Our study showed a U-shaped relationship between overall serum sodium level and mortality and the lowest tertile of serum sodium was significantly associated with increased all-cause mortality even after adjusting for covariates. To the best of our knowledge, our results are the first to demonstrate an independent association between serum sodium level and all-cause mortality in insomnia patients.
The association between lower serum sodium level and insomnia has not been studied previously. We hypothesized that insomnia may be associated with a lower serum sodium level for the following reasons: first, the comorbidities of patients with insomnia may themselves be associated with lower serum sodium levels. In our study, 61.4% (n = 258) of patients had comorbidities, the most common of which was HT, followed by cardiovascular disease (CVD), Chronic respiratory disease (CRD), and DM. These comorbidities are known to be associated with decreased serum sodium levels and commonly cause hyponatremia. In other words, lower serum sodium levels may not be due to insomnia itself, but rather to comorbidities. Second, activated sympathetic nerve activity due to insomnia [20, 21], leading to increased renin release [22, 23] and tubular fluid reabsorption , may be associated with low serum sodium.
Previous studies indicated that hyponatremia is an independent predictor of increased mortality in the general population , as well as in patients with a variety of diseases such as acute ST-elevation myocardial infarction , heart failure , and liver disease . It has not yet been determined whether hyponatremia is simply an indicator of disease severity, or itself affects the disease. Chawla et al. suggested that serum sodium is seldom the cause of death but rather a marker of the severity of underlying disease . Another study suggested that hyponatremia is an independent predictor of mortality even after adjusting for age, gender, and several comorbidities in the general outpatient population .
In our study of patients with insomnia, the lowest serum sodium tertile had the highest risk of all-cause mortality. The exact mechanism underlying increased mortality in these patients remains unclear. However, it is possible that activation of the autonomic nervous system in insomnia patients could be associated with both lower serum sodium levels and increased mortality risk. Hyperarousal is also considered a key pathophysiological mechanism in insomnia , increasing the whole-body metabolic rate during sleep, high-frequency electroencephalographic activity during non-rapid eye movement sleep, and cortisol and adrenocorticotropic hormone levels during the early sleep period, and decreasing parasympathetic tone and heart rate variability [30, 31]. These hyperarousal states may be associated with increased cardiovascular activity, and insomnia is known to be associated with both CVD risk and mortality . In our study, we could only identify HR as a factor related to the sympathetic nerve activity, but there was no significant association between HR and serum sodium, mortality. Due to our study enrolled hospitalized patients, it is difficult to identify sympathetic nerve activity with HR alone.
Another hypothesis is that hyponatremia may be associated with various medical conditions including bone fractures, falls [9, 10], cardiovascular events , and cognitive dysfunction [3, 34], eventually leading to a high mortality rate . Our study showed that the lowest tertile of serum sodium had a higher proportion of comorbidities, although not statistically significantly. Also, certain demographic, hematologic, and biochemical parameters, such as older age and lower serum hemoglobin, calcium, phosphorus, protein, albumin, and uric acid levels, were commonly seen in our insomnia patients in the lowest tertile of serum sodium. These variables also had a direct or indirect impact on mortality.
Interestingly, all-cause mortality was significantly associated with CRD in insomnia patients. Previous studies showed that poor sleep quality was common among patients with chronic obstructive pulmonary disease (COPD) [35, 36] and disturbed sleep was associated with mortality and adverse COPD outcomes . Severe hypoxemia was observed during sleep in COPD patients, which not only causes insomnia, but also might be associated with poor clinical outcomes. Consistent with previous studies, our study shows that inpatients with insomnia are associated with high mortality in the presence of CRD as an underlying disease. And in light of this, when complaining of insomnia in patients with CRD, the exacerbation of respiratory disease should be considered and factors to be corrected should be sought.
Previous studies have shown that hyponatremia is associated with the development of AKI in hospitalized patients . Other reports have suggested that hyponatremia is a significant prognostic factor for renal replacement therapy in CKD patients treated with diuretics, eventually leading to AKI . Furthermore, one report showed that serum sodium itself would not have a significant effect on kidney function . However, no study has explored the relationship between AKI incidence and lower serum levels in insomnia patients. We hypothesized that lower serum is associated with AKI in insomnia patients. However, we could not demonstrate a significant relationship between these two factors. Instead, we showed that certain factors, including albumin, estimated glomerular filtration rate and CCI score were associated with AKI in insomnia patients. The lack of a relationship between low serum sodium and AKI may be related to the cause of the AKI, such as volume depletion, toxic agents, ischemic conditions, or obstruction, as well as the severity of the AKI.
One of curious characteristics of our study is the increased hazard ratio of mortality in low tertile sodium group even in normal ranges. Previous studies also demonstrated that low sodium group even in normal ranges was associated poor clinical outcomes such as hepatic encephalopathy and mortality and cognition [42, 43]. These phenomenon might be explained by the presence of absolute normal sodium range that are safe or low, but normal serum sodium which is an indicator of an underlying causal condition with implications for mortality. It could not be concluded in this study whether interventional trial to increase sodium level in these patients is effective or not. There have been so many risk factors to determine serum sodium level. We think that finding and regulating these risk factors should precede interventional trial. Likewise, controlling and regulating insomnia might have to precede natraemia intervention.
There were several limitations to our study. First, since it used a single-center retrospective design and relied on data from medical records, we could not tightly control certain factors that may affect the serum sodium level such as volume status, drugs (excluding thiazide), and hormone levels, and our results may thus not be generalizable. Second, we obtained serum sodium levels at baseline only; we could not obtain them at follow-up. Therefore, we could not monitor changes in the serum sodium level. Third, we enrolled insomnia patients based only on the ICD code and did not use other tools such as polysomnography or sleep habit questionnaires. However, we believe that these limitations were ameliorated by the large number of patients enrolled and the use of robust statistical methods. Relatively similar laboratory tests were applied and patients were followed-up at the same facility, since this was a single-center study.