Guanosine Exerts Neuroprotective Effect in an Experimental Model of Acute Ammonia Intoxication.

The nucleoside guanosine (GUO) increases glutamate uptake by astrocytes and acts as antioxidant, thereby providing neuroprotection against glutamatergic excitotoxicity, as we have recently demonstrated in an animal model of chronic hepatic encephalopathy. Here, we investigated the neuroprotective effect of GUO in an acute ammonia intoxication model. Adult male Wistar rats received an intraperitoneal (i.p.) injection of vehicle or GUO 60 mg/kg, followed 20 min later by an i.p. injection of vehicle or 550 mg/kg of ammonium acetate. Afterwards, animals were observed for 45 min, being evaluated as normal, coma (i.e., absence of corneal reflex), or death status. In a second cohort of rats, video-electroencephalogram (EEG) recordings were performed. In a third cohort of rats, the following were measured: (i) plasma levels of glucose, transaminases, and urea; (ii) cerebrospinal fluid (CSF) levels of ammonia, glutamine, glutamate, and alanine; (iii) glutamate uptake in brain slices; and (iv) brain redox status and glutamine synthetase activity in cerebral cortex. GUO drastically reduced the lethality rate and the duration of coma. Animals treated with GUO had improved EEG traces, decreased CSF levels of glutamate and alanine, lowered oxidative stress in the cerebral cortex, and increased glutamate uptake by astrocytes in brain slices compared with animals that received vehicle prior to ammonium acetate administration. This study provides new evidence on mechanisms of guanine-derived purines in their potential modulation of glutamatergic system, contributing to GUO neuroprotective effects in a rodent model of by acute ammonia intoxication.

Expensive cerebral blood flow measurements alone are useless and misinformative in comatose patients: a comprehensive alternative.

Since the first report addressing quantification of cerebral blood flow (CBF), concomitant assessment of cerebral oxygen consumption was also carried out. Over the years, however, some investigators have emphatically and mistakenly addressed cerebral ischemia in comatose patients, on the basis of CBF measurements alone. In contrast, we have repeatedly reported that ischemia in these patients must be precisely evaluated based on CBF-metabolism coupling or uncoupling, rather than CBF alone. Based on these previous findings, we therefore propose a comprehensive alternative approach, namely the evaluation of brain ischemia in comatose patients based on cerebral metabolic parameters, such as cerebral extraction of oxygen or cerebral lactate release, without expensive CBF measurements.

[Cerebral hemometabolism: variability in the acute phase of traumatic coma]. / Hemometabolismo cerebral: variações na fase aguda do coma traumático.

OBJECTIVE: to evaluate the interrelationships between cerebral and systemic hemometabolic alterations in patients with severe traumatic brain injury managed according to a standardized therapeutic protocol. DESIGN: prospective, interventional study in patients with traumatic coma. SETTING: a general Intensive Care Unit in a teaching hospital. PATIENTS AND METHODS: twenty-seven patients (21M e 6F), aging 14 - 58 years, with severe acute brain trauma, presenting with three to eight points on the Glasgow Coma Scale, were prospectively evaluated according to a cumulative protocol for the management of acute intracranial hypertension, where intracranial pressure (ICP) and cerebral extraction of oxygen (CEO2) were routinely measured. Hemometabolic interrelationships involving mean arterial pressure (MAP), ICP, arterial carbon dioxide tension (PaCO2), CEO2, cerebral perfusion pressure (CPP) and systemic extraction of oxygen (SEO2) were analyzed. INTERVENTIONS: routine therapeutic procedures. RESULTS: no correlation was found between CEO2 and CPP (r = -0.07; p = 0.41). There was a significant negative correlation between PaCO2 and CEO2 (r = -0.24; p = 0.005) and a positive correlation between SEO2 and CEO2 (r = 0.24; p = 0.01). The mortality rate in this group of patients was 25.9% (7/27). CONCLUSION: 1) CPP and CEO2 are unrelated; 2) CEO2 and PaCO2 are closely related; 3) during optimized hyperventilation, CEO2 and SEO2 are coupled.

Hemorrhagic shock and encephalopathy: clinical, pathologic, and biochemical features.

To further define the clinical, pathologic, and biochemical features of hemorrhagic shock and encephalopathy syndrome, we studied 25 affected children (aged 3 months to 14 years) admitted to a single center between 1982 and 1985. A prodromal illness comprising vomiting, diarrhea, listlessness, and fever was present in 84% of the cases. Acute onset of shock, convulsions and coma, bleeding (or laboratory evidence of disseminated intravascular coagulation), elevated plasma activity of hepatic enzymes, acidosis, and impaired renal function was present in every case. Twenty patients died, and all the survivors are neurologically damaged. At postmortem examination, intravascular microthrombi coexisting with hemorrhages and petechiae were found in most organs. Centrilobular liver necrosis and cerebral edema were prominent features. No microbiologic cause for the disorder was identified, but decreased plasma levels of the protease inhibitors alpha 1-antitrypsin and alpha 2-macroglobulin, together with increased levels of circulating proteolytic enzymes, were frequently present. An overrepresentation of the uncommon variant phenotypes of alpha 1-antitrypsin was found in first-degree relatives of affected patients (four had the MZ phenotype, and one each the MS or MC phenotype, of 19 relatives studied). Abnormal accumulation of alpha 1-antitrypsin was detected immunohistochemically in the livers of six of the patients. Defective protease inhibitor production or release may be involved in the pathogenesis of the disorder.