was shown in 11 patients immediately after rt-PA treatment by a second angiogram and in altogether 18 patients 1 day later by transcranial Doppler ultrasound or a third angiogram. During follow-up the extent of hypodensity increased in 5 of 18 patients (28%) with reperfusion at 24 h after symptom onset and in 23 of 35 patients (66%) without reperfusion (p < 0.01). The ischemic edema caused a midline shift in 1 of 18 patients (6%) with reperfusion at 24 h after symptom onset, but in 14 of 35 patients (40%) without reperfusion (p < 0.05). Hemorrhagic transformation was associated with reperfusion at 24 h in 7 (39%) patients and occurred in 13 (37%) patients without reperfusion (p > 0.5). Our data suggest that recanalization of MCA trunk occlusion within 24 h after symptom onset does not promote edema or hemorrhagic transformation of ischemic brain tissue.

ＴＳＡ‐２３４（ｒｅｃｏｍｂｉｎａｎｔ ｈｕｍａｎ ｓｕｐｅｒｏｘｉｄｅ ｄｉｓｍｕｔａｓｅ）の抗炎症作用

Anti-inflammatory effects of TSA-234 (recombinant human superoxide dismutase, rhSOD) were studied in vitroand in vivo. TSA-234, 0.1-100 μg/ ml, significantly inhibited damage of chondrocytes, reduction inviscosity of hyaluronic acid and osteoarthrosis-derived joint fluid, delayed gelation of collagen and inactivation of α1-proteinase inhibitor (PI) which were induced by active oxygen species generated in the system of hypoxanthine-xanthine oxidase. Intraarticular injection of TSA-234 significantly inhibited both carrageenin-induced arthritis in rabbit knees and sodium urate-induced arthritis in dog knees. Furthermore, TSA-234 significantly inhibited rat carrageenin-induced paw edema and mouse ischemic paw edema by 0.125-1 mg/kg, i. v. and 1 mg/kg, i. v., respectively.These results suggest that TSA-234 will be useful with an Intraarticular injection on the therapy of osteoarthrosis in knees.

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)

Blockade of nitric oxide formation by [formula omitted] mitigates ischemic brain edema and subsequent cerebral infarction in rats

In order to investigate whether or not nitric oxide (NO) formation underlies the cellular mechanisms of ischemic brain damage, we examined the effects of Nω-nitro-l-arginine (l-NNA), a NO synthase inhibitor, on ischemic brain edema and subsequent infarction in rats with middle cerebral artery occlusion (MCAo). For this purpose, administrations of l-NNA (1 mg/kg, i.p.) to each animal were done at the time of 5 min, 3, 6 and 24 h after MCAo, respectively. It was shown from this study that l-NNA significantly mitigated ischemic cerebral edema, and histological examinations revealed that this compound markedly reduced infarction size that occurred following MCAo. These results strongly suggest that NO formation is at least partly involved in the pathogenetic mechanisms of ischemic brain edema and subsequent cerebral infarction.

Effects of retrograde perfusion of the brain with combined drug therapy after focal ischemia in rat brain.

The ischemic edema associated with blood-brain barrier permeability changes and the excess production of free radicals are serious complications in prolonged cerebral ischemia. We examined the efficacy of transvenous perfusion of the brain, starting treatment 5 hours after occlusion of the middle cerebral artery for a period of 2 hours in rats with the combined agents mannitol (10 ml/2 hr) and dexamethasone (1 mg/2 hr) to counter edema and verapamil (0.05 mg/kg/2 hr) for vasodilation. In experiment 1, blood-brain barrier permeability changes were examined in five groups with six rats each: group C rats underwent 7 hours of middle cerebral artery occlusion with no treatment; group V, treatment with verapamil alone; group VD, treatment with verapamil and dexamethasone; group VM, treatment with verapamil and mannitol; and group VDM, treatment with verapamil, dexamethasone, and mannitol. In experiment 2, we examined local cerebral blood flow, ischemic tissue damage volume, and water content of cerebral hemispheres in two groups of 16 rats each subjected to the same treatment as groups C and VDM rats in experiment 1. There was a significant reduction of blood-brain barrier permeability changes in the ischemic cortex of rats in group VDM compared with rats in the other groups. In the group undergoing transvenous perfusion of the brain with the three combined agents, there was a significant improvement of cerebral blood flow (39-58%, p < 0.05) in the ischemic cortex and reduction of ischemic cerebral damage volume (22%, p < 0.01) and water content of the ischemic hemisphere (p < 0.05) compared with the control group. The therapeutic approach using combined agents is effective treatment when initiated within 5 hours of focal cerebral ischemia in rats.

