In a retrospective cohort study at a single tertiary emergency medical center in Japan, rapid correction of serum sodium was associated with rhabdomyolysis in patients with water intoxication after adjusting for potential confounding variables. Among the secondary outcomes, hospital stay was longer in the rapid serum sodium correction group, but there were no significant differences in complications or mortality between the two groups.
Our findings are consistent with two previous observational studies suggesting rapid serum sodium correction is associated with rhabdomyolysis [7, 8]. In addition, although rhabdomyolysis is a rare complication of hyponatremia according to previous case reports, rhabdomyolysis would be an under-recognized complication based on our results [5, 12]. Previous studies have suggested that the incidence of rhabdomyolysis in water intoxication patients is approximately 30 to 55% [7, 8].
Two hypotheses regarding the cause of rhabdomyolysis have been described thus far. First, hyponatremia and hyposmolarity may lead to depletion of potassium levels in the muscular system, which in turn may cause rhabdomyolysis . Second, rapid correction of serum sodium levels may lead to failure in regulation of muscular cell volume. As a result, membrane fragility and enzyme leakage may be induced, leading to rhabdomyolysis [7, 14, 15]. In the present study, serum sodium levels at admission did not differ significantly between the rapid and slow serum sodium correction groups. Our results thus support the second hypothesis. Furthermore, in the patients with rhabdomyolysis, the hospital stay was longer and the incidence of acute kidney injury was higher. This result is similar to that of previous studies [7, 8]. Therefore, preventing CK increase by controlling sodium correction rate may lead better outcome of water intoxication patients.
Our analyses showed that both 12- and 24-h serum sodium correction rates were independently associated with rhabdomyolysis. However, analysis of the 48-h serum sodium correction rate did not show any significant difference between the two groups. This may suggest that an early change in the serum sodium level plays a more important role in rhabdomyolysis than does a later change . Therefore, serum sodium level should be strictly controlled in the early phase of hyponatremia treatment. In addition, the ROC in the present study showed that the serum sodium correction rate should be maintained <0.80 mEq/L/h. In general, to prevent osmotic demyelination syndrome, the serum sodium correction should be within 10 to 12 mEq/L in the first 24 h . Therefore, based on the present results, the serum sodium correction rate should be <0.50 mEq/L/h despite no occurrence of osmotic demyelination syndrome. More than half of the subjects failed to achieve such recommendation in the present study. The serum sodium level tends to rise spontaneously in water intoxication unlike syndrome of inappropriate secretion of antidiuretic hormone. Therefore, strict serum electrolyte monitoring should be required, especially in the early treatment phase.
Several limitations of our study must be acknowledged. First, it is a single-center, retrospective observational study. Although this kind of study could not be performed as an interventional study, similar multicenter and prospective studies should be conducted in the future. Second, CK levels at admission were higher in the cases with rhabdomyolysis. Therefore, serum CK level at admission per se might influence the results of the present study. For example, the odds ratio is high for lying down for >8 h before admission, which could lead to non-traumatic crush injury. Therefore, rhabdomyolysis may have occurred before admission. However, the serum sodium correction rate is also an independent risk factor for rhabdomyolysis. Therefore, treatment after admission is also important to prevent rhabdomyolysis. Third, the type of treatment administered, such as fluid intake and sodium administration, was not considered, although almost all patients were treated by water restriction. Finally, it remains unclear whether rapid correction of hyponatremia with or without water intoxication is at a risk of rhabdomyolysis because only cases with hyponatremia due to water intoxication were included in the present study. Despite these limitations, our study has several advantages over previous exploratory studies, including a larger sample size and adjustment for important potential confounders [7, 8].