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 (δSNa+) of 20 mmol day−1 l−1. Above this limit neurological injuries gradually worsened, and beyond a transition zone (δSNa+ 20–23 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 δSNa+ 1 h after a bolus injection, 19 mmol/l) and in group III (mean δSNa+ 1 h after an injection, 2 mmol/l), both groups achieving similar daily δSNa+.

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. This can be deleterious even if a mildly hyponatraemic level (>120 <129 mmol/l) is achieved after 48 h. The maximum δSNa+ over 48 h tolerated by the brain can exceed 30 mmol/l (31−42 mmol/l), with a correction of serum Na+ concentration up to a normonatraemic level, provided that the successive daily δSNa+ was not greater than 20 mmol/l. The severity of the pre-existing hyponatraemia does not influence the outcome of the correction phase.

4. We have confirmed the protective effect of urea against the development of brain damage when used to correct hyponatraemia. The threshold of tolerance to daily δSNa+ after urea is identical to the limit defined for hypertonic saline, but a further rise in serum Na+ concentration (range of daily δSNa+ >23 >30 mmol/l) leads to a significantly lower incidence (47%, P <0.01 compared with group II and P <0.02 compared with group III) and severity (P <0.03 compared with group II and P <0.005 compared with group III) of neurological complications.

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