Pharmacologically induced preconditioning with diazoxide: a novel approach to brain protection.

BACKGROUND: Ischemic preconditioning is an endogenous mechanism whereby brief periods of ischemia render neurons resistant to subsequent lethal insults. This protection appears to alter cellular apoptosis and can be induced by potassium channel openers acting on the inner membrane of the mitochondria (mitoK(ATP)). To test the hypothesis that pharmacologic preconditioning could provide neuroprotection, the mitoK(ATP) opener diazoxide was used in a canine model of brain injury induced by hypothermic circulatory arrest (HCA). METHODS: Seventeen dogs were placed on cardiopulmonary bypass (CPB) and cooled to 18 degrees C. After 2 hours of HCA, animals were rewarmed and weaned from CPB. Six dogs received intravenous diazoxide (2.5 mg/kg bolus 15 minutes prior to CPB, then 0.5 mg/min until circulatory arrest, then restarted for the first hour of rewarming). Six animals received vehicle only. Five received diazoxide and the mitoK(ATP) blocker 5-hydroxydecanoate (5-HD). Using a modified Pittsburgh Canine Neurological Scoring System (0 = normal, 500 = brain death), animals were evaluated every 24 hours for 3 days. The brains were removed and histologic sections of four regions characteristically injured in this model were scored (0 = no injury, 4 = infarction) by a neuropathologist in a blinded fashion. RESULTS: Clinical scoring showed marked improvement in the diazoxide group at 48 hours (101 +/- 10.5 vs 165 +/- 14.8, p < 0.01) and 72 hours (54 +/- 9.3 vs 137 +/- 12.1, p < 0.01). This neuroprotection was attenuated when 5-HD was concomitantly administered. Three of four brain regions typically injured in this model (cortex, hippocampus, and entorhinal cortex) had significant neuron preservation in the diazoxide group. Likewise, combined region scores were significantly improved in the treatment group (1.18 +/- 0.2 vs 2.46 +/- 0.2, p < 0.01). CONCLUSIONS: Pretreatment with diazoxide resulted in significant improvement in both clinical neurologic scores and histopathology in our model of HCA. This suggests that pharmacologic preconditioning with the mitoK(ATP) channel opener diazoxide may offer effective neuroprotection during HCA.

Immediate postoperative thrombolytic therapy: an aggressive strategy for neurologic salvage when cerebral thromboembolism complicates carotid endarterectomy.

A 42-year-old man with a high-grade left internal carotid artery (ICA) stenosis demonstrated on a duplex scan was referred to us. A cerebral arteriogram confirmed a greater than 90% left internal carotid stenosis, but with the unexpected finding of a moderate amount of thrombus in the proximal ICA. He underwent emergent left carotid endarterectomy, but during the operation, only a small amount of thrombus was identified as adherent to the atherosclerotic plaque. he awakened in the operating room with a dense right hemiplegia and aphasia. Immediate reexploration demonstrated a patent endarterectomy site, a distal thromboembolectomy was performed without extraction of thrombus, and urokinase (250,000 Units) was infused into the distal ICA. He reawakened with an unchanged right hemiplegia and aphasia. The patient then underwent an urgent postoperative carotid and cerebral arteriogram that demonstrated an embolus to the middle cerebral artery. he was treated with the superselective infusion of urokinase (500,000 Units), with almost complete resolution of the clot. Over the course of the next 48 hours, the patient made a nearly complete neurologic recovery, and he was discharged from the hospital with only a slight facial droop. At 2 months' follow-up he was completely neurologically healthy. To our knowledge this is the first reported case of urokinase administered in the immediate postoperative period in the angiography suite to treat a thromboembolus complicating a carotid endarterectomy.

The role of electrolyte in lesion size using an irrigated radiofrequency electrode.

Multiple attempts have been made to eliminate atrial fibrillation by performing the surgical maze procedure with radiofrequency energy. Currently, this is limited because of the risk of atrial perforation and the lack of transmural penetration. Saline irrigation has been investigated as a method of radiofrequency cautery tip cooling to prevent rapid temperature and impedance rises, which have been shown to lead to perforation or decreased radiofrequency penetration after eschar formation. There are few data on the influence that different types of electrolyte irrigation solutions have on lesion depth. Using a novel hollow cautery pen, we infused either an electrolyte solution (0.9%, 3%, 14.6%, or 23.4% sodium chloride), a nonelectrolyte solution (1.5% glycine), or no irrigation to produce 819 lesions on 14 left ventricles in swine using radiofrequency energy (450+/-10 kHz) applied at two output settings (20 and 75 watts). The nonelectrolyte solution increased lesion depth compared with no infusion at 20 watts but produced shallower lesion depths compared with electrolyte solutions at 75 watts. Compared with the other electrolyte solutions, the 0.9% sodium chloride solution produced the deepest lesions (3.34+/-0.06 mm) at 75 watts (p < 0.001). As the concentration of electrolyte increased, lesion depth decreased unless generator output increased. Formation of eschar and tissue destruction was seen in the noninfusion and nonelectrolyte groups but not in the electrolyte group. A conductive media coupled with radiofrequency energy allowed for greater lesion depth than irrigated cooling with a nonelectrolyte solution or no irrigation. There was an inverse relationship between electrolyte concentration and lesion depth. We conclude that the concentration of electrolyte irrigant is an important consideration when choosing a solution to improve transmural penetration and decrease the risk of tissue destruction from radiofrequency energy.

Role of renin isoelectric heterogeneity in renal storage and secretion of renin.

Renin is a glycoprotein that is heterogeneous with respect to carbohydrate content and net charge. In an attempt to clarify the role of renin isoelectric heterogeneity in renal renin storage and secretion, the isoelectric profile of renal renin, secreted renin, and circulating renin were directly assessed and compared under basal and stimulated conditions by the use of an in vivo blood perfused rabbit kidney preparation. Under basal conditions, the kidney preferentially stored and secreted the relatively basic isoelectric forms of renin. Acute stimulation of renin secretion (reduced renal perfusion pressure and angiotensin-converting enzyme inhibition) significantly increased the secretion of the relatively basic isoelectric forms but had very little effect on the secretion of the relatively acidic renin forms. Circulating renin was composed primarily of relatively basic forms, which increased disproportionately after stimulation of renin secretion. These findings suggest that the isoelectric heterogeneity of renin is important in the cellular processing of renin and can be explained by a two-pool model in which the relatively acidic isoelectric forms of renin are constitutively secreted (and not stored) and the relatively basic isoelectric forms represent a regulated pathway in which they are stored and rapidly released in response to acute secretory stimuli. Preferential hepatic extraction of the more basic isoelectric forms has previously been described. Data from this study suggest that the disproportionate increase in circulating basic forms of renin observed after acute stimulation reflects the net effect of preferential renal the more basic renin isoelectric forms. The disproportionate increase in relatively basic circulating renin forms after acute secretory stimulation results in an overall circulating renin activity with a shorter half-life.