Azotemia (48 h) decreases the risk of brain damage in rats after correction of chronic hyponatremia.

Brain myelinolysis complicates excessive correction of chronic hyponatremia in man. Myelinolysis appear in rats for correction levels deltaSNa) > 20 mEq/l/24 h. We previously showed in rats that when chronic hyponatremia was corrected with urea, the incidence and the severity of brain lesions were significantly reduced compared to hypertonic saline. In man, hyponatremia is frequently associated with azotemia and hemo-dialysis usually corrects rapidly the serum sodium (SNa) but only few patients apparently develop demyelination. We hypothesize that uremic state protects brain against myelinolysis. This hypothesis was evaluated in rats developing azotemia by administration of mercuric chloride (HgCl2, 1.5 mg/kg). Severe (SNa < 120 mEq/l) hyponatremia (3 days) was induced by S.C. AVP and i.p. 2.5% D-glucose for 3 days. HgCl2 was injected on day 2. Hyponatremia was corrected on day 4 by i.p. injections of 5% NaCl in order to obtain a correction level largely above the toxic threshold for brain (deltaSNA approximately 30 mEq/l/24 h). Surviving rats were decapitated on day 10 for brain analysis. In the group with renal failure (Group I, n = 15, urea 59 mmol/l) the outcome was remarkably favourable with only three rats (3/15) dying before day 10 and only one of them (1/3) presenting myelinolysis-related neurologic symptoms. The 12 other rats (80%) survived in Group I without symptoms and brain analysis was normal in all of them despite large correction level (deltaSNa: 32 mEq/l/24 h). On the contrary in nine rats in which HgCl, did not produce significant azotemia (control 1, n = 9, urea: 11 mmol/l), all the rats developed severe neurologic symptoms and eight of them died before day 10. Similar catastrophic outcome was observed in the non-azotemic controls (control 2, no HgCl2 administration, n = 15, urea: 5 mmol/l). All of them developed myelinolysis-related neurologic symptoms and only four of them survived with severe brain lesions (survival 12/15 in Group I vs. 5/24 in pooled controls 1 and 2, p < 0.001). In conclusion, we showed for the first time that chronic hyponatremic rats with azotemia (48 h) tolerated large increases in SNa (approximately 30 mEq/l/24 h) without significant brain damage.

Lack of major hypoxia and significant brain damage in rats despite dramatic hyponatremic encephalopathy.

Brain myelinolysis could complicate the excessive correction of chronic hyponatremia. Recently it was suggested that hypoxia rather than correction of hyponatremia would be responsible for myelinolysis. We analyzed the incidence and the severity of potentially associated hypoxia and its consequences on survival and on the development of brain damage in rats in which major hyponatremic encephalopathy had developed after either pure acute hyponatremia (serum sodium concentration: -40 mEq/L/3 hr, group I, n = 8) or acute hyponatremia (serum sodium concentration: -30 mEq/L/3 hr, group II, n = 12) superimposed on chronic hyponatremia of 3 days' duration (serum sodium concentration: 113 mEq/L). Our study revealed the following: (1) Despite dramatic hyponatremic encephalopathy (convulsions, coma), hypoxia (PO2 < 70 mm Hg) was present, but the PO2 was not decreased below 40 mm Hg. All of these rats died rapidly if they remained hyponatremic. (2) In the animals rescued by NaCl, the incidence of brain myelinolysis was low (10%), whatever the duration (pure acute or chronic plus acute) of the hyponatremia and despite the combination of hypoxia with major hyponatremic encephalopathy. (3) When acute hyponatremia is superimposed on a chronic preexisting hyponatremic state, the acute component of serum sodium concentration decrease could be rapidly corrected (serum sodium concentration: +35 mEq/L/21 hr) without fear of permanent brain damage. Our results suggest that even in the presence of dramatic hyponatremic encephalopathy and associated hypoxia, neuropathologic sequelae are uncommon. Brain lesions related to post-anoxic encephalopathy probably develop only after respiratory arrest occurs.

Reinduction of hyponatremia improves survival in rats with myelinolysis-related neurologic symptoms.

