Two major causes of hypervolemia are renal failure (RF) and heart failure (HF). Impaired renal function can be present in 50% of patients treated for acute HF.1 Even moderate degrees of renal insufficiency are independently associated with an increased risk of mortality from any cause in patients with HF.2 Patients with RF have a significantly increased risk of mortality, with half of these deaths attributed to cardiovascular disease. Therefore, RF and HF are two intertwined conditions.

Thiamine deficiency causes high-output HF and volume overload.3 The cardiovascular symptoms of thiamine deficiency may be difficult to distinguish from those of HF. Although overt symptoms and signs of thiamine deficiency might not be present, functional thiamine deficiency may contribute to various complications including hypervolemia and ultimately increased mortality in RF and HF patients. But, it is not known exactly how thiamine level is changing with diuretic treatment in hypervolemic patients with RF and/or HF.

Furosemide is a loop diuretic which is commonly used in hypervolemic patients in HF and RF. Studies of the association between the use of furosemide and thiamine levels gave conflicting results. Findings of two different studies were consistent with thiamine deficiency in a high proportion of patients treated with furosemide for HF.4,5 On the other hand, the other study found no significant difference in thiamine levels between a group with HF and a control group.6 Although there are studies evaluating thiamine deficiency in HF patients using diuretics as in the mentioned studies in the literature, there are not enough studies evaluating diuretic related thiamine deficiency in RF patients without HF. It is not known whether the effect of furosemide on thiamine levels is different when RF is present alone.

The incidence and consequences of thiamine deficiency and the related conditions of this deficiency among hypervolemic patients are not well known. For these reasons, in the performed study, we aimed (1) to describe the thiamine status in hypervolemic HF and/or RF patients treated with furosemide; (2) to establish the impact of ongoing doses of furosemide during hospitalization on thiamine blood concentrations; (3) to investigate whether there was a difference in furosemide-related thiamine deficiency between patients with RF and HF; and (4) to examine the potential role of renal function in conflicting results of the previous studies considering furosemide-related thiamine loss. Moreover, filling the gap in knowledge about the influence of furosemide on thiamine losses may help to establish what is an adequate dose of thiamine supplementation in hypervolemic patients with RF and/or HF.

In this study, we evaluated 61 patients who diagnosed with hypervolemia and hospitalized in the clinic, of which 22 (36%) were men and 39 (64%) were women, with a mean age of 69.00±10.4 (45–90) years. Patients baseline characteristics were as follows: 13 patients (21.3%) had hypertension, 42 patients (70.5%) had diabetes mellitus, and 45 patients (73.8%) were receiving furosemide treatment for at least 4 weeks before hospitalization. While RF and HF coexisted in 28 hypervolemic patients, 12 hypervolemic patients had only HF and 21 hypervolemic patients had only RF. Baseline and clinical follow-up characteristics of study participants were showed in Table 1 according to groups. There was no significant differences between the groups in terms of demographic, clinical and laboratory parameters, except for hemoglobin and renal function tests. Hemoglobin was significantly lower in RF patients than HF patients (p=0.003) and creatinine was significantly higher in RF patients than other groups (p<0.001) (Table 1). Furthermore, we compared demographic, clinical and laboratory parameters between HF patients without RF and other patients who had RF in Table 2. Patients who had RF had significantly lower hemoglobin value (p=0.011) and higher first day furosemide dose (p=0.045) than heart failure patients without renal failure.

In all subjects, the baseline and post-hospital admission days 2 and 4 whole blood mean thiamine levels in the hospital were 51.71±20.66ng/ml, 47.64±15.43ng/ml and 43.78±16.20ng/ml, respectively. Thiamine levels of the hypervolemic patients decreased significantly during the hospital stay while furosemide treatment was continuing (p=0.029) (Table 3). Thiamine deficiency (thiamine levels<35ng/ml) was detected in 19.7% (n=12) of our patients at the time of hospitalization, 44.3% (n=27) of patients had thiamine deficiency on the 4th day of hospitalization. There was a significant decrease in thiamine levels in patients who had eGFR 90 or greater during hospital stay (Table 3). However, there was no such decrease in stage 5 RF patients and there was even an increase (Table 3), although they had higher first day furosemide dose (Table 2).

