Brain adaptation to acute hyponatremia in young rats.

Brain swelling after acute hyponatremia in prepubescent rats, in contrast to adults, has recently been associated with an increase in brain sodium and a high mortality that could be prevented by preadministration of testosterone. To reexamine the effect of acute hyponatremia in young brain, we measured brain water and solute content in prepubescent rats after induction of hyponatremia over 4 h with water and arginine vasopressin. An 18% decrease in plasma sodium was associated with a 13% increase in brain water and a decrease in brain sodium and glutamate contents. No animals died. To assess the effect of sex hormones on brain adaptation, prepubescent rats were pretreated with estrogen or testosterone before acute hyponatremia. Brain sodium and potassium contents were significantly reduced in comparison to normonatremia in testosterone-pretreated but not estrogen-pretreated animals. However, there was no difference between estrogen-pretreated and testosterone-pretreated groups in mortality or in brain contents of water, electrolytes, or major organic osmolytes. In conclusion, we found that brain adaptation to acute hyponatremia in prepubescent rats is similar to that observed in adults.

Pathogenesis of cerebral edema after treatment of diabetic ketoacidosis.

We studied the roles of acidosis, plasma osmolality, and organic osmolytes in the pathogenesis of cerebral edema in an animal model of diabetes mellitus. Normonatremic rats with streptozotocin-induced non-ketotic (NKD) and ketotic (DKA) diabetes were sacrificed before or after treatment with hypotonic saline and insulin. Brains were analyzed for water, electrolyte, and organic osmolyte content. Brain water decreased by 2% in untreated DKA and NKD despite a 12% increase in plasma osmolality due to hyperglycemia. After treatment of both NKD and DKA, brain water increased equivalently by 8%. The cerebral edema that occurred after treatment was associated with decreased brain sodium content and no change in total major brain organic osmolytes in both NKD and DKA. However, brain content of the individual osmolytes glutamine and taurine increased after treatment of DKA. In a separate study, brain water and solute content of rats with DKA were compared after treatment with either hypotonic or isotonic fluid. Animals treated with isotonic fluid had significantly less cerebral edema and higher brain sodium content than those treated with hypotonic fluid. In our studies, brain swelling after treatment of DKA and NKD was primarily due to a rapid reduction of plasma glucose and osmolality, and was not caused by sodium movement into the brain. Acidosis did not appear to play a major role in the pathogenesis of cerebral edema after treatment of DKA.

Brain swelling after dialysis: old urea or new osmoles?

The pathogenesis of brain swelling and neurological deterioration after rapid hemodialysis (dialysis disequilibrium syndrome) is controversial. The "reverse urea hypothesis" suggests that hemodialysis removes urea more slowly from the brain than from the plasma, creating an osmotic gradient that results in cerebral edema. The "idiogenic osmole hypothesis" proposes that an osmotic gradient between brain and plasma develops during rapid dialysis because of newly formed brain osmoles. In this review, the experimental basis for the two hypotheses are critically examined. Based on what is known about the physiology of urea and water diffusion across the blood-brain barrier, and empiric observations of brain solute composition after experimental hemodialysis, we conclude that the "reverse urea hypothesis" remains a viable explanation for dialysis disequilibrium and that rapid reduction of a high urea level in and of itself predisposes to this condition.

Depletion of glutathione from brain cells in hyponatremia.

In response to hyponatremia, brain cells extrude electrolytes and organic osmolytes, thereby minimizing brain edema. We demonstrate that rat brain is depleted of the antioxidant glutathione in response to hyponatremia and that osmotically-induced loss of glutathione makes neuronal cells more susceptible to oxidative injury. Total glutathione content of brain tissue decreased from 6.80 +/- 0.14 mumol/g dry wt in normonatremic controls to 5.00 +/- 0.31 mumol/g dry wt after 72 hours of hyponatremia. Following slow correction of hyponatremia, brain glutathione content returned to control values (6.77 +/- 0.34 mumol/g dry wt). Brain content of taurine, a beta-amino acid with antioxidant properties, similarly decreased in hyponatremia (29.6 +/- 0.9 to 17.1 +/- 1.2 mumol/g dry wt), then increased with slow correction (24.8 +/- 1.3 mumol/g dry wt). Although taurine served as an osmolyte in rat heart, liver and brain, osmotically-induced changes in glutathione content were found only in brain. We also studied osmotically-induced changes in glutathione and taurine content in C6 glioma and SK-N-SH neuroblastoma cells. In both cell lines, adaptive decreases in glutathione and taurine content were found in response to lowering medium sodium concentration from 140 mM to 100 mM. The cell content of these solutes increased after returning to media containing 140 mM sodium. Following exposure of both cell lines to hypoosmolar media, there was no increase in media content of glutathione. This suggest that osmotic depletion of glutathione is not due to cellular efflux of intact glutathione. We questioned if osmotic depletion of glutathione and taurine renders brain cells more susceptible to oxidative stress. Incubation of SK-N-SH cells with 1.0 mM H2O2 for four hours induced greater cytolytic injury in cells adapted to hypoosmolar media than in isoosmolar controls. Hypoosmolar C6 glioma cells were not significantly more sensitive to cytolytic injury from H2O2 than were cells grown in isosmolar media. We conclude that hypoosmolality induces glutathione depletion in rat brain in vivo and in cultured brain cells in vitro. Osmotic depletion of this antioxidant renders SK-N-SH neuronal cells more susceptible to oxidative injury.

