Allen I. Arieff

Studies on Mechanisms of Cerebral Edema in Diabetic Comas. EFFECTS OF HYPERGLYCEMIA AND RAPID LOWERING OF PLASMA GLUCOSE IN NORMAL RABBITS

To investigate the pathophysiology of cerebral edema occurring during treatment of diabetic coma, the effects of hyperglycemia and rapid lowering of plasma glucose were evaluated in normal rabbits. During 2 h of hyperglycemia (plasma glucose=61 mM), both brain (cerebral cortex) and muscle initially lost about 10% of water content. After 4 h of hyperglycemia, skeletal muscle water content remained low but that of brain was normal. Brain osmolality (Osm) (343 mosmol/kg H(2)O) was similar to that of cerebrospinal fluid (CSF) (340 mosmol/kg), but increases in the concentration of Na+, K+, Cl-, glucose, sorbitol, lactate, urea, myoinositol, and amino acids accounted for only about half of this increase. The unidentified solute was designated idiogenic osmoles. When plasma glucose was rapidly lowered to normal with insulin, there was gross brain edema, increases in brain content of water, Na+, K+, Cl- and idiogenic osmoles, and a significant osmotic gradient from brain (326 mosmol/kg H(2)O) to plasma (287 mosmol/kg). By similarly lowering plasma glucose with peritoneal dialysis, increases in brain Na+, K+, Cl-, and water were significantly less, idiogenic osmoles were not present, and brain and plasma Osm were not different. It is concluded that during sustained hyperglycemia, the cerebral cortex adapts to extracellular hyperosmolality primarily by accumulation of idiogenic osmoles rather than loss of water or gain in solute. When plasma glucose is rapidly lowered with insulin, an osmotic gradient develops from brain to plasma. Despite the brain to plasma osmotic gradient, there is no net movement of water into brain until plasma glucose has fallen to at least 14 mM, at which time cerebral edema occurs.

Changes in the electroencephalogram in acute uremia. Effects of parathyroid hormone and brain electrolytes.

Studies were carried out in order to evaluate the effects of changes in brain calcium and the influence of parathyroidectomy and administration of parathyroid extract on the electroencephalogram (EEG) of normal and uremic dogs. Manual analysis of frequency and power distribution of the EEG in uremic dogs revealed a significant increase in both the percentage distribution and the area or power occupied by frequencies below 5 Hz. In addition, high amplitude bursts of delta activity were apparent in the uremic dog. These changes were largely prevented by parathyroidectomy before the induction of uremia, but the administration of parathyroid extract to either normal dogs, or to previously parathyroidectomized uremic dogs, induced EEG changes similar to those noted in uremic animals with intact parathyroid glands. In all groups of animals which showed EEG changes, brain content of calcium was significantly higher than in either normal dogs or previously parathyroidectomized uremic dogs. Changes in arterial pH and bicarbonate, or in the concentrations of Na+, K+, urea, or creatinine in plasma or cerebrospinal fluid were similar in uremic animals with intact parthyroid glands and in previously parathyroidectomized uremia dogs. The results indicate that the EEG changes found in dogs with acute renal failure require the presence of excess parathyroid hormone in blood, and they may be related to the observed changes in brain content of calcium.

Central nervous system pH in uremia and the effects of hemodialysis.