Patients with low thiamine levels had longer hospital stay (10.9±7.9 day, 7.3±3.8 day; respectively), although not statistically significant (p=0.148). There was no significant difference in echocardiographic findings at the time of hospitalization in patients with low thiamine levels (Table 4).

Hemodialysis treatment was needed in 12 patients (19.7%). Thiamine levels in patients who needed hemodialysis were significantly decreased during hospital stay (p=0.032). However, there was no significant decrease in thiamine levels in patients who did not require hemodialysis (p=0.193) (Fig. 1).

Fig. 1.

Thiamine levels of hemodialysis and non-hemodialysis patients.

(0.1MB).

During hospital follow-up, 8.2% of the patients (n=5) died. There was no significant difference in thiamine levels between patients who had death and patients who had no death from hypervolemia, but thiamine levels were lower in patients who had death (37.30±8.09, 48.14±15.64; respectively, p=0.178).

To better establish the effects of RF and HF on thiamine levels, it was investigated for three different groups. One of the groups (n=12) consisted only patients who had HF, the other group (n=21) consisted only patients who had RF alone and RF and HF coexisted in patients in the third group (n=28). While there was no significant change in thiamine levels in patients who had RF alone, there was a significant decrease in patients who had HF and patients who had HF and RF in paired comparisons of thiamine levels on different hospitalization days (Fig. 2).

Fig. 2.

Serial whole blood thiamine concentrations (ng/ml) over time in only RF patients (a), only HF patients (b), and HF and RF coexisted patients (c). The thiamine level changes over time within each group (RF, HF and RF+HF) were compared using a Friedman's non-parametric test and p values were 0.829, 0.078 and 0.042; consecutively. A separate Wilcoxon-signed rank test was used in paired comparisons of thiamine levels on different hospitalization days and p values were shown in figure.

(0.2MB).

We investigated the effects of furosemide on baseline thiamine levels in the HF and RF patients who had recieved furosemide for more than 4 weeks before the hospitalization. Baseline thiamine was significantly lower in HF patients who had previously used furosemide (Table 5). But, there was no significant difference in baseline thiamine levels at the time of hospitalization in RF patients and patients who had HF and RF.

In this prospective observational study, it was found that thiamine levels decreased gradually with furosemide treatment in hospitalized hypervolemic patients and this finding was prominent in HF patients. Significant depletion of thiamine was present in hypervolemic HF patients receiving chronic diuretic therapy prior to hospital admission. However, these findings were not present in patients with RF. To date, there are many studies related to this subject in HF patients, but a few studies have evaluated furosemide related thiamine status in RF patients and those studies yielded conflicting results.12 There is no comparative study in the literature and this is the first time that the differences in thiamine levels between RF and HF patients are described in association with furosemide treatment. Our study reveals that furosemide related thiamine deficiency is not as prominent in RF patients as in HF patients.

Thiamine is eliminated from the body by renal excretion that is dependent on glomerular filtration rate and on thiamine plasma concentrations.13 Several studies documented thiamine deficiency secondary to diuretic therapy.5,14,15 The mechanism of thiamine deficiency with diuretic therapy is increased urinary thiamine excretion, which depends on urinary flow rate. 14,16–18 However, our study and Saka et al.’s study which investigated thiamine status in end-stage chronic kidney disease patients did not show any such correlation.19 The reason for the difference between this study and previous studies could be as follows. In most previous studies, diuretics were used in patients with congestive heart failure in whom kidney function was not severely impaired.5,16,20,21 In those cases, urinary flow rate might have increased in response to diuretic therapy. In contrast, the diuretic response is poor in RF patients, such as those in our study. This could explain why the current study showed no significant association between blood thiamine concentration and loop diuretic usage in RF patients. We thought that the poor diuretic response in RF patient population and therefore inadequate increase in urinary thiamine excretion secondary to diuretic therapy were the main contributing factors to this outcome. Although it was not significant, there was an increase in thiamine levels on the second day of hospitalization in patients with RF. This may be associated with impaired renal function in these patients due to acute phase of disease in the early period of hospitalization. On the other hand, thiamine levels in patients who needed hemodialysis were significantly decreased during hospital stay in our study. This observation is in accordance with the previous findings of Heinz et al.22 and Jankowska et al.23