Late ultrastructural changes in the retina of the rat following low-dose X-irradiation.

This study describes ultrastructural changes in the pigmented hooded Lister rat retina, 3-12 months following X-irradiation with single doses of between 200 and 2000 cGy. The extreme radiosensitivity of the photoreceptor cells was underlined by the continued manifestation of fine structural changes and cell death up to 6 months post-radiation in animals receiving doses above 500 cGy. The retinal pigment epithelial (RPE) cells were more radioresistant than photoreceptors and RPE cell loss was only observed at doses of more than 1500 cGy. One year after irradiation with 1500 cGy the retinal vasculature showed capillary occlusion with some evidence of recanalisation. Telangiectasia was observed in the large retinal veins. Although the inner retinal neurones and glial cells showed no evidence of direct radiation damage, the nerve fibre layer adjacent to occluded retinal vessels demonstrated ultrastructural evidence of ischaemic neuropathy and retinal oedema. At doses above 1500 cGy the choriocapillaris showed platelet aggregation and capillary loss.

P-130 - The effect of a novel loop diuretic, torasemide, on ischemic cerebral edema in mongolian gerbils

P-130 - The effect of a novel loop diuretic, torasemide, on ischemic cerebral edema in mongolian gerbils

Effects of cervical spinal cord stimulation in experimental ischaemic oedema

Cervical spinal cord stimulation (SCS) has been used in an animal model of acute ischaemic brain oedema. In anaesthetized rats a temporary carotid bilateral occlusion of 60 minutes was carried out, followed by a reperfusion period of 30 minutes before sacrifice. Two electrodes were placed in each side of the duramater at C2 level. SCS was started either 60 minutes before ischaemia or at the beginning of the reperfusion period. The parameters of stimulation were: pulse width 0.1 ms; frequency of 25 cps; intensity at one third of the threshold which produced motor responses. The specific gravity of the brain was measured at different areas using a microgravimetric technique in a bromobenzene-petroleum column. Our results indicate that: 1) cervical SCS reduces ischaemic cerebral oedema, 2) the effect is more prominent using stimulation during the reperfusion period, and 3) there were no differences in mortality rates or in the pathological study.

Acute effects of a pedicled omental graft on cold-induced brain oedema in cats

When used as a prophylactic measure and in chronic experiments, omental transposition has been shown to reduce ischaemic and traumatic oedema in the spinal cord and ischaemic oedema in the brain. We designed this experiment to evaluate the acute effects of a pedicled omental graft on cold-induced brain oedema in cats. Focal oedema was induced in the left frontoparietal region of the brain of nine anaesthetized cats. In five cats, a laparotomy was done and a pedicled omental graft was placed on the lesioned left hemisphere immediately after the cold lesion was made. All cats were sacrificed 72 hours later, and the water content of the white matter was determined in the lesioned and the normal hemispheres. The mean water content of the lesioned hemisphere of the treated group of animals was not significantly different from that of the control group. We conclude that a pedicled omental graft failed to reduce vasogenic oedema in an acute model and probably has no role in the acute management of brain oedema.

Effects of Dextromethorphan on Regional Cerebral Blood Flow in Focal Cerebral Ischemia