Brain myelinolysis occurs after excessive correction (delta SNa > 20 mEq/1/24 hours) of chronic hyponatremia. However, we showed recently that the mechanisms leading to brain myelinolysis remain reversible. Indeed, reinduction of the hyponatremia by water administration despite 12 hours of sustained excessive correction could prevent the development of demyelination in rats still asymptomatic at that time. Whether this therapeutic maneuver could be also beneficial to rats with preexisting myelinolysis-related neurologic symptoms is unknown. Therefore we evaluated here the effect of reinduction of the hyponatremia on the survival and on brain damage in rats presenting obvious neurologic symptoms after excessive correction of hyponatremia. After 3 days of severe hyponatremia induced by 2.5 D-glucose in water and continuous infusion of AVP, rats were submitted to a large correction (delta SNa approximately 30 mEq/l) by 2 i.p. injections of hypertonic saline given over 24 hours. In group I (n = 15) the rats developing neurologic symptoms during the first 24 hours of correction received one i.p. injection of distilled water which rapidly decreased the natremia to a final correction gradient <20 mEq/l/24 hour. In group II (n = 13, controls) the symptomatic rats were left permanently overcorrected. In group I, after water administration, the neurological manifestations were generally attenuated or disappeared. Seven of the 15 rats (47%) in this group survived up to day 10 with a mean survival time of 7.5 +/- 2 days, an outcome clearly improved as compared to group II (controls): only 1 of the 13 rats (7%, p < 0.03) was still alive on day 10 and the mean survival time was 3.3 +/- 2 days (p < 0.001) in this group II. The duration of the symptoms also influences the prognosis. In group I, in 9 rats the water administration was performed 4 hours after symptoms onset. These rats had a better outcome than the 6 rats with more sustained (8-10 hours) neurologic symptoms before water loading. Brain analysis in the 7 surviving rats of group I demonstrated demyelinating lesions in only 2 of them, suggesting the reversibility of the process even when neurologic manifestation developed. In conclusion, after exposure to an excessive correction of chronic hyponatremia, even when rats have developed myelinolysis-related neurologic symptoms, hypotonic fluids administration could improve survival and could prevent the subsequent development of brain myelinolysis.

Brain myelinolysis following hypernatremia in rats.

Brain myelinolysis could develop after excessive correction (delta SNa > 20-25 mEq/1/24 hour [h]) of chronic hyponatremia; however, this neurological event is not recognized as a complication of hypernatremia when arising from a normonatremic baseline. Previous animal studies were unable to reproduce these brain lesions in hypernatremia after acute increase of serum sodium to moderately hypernatremic levels. We hypothesize that to produce brain dehydration and myelinolysis from normonatremic baseline requires a more important osmotic gradient than when starting from hyponatremic state. Rapid and sustained hypernatremia (at least > 6 to 12 h) was induced in male rats by i.p. administration of NaCl 2 M (3 injections at 6 h intervals). The NaCl doses were determined to define two groups of hypernatremic rats (moderate and severe hypernatremia) for further analysis of the neurological outcome. In group 1 (moderate hypernatremia, n = 26) 8 rats died early (< 12 h) after the beginning of the NaCl administration without specific neurologic manifestations. All the surviving rats fared well and were asymptomatic at time of death (day 8). They were submitted for at least 6 to 12 h to a serum sodium gradient of 28 +/- 6 mEq/l. Brain analysis was normal in all of them without brain demyelinating lesions. In group 2 (n = 51), 24 rats also died rapidly (< 12 h). The surviving rats developed severe neurologic symptoms as typically encountered in hyponatremic rats with myelinolysis. The majority of them died before day 8. The hypernatremic gradient in this group was significantly higher than rats in group 1 that completely recovered (mean delta SNa: 39 +/- 8 mEq/l, p < 0.001). In the 7 surviving rats (mean delta SNa: 33 +/- 3 mEq/l) brain analysis demonstrated severe demyelinating lesions similar to the histologic changes observed in hyponatremia-related myelinolysis. We demonstrated for the first time that high and sustained levels of hypernatremia could induce brain myelinolysis and that the osmotic gradient necessary to produce brain lesions is higher for normonatremic than for hyponatremic rats.

Prevention of brain demyelination in rats after excessive correction of chronic hyponatremia by serum sodium lowering.