In the study of Brady et al.,24 it was found that HF patients appeared more likely to have evidence of thiamine deficiency. Seligmann et al.4 showed that long-term high-dose furosemide treatment has been shown to induce clinically significant thiamine deficiency in an elderly HF patient population. Lubetsky et al.’s study findings suggest that diuretic-induced thiamine deficiency may occur not only in HF patients undergoing long-term furosemide therapy but also in other patient groups using other diuretics or experiencing polyuric states.18 But, furosemide therapy did not influence the blood thiamine level in Yue et al.’s study in which the included HF patients were treated with furosemide.6 The reason for this difference in thiamine status between studies may be related to renal function of patients. In the study of Yue et al., there was no information about the renal functions of the patients.

Nazmi et al. did not find a significant difference in red cell thiamine pyrophosphate concentration comparing older adult inpatients who were taking furosemide and found no relationship between thiamine concentration and furosemide dose.25 In Nazmi et al.’s study, there was a weak relationship between glomerular filtration rate and thiamine concentration, those with higher glomerular filtration rate had lower erythrocyte thiamine pyrophosphate concentration. These results support our findings that preserved renal function was needed for furosemide-induced thiamine deficiency.

Thiamine deficiency has been closely linked with cardiovascular disease. In this study, we also examined the cardiovascular effects of thiamine deficiency in hypervolemic patients at the time of hospitalization. But, we did not find significant difference in echocardiographic findings of patients with low thiamine levels. This result may be related to the lower percentage of patients with thiamine deficiency compared to the literature and related to the fact that echocardiographic evidence of thiamine deficiency is not apparent until deficiency is severe. On the other hand, there are some studies with conflicting results regarding the use of thiamine in heart failure treatment. In Smithline et al.’s study, the administration of thiamine did not improve dyspnea in acute heart failure patients.26 However, Schoenenberger et al. showed a significant improvement in ejection fraction with thiamin treatment in chronic stable heart failure patients.27 Additional studies are needed to understand the cardiac effects of thiamine.

Our study has several limitations. First, the number of patients was relatively small. Second, we did not evaluate the daily urine output of patients and did not measure urinary thiamine levels. Third, we used a HPLC method to determine whole blood thiamin levels and it may not fully reflect thiamine deficiency. There are more sensitive methods like erythrocyte thiamin pyrophosphate assay that show state of thiamine deficiency. Fourth, RF and HF are two conditions that can often accompany each other and it can be difficult to distinguish one from the other in hypervolemic patients in some cases.

In conclusion, we report that thiamine substantially decreases in most hypervolemic patients receiving intravenous furosemide treatment during the hospital stay. The quantity of this decrease was associated with etiology of hypervolemia. Thiamine levels were significantly decreased with furosemide treatment in especially HF patients, but the decrease in thiamine levels did not detected at the same rate in RF patients. Also, thiamine deficiency at hospital admission was present in most patients receiving chronic oral diuretic therapy for HF. But this was not the case for RF patients receiving chronic oral diuretic therapy. These results suggest that diuretic-induced thiamine loss may be less likely in RF patients, probably due to a reduction in excretion. Thiamine therapy cannot yet be recommended for all patients treated with furosemide, more clinical trials are needed. Our study presents a new perspective about the association between furosemide treatment and thiamine deficiency.

None declared.

The authors have no conflicts of interest to declare.