The results showed that terlipressin administration for variceal hemorrhage and hepatorenal syndrome frequently lowered blood sodium concentrations. The decreases ranged from 134.0 ± 6.5 mmol/L to 130.4 ± 6.2 mmol/L, and 35.4% (45/127) of the patients showed a decrease in blood sodium concentration by > 5 mmol/L. In general, serum sodium concentration decreased to the minimum level between days 3 and 4 after terlipressin administration was initiated. Although some factors, including age, sex, initial sodium level, and severity of liver damage were significantly different between the “decreased” and “non-decreased” groups, the multivariate analysis indicated that only higher baseline serum sodium concentration was significant for a decreased sodium level. Similarly, in the group in which serum sodium concentration decreased by > 10 mmol/L, the baseline serum sodium concentration was the only factor that was associated with serum sodium concentration.
In a study on the effects of terlipressin to treat blood sodium concentration of patients with variceal hemorrhage, (Sola et al. 2010) reported that MELD score and baseline blood sodium concentration were important factors. However, that study had limitations in that it focused only on patients with variceal hemorrhage and included no more than 58 subjects, which may have been insufficient for a multivariate analysis. Another limitation was that despite the small number of subjects, they were divided into three groups. If more subjects had been involved, the MELD score might not have been an influential factor. Our data may be more meaningful because we included 127 patients, approximately twice the number of the subjects in the study of Sola and co-workers, and patients with hepatorenal syndrome were included.
(Sola et al. 2010) found that terlipressin decreased blood sodium concentration by > 5 mmol/L in 67% of the patients and by > 10 mmol/L in 31%. This is more than the 35.4% occurrence rate in the present study. They divided subjects into three groups and found no difference in the cumulative dose of terlipressin among the groups; however, the average cumulative dose was 28 mg, which was almost twice that (15 mg) used in this study. Such a difference in the cumulative terlipressin dose may explain the number of patients with a difference of > 5 mmol/L in serum sodium concentration.
Another study, which reported that terlipressin lowers blood sodium concentration, found that the duration of terlipressin treatment is closely associated with the decrease in serum sodium concentration (Bruha et al. 2009; Krag et al. 2010). Therefore, these studies support the notion that even short-term use of terlipressin, as recently suggested, is effective for controlling variceal hemorrhage and preventing decreases in blood sodium concentrations (Lo et al. 2009). However, according to (Sola et al. 2010), the blood sodium concentration had decreased by > 5 mmol/L in 50% of the patients and by > 10 mmol/L in 16% 48 h after terlipressin administration was initiated (Krag et al. 2011), which coincides with our finding that blood sodium concentration decreased by > 5 mmol/L in 57.8% of the patients 3 days after initiation of terlipressin treatment. This result suggests that even short-term use of terlipressin can reduce blood sodium concentration. Therefore, electrolyte tests should be carried out in patients receiving terlipressin.
Our data suggest that some liver function indices, such as the MELD and Child–Pugh scores, were negatively correlated with blood sodium concentrations. This result is consistent with the observation that hyponatremia frequently accompanies deteriorated liver function. Another study showed that both lower MELD score (OR, 0.9; 95% CI, 0.8–1.0, P < 0.05) and higher baseline blood sodium concentration (OR, 1.10; 95% CI, 1–1.2, P < 0.05), which were significant factors in a multivariate analysis, led to a greater decrease in blood sodium concentration after terlipressin administration (Sola et al. 2010), whereas our study showed that initial sodium concentration was the sole factor. However, we believe that the MELD score had only weak statistical power in that study, because the 95% CI included “1.0”. In the present study, although the severity of liver function damage showed associations in the simple comparison, these might not have been evident in the multivariate analysis because initial sodium level was so strong factor that other ones might seem to have not influence on the change of sodium level.
The pathological mechanism of hepatorenal syndrome involves splanchinic arterial dilation, which decreases the effective arterial blood volume and, secondarily, causes renovascular contraction, which is characterized by decreased urination and dilutional hepatorenal syndrome (Ackermann 2009; Bosma et al. 2010; Testro & Angus 2009; Oliver & Verna 2009). Few studies have been conducted on terlipressin-induced changes in blood sodium concentration; the frequency of hyponatremia after the use of terlipressin for hepatorenal syndrome was 10% (Nazar et al. 2010), which was considerably lower than that of variceal hemorrhage. Although the number of patients was small, the baseline blood sodium concentration in patients with hepatorenal syndrome was 128 mmol/L, which was considerably lower than the 135 mmol/L in patients with variceal hemorrhage who received the same treatment. The V2 vasopressin receptor may be already saturated in patients with hepatorenal syndrome due to full activation by endogenous hormones. Therefore, terlipressin administration may limit the effects of these hormones, resulting in smaller changes in serum sodium concentration. In the present study, there was significant difference between bleeding group and HRS group in terms of the decrease in serum sodium concentration (41% vs 14%), although use of purpose was not a significant predictor in the multivariate analysis.
Studies of the side-effects of terlipressin and its efficacy in combination with somatostatin against variceal hemorrhage reported that terlipressin induces hyponatremia only rarely (Escorsell et al. 2000; Feu et al. 1996; Walker et al. 1997). In these studies, no effect of terlipressin on blood sodium concentration was detected, because hyponatremia was defined as < 130 mmol/L sodium and the baseline sodium concentration was not mentioned. In the present study, the baseline sodium concentration and changes in blood sodium concentration during the follow-up period were evaluated, and a difference of > 5 mmol/L was used as the criterion for hyponatremia. Therefore, our study is a more reasonable evaluation of the effect of terlipressin on changes in blood sodium concentrations.
The limitations of this study are its retrospective cohort design, it was not controlled, and factors that could affect blood sodium concentration were not controlled for. Fluid administration may have an effect on the results. The effects of fluid volume and type on blood sodium concentration cannot be ignored. Because the amount of sodium supplied was roughly estimated based on prescription data in the medical records and the timing of admission to the hospital, the actual result may be substantially different from the volume of fluid and the amount of sodium administered. However, our conclusions remain valid because treatment practices at any single institution are usually consistent, and more objective data, such as blood test results, were available.
In conclusion, terlipressin is used to treat variceal hemorrhage and hepatorenal syndrome, two serious complications of liver cirrhosis, but often results in a decreased blood sodium concentration. Since hyponatremia occurs a relatively short time after terlipressin administration, it is necessary to start electrolyte testing at the initial stage and to monitor possible neurological symptoms of hyponatremia. Similarly, care must be taken during administration of terlipressin to patients with a high baseline blood sodium concentration, since this is associated with a decreased blood sodium concentration.