Glycine-induced hyponatremia in the rat: a model of post-prostatectomy syndrome.

Post-prostatectomy syndrome (PPS) is characterized by hyponatremia after absorption of glycine irrigant. To study the pathogenesis of this syndrome, adult male rats with ligated ureters were infused over 15 minutes with 7.5 ml/100 g body weight of isosmotic glycine (N = 9) or mannitol (N = 9) and were compared to non-infused, ureter-ligated controls (N = 9). Immediately post-infusion, plasma sodium had decreased similarly in glycine- and mannitol-infused animals (111 +/- 2 vs. 106 +/- 1 mmol/liter), but plasma osmolality remained at control levels in both groups (285 +/- 1 vs. 288 +/- 1 mOsm/kg). Two hours post-infusion, hyponatremia was stable in the mannitol group (108 +/- 1 mmol/liter), but in the glycine group plasma sodium increased significantly (to 120 +/- 1 mmol/liter). Plasma osmolality two hours post-infusion was maintained in both the glycine (287 +/- 2) and mannitol (292 +/- 2) groups. Brain water in glycine-infused animals (3.90 +/- 0.01 liter/kg dry wt) was not significantly different from the mannitol-infused group (3.85 +/- 0.01) and only 1.8% higher than non-infused controls (3.83 +/- 0.02). Brain tissue glycine did not differ between the three groups. In contrast, muscle water two hours post-infusion in the glycine group was 6% higher than mannitol-infused and 13% higher than non-infused animals. Muscle glycine content in the glycine group (67 +/- 4 mM/kg dry tissue) was increased when compared to both mannitol-infused (25 +/- 1) and non-infused (20 +/- 1) groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Extrarenal potassium adaptation: review of a concept.

Animals chronically fed a high-potassium diet may survive an acute potassium load which is lethal to animals fed a control diet. This 'potassium tolerance' is clearly related to an enhanced ability of the kidneys to excrete potassium. However, in their now classic studies, Alexander and Levinsky suggested that a nonrenal mechanism also contributes to this phenomenon. They showed that despite nephrectomy just prior to acute potassium loading, animals accustomed to a high-potassium diet had a smaller increment in plasma potassium than did controls. As a result of this work, it is now widely believed that chronic exposure to large amounts of potassium somehow directly enhances cellular potassium uptake, a process referred to as extrarenal potassium adaptation. However, it is important to note that in these studies, the animals were fasted prior to nephrectomy. We have shown that when potassium is withdrawn from potassium-adapted animals, high rates of potassium excretion persist and eventually result in the development of paradoxical potassium depletion. We believe that it is this potassium depletion which accounts for the enhancement of cellular potassium uptake sometimes seen in potassium-adapted animals. Indeed, extrarenal potassium adaptation can only be demonstrated after a prolonged period of dietary potassium withdrawal has provided the opportunity for potassium depletion to occur. Furthermore, there is actually little evidence that chronic potassium feeding directly enhances the cellular uptake of an acute potassium load. We conclude that extrarenal potassium adaption is a time-honored concept which, for practical purposes, does not exist.

Neurologic sequelae after treatment of severe hyponatremia: a multicenter perspective.