Brain myelinolysis occurs after correction of chronic hyponatremia in rats when the magnitude of increase in serum sodium (delta SNa) exceeds 20 to 25 mEq/liter/24 hr (the critical threshold for brain). We tested the hypothesis that after a sustained excessive correction, brain lesions (BL) could be prevented by subsequently decreasing the serum sodium below the critical threshold for brain through the administration of hypotonic fluids. After three days of severe (< 115 mEq/liter) chronic (3 days) hyponatremia, 55 rats were submitted to an excessive correction (delta SNa > 25 mEq/liter) by a single i.p. infusion of hypertonic saline (NaCl). This osmotic stress was maintained during 12 hours before the serum sodium decrease was initiated. Thirty-two rats reached the twelfth post-correction hour without symptoms. In group 1 after a large (delta SNa 32 mEq/liter) and sustained (12 hr) osmotic stress, the natremia was rapidly (2 hr) decreased by the administration of oral tap water and, at the end of the first 24 hours, the magnitude of correction was maintained below 20 mEq/liter/24 hr. All the rats fared well in this group and were free of neurologic symptoms. Mild BL were noticed in only 20% of them. On the contrary, in controls (no hypotonic fluids administration at the twelfth hour) whose serum sodium was left overcorrected, all the rats became symptomatic and 57% of them died rapidly. Brain damage developed in 100% of the surviving rats. In group 2, despite hypotonic fluids administration, the serum sodium decreased insufficiently and the correction was > 20 mEq/liter at the end of the first 24 hours (delta SNa 25 mEq/liter).(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of chronic hyponatremia in rats by intravenous saline: comparison of rate versus magnitude of correction.

The role of the rate of correction in the development of demyelinating brain lesions after correction of chronic severe hyponatremia is controversial. It has been recently suggested in rats treated by intravenous (i.v.) hypertonic saline (NaCl) that both the rate and the absolute change in serum sodium represent critical risk factors. However, we previously demonstrated in rats treated by intraperitoneal (i.p.) injections of NaCl that below a threshold of serum sodium rise of 20 mEq/liter/24 hr, only 5% of the brain lesions were recorded, even in rats submitted to a rapid (1 hr) serum sodium increment following the i.p. injection. Working below this threshold (serum sodium rise less than 20 mEq/liter/24 hr) in the present work, allowed us to independently determine the role of the rate in the outcome of the correction. This was done by submitting the rats to a rapid (1 hr) intravenous infusion of NaCl. As a difference between the i.p. and i.v. route in the degree of volume expansion produced by the NaCl administration could also play a role in the pathogenesis of the brain lesions, rats treated with rapid i.v. infusion of NaCl (associated with volume expansion) were compared to a group of rats treated with water restriction (associated to volume contraction) to evaluate the role of volemia on the incidence of neurological damage. Hyponatremia was induced over three days with d-glucose in water and vasopressin. The group 1 was corrected by intravenous (i.v.) infusion of hypertonic saline over one hour.(ABSTRACT TRUNCATED AT 250 WORDS)

Limits of brain tolerance to daily increments in serum sodium in chronically hyponatraemic rats treated with hypertonic saline or urea: advantages of urea.

1. At present there is no consensus about the optimal management of hyponatraemia to prevent demyelinating brain lesions. We have evaluated in a large series of rats (n = 136) the protective role of urea for the brain in the treatment of severe chronic hyponatraemia. Urea (group I, n = 51) was compared with hypertonic saline in boluses (group II, n = 46) and with hypertonic saline in divided doses (group III, n = 39). Treatment was administered intraperitoneally over 48 h. The severity of brain lesions was assessed by histological scoring. 2. For 95% of the injured animals treated with hypertonic saline, brain lesions appeared for an absolute increment in serum Na+ concentration (delta SNa+) of 20 mmol day-1 l-1. Above this limit neurological injuries gradually worsened, and beyond a transition zone (delta SNa+ greater than or equal to 20 less than or equal to 23 mmol day-1 l-1) 89% (group III) to 100% (group II) of the animals were injured. This limit can be reached rapidly, as attested by the comparable severity of brain lesions observed in group II (mean delta SNa+ 1 h after a bolus injection, 19 mmol/l) and in group III (mean delta SNa+ 1 h after an injection, 2 mmol/l), both groups achieving similar daily delta SNa+. 3. A correction above the threshold of 20 mmol day-1 l-1 is as toxic during the first 24 h as during the second day of the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

[Alternate red nucleus syndrome (Claude variant). Apropos of a case report]. / Syndrome alterne du noyau rouge (variante de Claude). A propos d'une observation.

The authors describe a case of Claude's syndrome corresponding to a third cranial nerve palsy with contralateral cerebellar ataxia, due to a red nucleus softening. They review the different varieties of red nucleus syndromes and their usual causes.