Rapid hemodialysis of uremic animals may induce a syndrome characterized by increased cerebrospinal fluid (CSF) pressure, grand mal seizures, and electroencephalographic abnormalities. There is a fall in pH and bicarbonate concentration in CSF, and brain osmolality exceeds that of plasma, resulting in a net movement of water into the brain. This syndrome has been called experimental dialysis disequilibrium syndrome. The fall in pH of CSF may be secondary to a fall of intracellular pH (pHi) in brain. Since changes in pHi can alter intracellular osmolality in other tissues, it was decided to investigate brain pHi in uremia, and the effects of hemodialysis. Brain pHi was measured by evaluating the distribution of 14C-labeled dimethadione in brain relative to CSF, while extracellular space was calculated as the 35504=/4 space relative to CSF. In animals with acute renal failure, brain (cerebral cortex) pHi was 7.06+/-0.02 (+/-SE) while that in CSF was 7.31+/-0.02, both values not different from normal. After rapid hemodialysis (100 min) of uremic animals, plasma creatinine fell from 11.8 to 5.9 mg/dl. Brain pHi was 6.89+/-0.02 and CSF pH and 7.19+/-0.02, both values significantly lower than in uremic animals (P less than 0.01), and there was a 12% increase in brain water content. After slow hemodialysis (210 min), brain pHi (7.01+/-0.02) and pH in CSF (7.27+/-0.02) were both significantly greater than values observed after rapid hemodialysis (P less than 0.01), and brain water content was normal. None of the above maneuvers had any effect on pHi of skeletal muscle or subcortical white matter. The data show that rapid hemodialysis of uremic dogs is accompanied by a significant fall in pH of CSF and pHi in cerebral cortex. Accompanying the fall in brain pHi is cerebral edema.

Renal Bicarbonate Wasting during Phosphate Depletion A POSSIBLE CAUSE OF ALTERED ACID-BASE HOMEOSTASIS IN HYPERPARATHYROIDISM

With hyperparathyroidism, serum bicarbonate (HCO(3) (-)) is low, urinary excretion of HCO(3) (-) is increased and the apparent T(m) for HCO(3) (-) is reduced. These findings have been ascribed to a direct renal action of parathyroid hormone (PTH). Since hypophosphatemia and phosphate depletion may occur in hyperparathyroidism, it is possible that phosphate depletion could account for the abnormal renal HCO(3) (-) handling. To test this possibility, renal reabsorption of HCO(3) (-) was evaluated in dogs before and after phosphate depletion. Serum HCO(3) (-) was significantly lower in phosphate depleted dogs than in normal animals, and serum HCO(3) (-) was directly related to serum phosphorus. Both the threshold at which HCO(3) (-) appeared in the urine and the T(m) for HCO(3) (-) were reduced during phosphate depletion. Intracellular pH of muscle was significantly higher in phosphate depleted dogs than in normals and the pH returned to normal after phosphate repletion. These data show that phosphate depleted dogs, which probably have physiological hypoparathyroidism, display abnormalities in both serum HCO(3) (-) and its renal handling which are similar to those seen in hyperparathyroidism, supporting the concept that the PTH-induced alterations in HCO(3) (-) homeostasis may be due to phosphate depletion. The latter could alter cell metabolism, resulting in reduced intracellular H(+) concentration, which may then impair H(+) secretion by the renal tubules and decrease their ability to reabsorb HCO(3) (-). Consequently, T(m) HCO(3) (-) and serum HCO(3) (-) fall.

Mechanisms of Seizures and Coma in Hypoglycemia EVIDENCE FOR A DIRECT EFFECT OF INSULIN ON ELECTROLYTE TRANSPORT IN BRAIN