Severe, symptomatic hyponatremia is often treated urgently to increase the serum sodium to 120 to 130 mmol/L. Recently, this approach has been challenged by evidence linking "rapid correction" (> 12 mmol/L per day) to demyelinating brain lesions. However, the relative risks of persistent, severe hyponatremia and iatrogenic injury have not been well quantified. Data were sought on patients with serum sodium levels < or = 105 mmol/L from the membership of the American Society of Nephrology. Respondents were given a report form asking specific questions regarding the cause of hyponatremia, presenting symptoms, rate of correction, and neurologic sequelae. Data on 56 patients were analyzed. Fourteen developed posttherapeutic complications (10 permanent, 4 transient) after correction to a serum sodium > 120 mmol/L. Eleven of these 14 patients (including 3 with documented central pontine myelinolysis) had a biphasic course in which neurologic findings initially improved and then worsened on the second to sixth day. Posttherapeutic complications were not explained by age, sex, alcoholism, presenting symptoms, or hypoxic episodes. Increased chronicity of hyponatremia and a high rate of correction in the first 48 h of treatment were significantly associated with complications. No neurologic complications were observed among patients corrected by < 12 mmol/L per 24 h or by < 18 mmol/L per 48 h or in whom the average rate of correction to a serum sodium of 120 mmol/L was < or = 0.55 mmol/L per hour. It was concluded that patients with severe chronic hyponatremia are most likely to avoid neurologic complications when their electrolyte disturbance is corrected slowly.

Organic osmolytes in acute hyponatremia.

The defense of brain volume during hyponatremia cannot be explained by the losses of brain sodium and potassium. We have examined the brain losses of organic osmolytes in rats after 24 h of severe hyponatremia induced by the administration of vasopressin and 5% dextrose in water. Normonatremic controls and animals with intermediate plasma sodium concentration ([Na]) were produced in vasopressin-treated animals by the administration of isocaloric gavages containing varying amounts of NaCl and free water. The animals were killed at 24 h by decapitation, and one brain hemisphere was quickly frozen in liquid nitrogen for organic osmolyte determinations. When compared with controls (plasma [Na] = 139 +/- 1.5 mM), hyponatremic animals (plasma [Na] = 96 +/- 1 mM) had significantly reduced brain contents for sodium, potassium, chloride, glutamate, myo-inositol, N-acetylaspartate, aspartate, creatine, taurine, gamma-aminobutyric acid, and phosphoethanolamine. Plasma [Na] was highly correlated (P < 0.001) with the brain contents for sodium, potassium, and organic osmolytes. Whereas the observed increase in brain water during hyponatremia was only 4.8%, by calculation, brain swelling without brain organic osmolyte losses would have been 11%, an amount that jeopardizes survival.

Dialysis disequilibrium syndrome (DDS) in the rat: role of the "reverse urea effect".

DDS is characterized by neurologic deterioration and cerebral edema which occurs after hemodialysis. To investigate the pathogenesis of DDDS, we studied the effects of rapid hemodialysis on plasma and brain electrolytes, urea, and osmolality in the rat. Forty-two hours after bilateral nephrectomy, nine uremic rats were hemodialyzed for 90 minutes against dialysate without urea (model of DDS), yielding a decrease in plasma urea from 72 +/- 2 mM to 34 +/- 2 mM (P less than 0.01) and an 8% (29 mOsm/kg) decrease in plasma osmolality. This group was compared to three control groups: 11 uremic animals dialyzed against a bath with urea added so that no fall in plasma urea occurred, and 15 uremic and 12 nonuremic animals that were not dialyzed. In animals dialyzed without urea, compared to uremic non-dialyzed animals, there was a 6% increase in brain water (3.89 +/- 0.04 liter/kg dry wt vs. 3.67 +/- 0.03, P less than 0.01) and an increase in the brain to plasma (urea) ratio (1.30 +/- 0.06 vs. 0.79 +/- 0.05, P less than 0.01). Comparison of these parameters in animals dialyzed without urea versus other control groups yielded similar results. In animals dialyzed without urea, the 53% decrease in plasma urea was associated with only a 13% decrease in brain urea content. Brain content of sodium and potassium was not significantly different among groups. Retention of brain urea despite the large decrease in plasma urea was able to account for the increased brain water observed in animals dialyzed without urea.(ABSTRACT TRUNCATED AT 250 WORDS)

The management of hyponatremic emergencies.

Given time, the brain can tolerate extraordinarily severe hyponatremia, but it does not take well to sudden changes; both rapid onset and rapid correction of hyponatremia can be injurious. Emergency treatment of hyponatremia should be reserved for the patient who has not had time to fully adapt to the disturbance. When the clinical situation demands it, treatment can be safely initiated by infusing 3% saline at 1 to 2 mL/kg/hour for 2 to 3 hours. Once the emergency has passed, more conservative measures can be substituted so that the overall rate of correction does not exceed 12 mEq/L/day. Limiting therapy in this manner avoids the osmotic demyelination syndrome, a complication of overly rapid correction of hyponatremia.