Dextromethorphan (DM), a noncompetitive NMDA antagonist, has been demonstrated to reduce ischemic neuronal damage and edema, but DM's influence on cerebral blood flow has not been extensively studied. In this investigation, it is shown that DM has significant effects on regional cerebral blood flow (rCBF) patterns in a rabbit model of focal cerebral ischemia. rCBF was measured using radioactive microspheres following a 1 h permanent occlusion of the left internal carotid, anterior cerebral, and middle cerebral arteries in rabbits. Somatosensory evoked potentials (SEPs) were used to assess the degree of ischemia; only animals where SEPs were completely abolished were used for a frequency distribution analysis of rCBF. It was found that there were significantly more regions with lower flows in animals treated with normal saline (NS) (n = 7) compared to animals treated with DM (n = 7) (p less than 0.05, ipsilateral left side; p less than 0.001, contralateral right side). The frequency distribution medians were 27.5 ml 100 g-1 min-1 (left) and 70.0 ml 100 g-1 min-1 (right) in the NS group vs. 34.5 ml 100 g-1 min-1 (left) and 80.5 ml 100 g-1 min-1 (right) in the DM group. The left and right hemispheric regional means were 29.4 +/- 20 and 74.3 +/- 23 ml 100 g-1 min-1, respectively, in the NS group vs. 34.4 +/- 16 and 91.0 +/- 28 ml 100 g-1 min-1, respectively, in the DM group.(ABSTRACT TRUNCATED AT 250 WORDS)

Neutrophil as a mediator of ischemic edema formation in the brain

We investigated the contribution of neutrophils to brain edema formation using a transient focal ischemia model in rats. Rats were given antineutrophil monoclonal antibody (RP3) intraperitoneally to deplete circulating neutrophils. In RP3-treated rats, ischemic brain edema formation 1 day after reperfusion was significantly decreased compared to that of saline-treated control rats. We speculate that chemical mediators released by infiltrating neutrophils alter vascular permeability and play an important role in post-ischemic brain edema formation.

A novel treatment for ischemic intracranial hypertension in cats.

There is no accepted efficacious treatment for ischemic cerebral edema. We show in a cat model of focal cerebral ischemia that infarct volume can be reduced (p less than 0.05) by ventriculocisternal perfusion with an oxygenated fluorochemical emulsion (bis-perfluorobutylethylene). An accompanying effect of such ventriculocisternal perfusion is a reduction in intracranial pressure. At 18 hours following the start of the perfusion, there was a significant (p less than 0.05) difference in intracranial pressure between nonperfused controls (mean 11.4 [range 2.3-23.0] torr, n = 6) and cats perfused with an oxygenated nutrient solution not containing fluorochemical (mean 11.3 [range 3.0-29.0] torr, n = 8) or animals perfused with the oxygenated fluorochemical emulsion (mean 2.21 [range 0-3.5] torr, n = 7). Perfusion with this oxygenated fluorochemical emulsion warrants further study as a treatment for elevated intracranial pressure.

Correlation Between Preoperative Ischemia and Major Cardiac Events After Peripheral Vascular Surgery

RABY, K. E.; GOLDMAN, L.; CREAGER, M. A.; COOK, E. F.; WEISBERG, M. C.; WHITTEMORE, A. D.; SELWYN, A. P. Author Information

Usefulness of semiquantitative analysis of dipyridamole-thallium-201 redistribution for improving risk stratification before vascular surgery

Preoperative dipyridamole-thallium-201 scanning is sensitive in identifying patients prone to ischemic cardiac complications after vascular surgery, but most patients with redistribution do not have an event after surgery. Therefore, its positive predictive value is limited. To determine which patients with thallium redistribution are at highest risk, dipyridamole-thallium-201 images were interpreted semiquantitatively. Sixty-two consecutive patients with redistribution on preoperative dipyridamole-thallium-201 planar imaging studies were identified. Each thallium scan was then analyzed independently by 2 observers for the number of myocardial segments out of 15, the number of thallium views out of 3 and the number of coronary artery territories with redistribution. Seventeen patients (27%) had postoperative ischemic events, including unstable angina pectoris, ischemic pulmonary edema, myocardial infarction and cardiac death. Thallium predictors of ischemic operative complications included thallium redistribution ≥4 myocardial segments (p = 0.03), ≥2 of the 3 planar views (p = 0.005) and ≥2 coronary territories (p = 0.007). No patient with redistribution in only 1 view had an ischemic event (0 of 15). Thus, determining the extent of redistribution by dipyridamole-thallium-201 scanning improves risk stratification before vascular surgery. Patients with greater numbers of myocardial segments and greater numbers of coronary territories showing thallium-201 redistribution are at higher risk for ischemic cardiac complications. In contrast, when the extent of thallium redistribution is limited, there is a lower risk despite the presence of redistribution.