The mechanisms involved in the production of hypoglycemic coma were studied in rabbits. Measurements were made in brain, cerebrospinal fluid (CSF), and plasma of osmolality, Na(+), K(+), Cl(-), water content, exogenous insulin, glucose, lactate, and glutamate, while pH, Pco(2), Po(2), and bicarbonate were evaluated in arterial blood, 35 min after i.v. injection of insulin (50 U/kg), plasma glucose did not change, but brain K(+) content increased significantly. Grand mal seizures were observed in unanesthetized animals (+/-SD) 133+/-37 min after administration of insulin, at a time when brain glucose was normal, but brain tissue content of Na(+), K(+), osmoles, and water was significantly greater than normal. Coma supervened 212+/-54 min after insulin injection, at which time brain glucose, lactate, and glutamate were significantly decreased. At both 35 and 146 min after insulin administration, exogenous insulin was present in brain, but not in the CSF. After 208 min of insulin administration, animals were given i.v. glucose and sacrificed 35 min later. Most changes in the brain produced by hypoglycemia were reversed by the administration of glucose. Hypoxia (Po(2) = 23 mm Hg) was produced and maintained for 35 min in another group of animals. Hypoxia caused brain edema but did not affect brain electrolyte content. However, brain lactate concentration was significantly greater than normal. The data indicate that the seizures noted early in the course of insulin-induced hypoglycemia are temporally related to a rise in brain osmolality secondary to an increased net transport into brain of Na(+) and K(+), probably caused by insulin, per se. As hypoglycemia persists, there is also depletion of energy-supplying substrates (glucose, lactate, glutamate) in the brain, an event which coincides with the onset of coma. The brain edema observed during hypoxia is largely due to an increase in brain osmolality secondary to accumulation of lactate.

Effects of a Magnesium-Free Dialysate on Magnesium Metabolism During Continuous Ambulatory Peritoneal Dialysis

While the use of magnesium-containing compounds is usually contraindicated in dialysis patients, the risk of toxicity from hypermagnesemia can be reduced by lowering the magnesium concentration in dialysate. We examined the effects of a magnesium-free dialysate on both serum magnesium level and the peritoneal removal rate of magnesium over 12 weeks in 25 stable patients undergoing continuous ambulatory peritoneal dialysis (CAPD). After 2 weeks, the serum magnesium level decreased from 2.2 to 1.9 mg/dL (0.9 to 0.8 mmol/L) (P less than .02) and the peritoneal removal rate increased from 66 to 83 mg/d (2.8 to 3.5 mmol/d) (P less than .05), with both values remaining stable thereafter. There was a strong association between these parameters (r = -0.62, P less than .05), suggesting that the serum magnesium level decreased as a result of the initial increased peritoneal removal rate. For an additional 4-week period, a subgroup of nine patients received magnesium-containing, phosphate binding agents instead of those containing only aluminum. During this phase, serum inorganic phosphorus was well controlled. The serum magnesium level increased only from 1.8 to 2.5 mg/dL (0.7 to 1.0 mmol/L) (P less than .05), due in great part to the concomitant 41% rise in peritoneal magnesium removal from 91 to 128 mg/d (3.8 to 5.3 mmol/d) (P less than .05). No toxicity was noted during the entire 16-week study period, nor did serum calcium change. Thus, serum magnesium levels remained within an acceptable range as magnesium-containing phosphate binders were given through the use of magnesium-free peritoneal dialysate.(ABSTRACT TRUNCATED AT 250 WORDS)

Uremic and Dialysis Encephalopathies

Because of advancements in dialysis therapy and renal transplantation, and their medical management, patients with end-stage renal disease (ESRD) rarely develop severe clinical manifestations before the institution of therapy. In the USA, there are currently about 450,000 patients receiving dialysis therapy (Meyer & Hostetter, 2007). Although uncommon in the USA and Canada, patients who have chronic renal failure (GFR below 30 ml/min) and have not yet received dialysis therapy may develop a symptom complex characterized by fatigue, mild sensorial clouding, decreased mental acuity, tremor, anorexia, nausea and sleep disturbances (Gusbeth-Tatomir et al., 2007; Perl et al., 2006;). However, the institution of apparently adequate maintenance dialysis therapy does not eliminate central nervous system (CNS) manifestations of uremia. CSN disorders of both untreated renal failure and those persisting despite dialysis are referred to as uremic encephalopathy. The treatment of end stage renal disease with dialysis has itself been associated with the emergence of several distinct disorders of the central nervous system. These disorders are: dialysis disequilibrium syndrome, dialysis dementia, stroke, sexual dysfunction and a new syndrome of chronic dialysis-dependent encephalopathy (Arieff, 2004).