thiopental and Uremia

The neurotoxic potential of intravenous administered benzylpenicillin (BPC) was studied in rabbits with intact blood-CNS barriers and rabbits with experimental E. coli meningitis. At onset of epileptogenic EEG activity or seizures, serum, CSF and brain tissue were collected for assay of BPC. Based on the fact that, in tissues, BPC seems to remain extracellularly, brain concentrations of BPC were expressed as brain tissue fluid (BTF) levels, calculated as 10x the concentration in whole brain tissue. Neurotoxicity could be precipitated in all rabbits. In normal rabbits BTF levels of BPC were considerably higher than those in CSF indicating a better penetration across the blood-brain barrier (BBB). BPC penetrated better to CSF and BTF in meningitic rabbits than in normal controls, suggesting some degree of damage of the BBB concomitant with meningeal inflammation. E. coli meningitis did not increase the neurotoxicity of BPC. In control rabbits the intracisternal injection of saline resulted in some degree of pleocytosis. Unmanipulated animals are therefore preferable as controls. Epileptogenic EEG-changes was the most precise of the two variables used for demonstration of neurotoxicity. EEG-changes were therefore used as neurotoxicity criterion in the following rabbit experiments. To evaluate the effect of uraemia alone and uraemia plus meningitis on the neurotoxity of BPC in rabbits, cephaloridine was used to induce uraemia. Meningitis was induced by intracisternal inoculation of a cephalosporin resistant strain of E. cloacae. Untreated rabbits were used as controls. Uraemia resulted in increased BTF penetration of BPC, possibly explained by permeability changes in the BBB and/or decreased binding of BPC to albumin. Uraemia did not result in increased penetration of BPC into the CSF of non-meningitic rabbits. Uraemic non-meningitic rabbits had the highest BTF levels of BPC at the criterion, indicating that cephaloridine-induced renal failure increased the epileptogenic threshold in these rabbits. The combination of uraemia and meningitis increased the neurotoxicity of BPC since the criterion was reached at considerably lower BTF levels of BPC. Meningitis, either alone or together with uraemia, did not increase the neurotoxicity in comparison to control rabbits. Higher BTF levels of BPC were found in meningitic rabbits than in controls with intact blood-CNS barriers at onset of EEG-changes. In all groups of rabbits there was a pronounced variability of BPC l

Topics: Acute Kidney Injury; Animals; Anti-Bacterial Agents; Blood-Brain Barrier; Brain; Carbapenems; Cilastatin; Drug Interactions; Electroencephalography; Enterobacteriaceae Infections; Female; Hippocampus; Imipenem; Male; Meningitis; Penicillin G; Rabbits; Rats; Rats, Inbred Strains; Seizures; Thiopental; Tissue Distribution; Uremia

It has been reported that patients suffering from azotemia attributable to urinary obstruction required significantly less thiopental for induction and maintenance of general anesthesia than did a comparable group of patients with normal blood urea concentrations. Moreover, the thiopental requirements of normal subjects could be reduced by urea administration. In rats, experimental renal dysfunction was associated with reduced concentrations of phenobarbital (PB) in serum, serum water, brain and cerebro-spinal fluid at onset of a defined hypnotic effect (loss of righting reflex) produced by a slow i.v. infusion of PB. To determine the mechanism of this effect, these studies have now been repeated in normal rats made azotemic (approximately 170 mg of urea nitrogen/100 ml of serum) by intra-arterial infusion of urea and in control animals infused with saline solution. The total dose of thiopental required to produce loss of righting reflex was significantly reduced in the rats infused with urea. confirming the clinical observations. Similar results were obtained with PB and heptabarbital, two barbiturates that (unlike thiopental) are not racemic mixtures and are therefore more suitable for this investigation. On the other hand, urea infusion had no apparent effect on the concentrations of PB and heptabarbital in serum, brain and cerebrospinal fluid at onset of loss of righting reflex. Urea apparently affects the distribution kinetics of barbiturates and this, rather than increased receptor sensitivity, appears to be responsible for the decreased barbiturate dose requirements in acute experimental azotemia produced by urea infusion.

Topics: Animals; Barbiturates; Blood Urea Nitrogen; Brain; Female; Kinetics; Phenobarbital; Postural Balance; Rats; Rats, Inbred Lew; Reflex; Thiopental; Urea; Uremia

Topics: Adolescent; Anemia; Anesthesia, Intravenous; Dose-Response Relationship, Drug; Hemoglobins; Humans; Surgical Procedures, Operative; Thiopental; Urea; Uremia

Binding of thiopental to proteins in plasma from healthy, cirrhotic, and uremic subjects was studied using equilibrium dialysis. In plasma from healthy volunteers 28.0 plus or minus 0.9 per cent of thiopental was unbound. In plasma from patients with hepatic disease 53.0 plus or minus 2.1 per cent was unbound, while in patients with renal disease 55.7 plus or minus 1.5 per cent remained unbound. The decreased binding in uremia could not be explained completely by competitive displacement by nitrogenous end products or by hypoalbuminemia, although hypoalbuminemia may account for the decreased binding in cirrhotic patients.

Topics: Binding, Competitive; Blood Proteins; Blood Urea Nitrogen; Creatinine; Dialysis; Humans; In Vitro Techniques; Kidney Diseases; Liver Cirrhosis; Protein Binding; Renal Dialysis; Serum Albumin; Spectrophotometry; Thiopental; Uremia

In unilateral nephrectomized beagle dogs the remaining kidney was subjected to 2 hrs of ischemia in situ. The ischemic organ was cooled to 22--23 degrees C by initial hypothermic perfusion over a 5-F catheter introduced into the renal artery via the carotid artery. It was then left in the open abdominal wound without any further attempts of cooling. Three perfusates were used: an isoosmolar Dextran solution (Eisenberger), a hyperosmolar, "intracellular" electrolyte solution (Sacks), and a hyperosmolar, "extracellular" electrolyte solution. There was a mean postoperative increase in serum creatinine levels of 0.6 mg-%. By the 3rd p.o. day at latest the serum creatinine was again within normal limits. The inulin and PAH clearances on the 7th and 14th p.o. day showed no significant differences to preoperative determinations. No definite advantage or disadvantage was noted among the three perfusates. All control dogs whose kidneys were made ischemic for 2 hrs without perfusion died due to acute tubular necrosis. Apparently the homogenous cooling and flushing by the initial perfusion is of more importance for good preservation in this situation than the composition of the perfusate.

Topics: Aminohippuric Acids; Animals; Catheterization; Cold Temperature; Creatinine; Dextrans; Dogs; Female; Hypothermia, Induced; Inulin; Ischemia; Kidney; Kidney Function Tests; Mannitol; Nephrectomy; Organ Preservation; Osmolar Concentration; Perfusion; Postoperative Complications; Radiography; Renal Artery; Thiopental; Time Factors; Tissue Preservation; Uremia

Topics: Acidosis; Acute Kidney Injury; Anemia; Anesthesia; Anesthesia, Epidural; Anesthesia, Spinal; Antihypertensive Agents; Arrhythmias, Cardiac; Heart Failure; Hepatitis; Humans; Hyperkalemia; Hypertension; Hypocalcemia; Hyponatremia; Kidney Failure, Chronic; Nausea; Preanesthetic Medication; Seizures; Thiopental; Uremia; Vomiting