Torsemide Versus Furosemide After Continuous Renal Replacement Therapy Due to Acute Renal Failure in Cardiac Surgery Patients

Abstract

Diuretic therapy in ARF (acute renal failure) is mainly done with loop diuretics, first of all furosemide. Torsemide has a longer duration of action and does not accumulate in renal failure. In chronic and acute renal failure, both diuretics have been effectively applied, with a more pronounced diuretic effect for torsemide. In this study, the effects of torsemide versus furosemide on renal function in cardiac surgery patients recovering from ARF after continuous renal replacement therapy (CRRT) were studied. Twenty-nine critically ill patients admitted to an intensive care unit at a university teaching hospital after cardiac surgery recovering from ARF after CRRT were included in this prospective, controlled, single-center, open-labeled, randomized clinical trial. Inclusion criteria were urine output > 0.5 mL/kg/h over 6 h under CRRT. Torsemide and furosemide dosages were adjusted with the target urine output being 0.8–1.5 mL/kg/h. Hemodynamic data, urine output, volume balance, serum creatinine clearance, electrolytes, blood urea nitrogen, serum creatinine, renin, and aldosterone concentrations were measured. Fourteen patients were included in the furosemide group and 15 patients in the torsemide group. Dosages of 29 (0–160) mg torsemide and a dosage of 60 (0–240) mg furosemide were given every 6 h in each group, respectively. The dosage given at the end of the study decreased significantly in furosemide and torsemide treated patients. Urine output, 24 h balance, and serum creatinine clearance did not differ significantly between groups. Urine output decreased in both groups, mostly dose-dependent in the torsemide group. The intragroup comparison of the first time-interval after inclusion with the last time-interval showed a significant increase in serum creatinine and blood urea nitrogen in the furosemide group. Renin and aldosterone concentrations did not show significant differences. In conclusion, torsemide and furosemide were effective in increasing urine output. Torsemide might show a better dose-dependent diuretic effect in ARF patients after CRRT treatment. Serum creatinine and blood urea nitrogen elimination were less pronounced in the furosemide group.

• torsemide
• furosemide
• ARF
• CRRT
• cardiac surgery
• aldosterone

Introduction

The incidence of acute renal failure (ARF) varies in critically ill patients, but it can be as high as 25%.[1] Cardiac surgery patients are at increased risk of developing ARF postoperatively.[2] Continuous renal replacement therapy (CRRT), being initiated in up to 20% of the intensive care unit (ICU) patients with ARF, has become the treatment of choice for ARF.[3] If the patient develops urine output under CRRT, CRRT can be discontinued under adequate volume and blood pressure monitoring to achieve sufficient renal perfusion.[4] The use of diuretics in ARF is controversially discussed, mainly because of the missing positive outcome results regarding renal recovery, requirement for dialysis, and death.[4&5] However, cardiac surgery patients often require diuretics because of concomitant heart insufficiency. To the best of our knowledge, no study has investigated diuretic therapy in patients recovering from ARF after CRRT. Standard clinical procedure in ARF is therapy with loop diuretics, first of all furosemide.[4] Torsemide, a pyridine-sulfonylurea loop diuretic, has a longer duration of action (3–6 h) than furosemide (1–3 h).[6&7] Torsemide is mainly metabolized in the liver (80%) and, in contrast to furosemide, which is mainly metabolized and excreted in the kidneys, does not accumulate in renal failure.[6],[8] Torsemide causes a greater sodium and chloride excretion than furosemide, whereas urinary potassium excretion rises to a much lesser extent under torsemide application.[6], [9] Reduced kaliuresis has been described in in vitro, animal, and human studies in chronic heart failure (CHF) and chronic renal failure (CRF) patients and was attributed to the inhibition of aldosterone binding to the receptor, causing an anti-aldosteronic effect.[10-14] Regarding the activation of the renin–angiotensin–aldosterone system (RAAS), different observations have been made.[10&11], [13-16] In CRF, both diuretics have been used effectively, with a more pronounced diuretic effect for torsemide in most studies.[15] In ARF, one study using torsemide and furosemide could not show any differences regarding urine volume.[17]

In this study, the effects on renal function of torsemide versus furosemide were studied in cardiac surgery patients recovering from ARF after CRRT. Both diuretics were compared regarding dosage, urine output, serum creatinine clearance, serum creatinine, blood urea nitrogen, and electrolyte levels as well as renin and aldosterone concentrations and costs of each diuretic/patient/day.

Patients and Methods

Patients

After ethical committee approval and written informed consent from the patients or a legal representative, 30 critically ill patients under CRRT (hemofiltration, blood flow 80–150 mL/min, replacement solution in postdilution mode 1000–1500 mL/h) recovering from ARF after cardiac surgery were enrolled in this prospective, controlled, single-center, open-labeled, randomized clinical trial. Exclusion criteria were age < 18 years, pregnancy, and patients with a preoperative history of CRF (serum creatinine > 180 µmol/L). Inclusion criteria were urine output > 0.5 mL/kg/h over 6 h under CRRT. No-go criteria were hyperhydration, hyperkalemia, hemodynamic instability, medicamentous or physically uncontrollable hyperthermia, rise in serum creatinine > 650 µmol/L or blood urea nitrogen > 42 mmol/L, urine output < 0.8 mL/kg/h over 4 h after study start, and unexpected adverse effects of the study drugs.

Group Assignment

After inclusion in the study CRRT was stopped, and the patients were randomly allocated into two groups (block randomization with blocks of four patients). After inclusion, one patient had to be excluded due to acute surgery with postoperative ARF. Therefore, a total of 29 patients remained in the study.

Study Protocol

The target urine output was 0.8–1.5 mL/kg/h. If urine output was > 1.5 mL/kg/h over 2 h, the dosage was adjusted according to the flowchart displayed in Figure 1. If urine output reached target values, the dosage was continued. If the urine output was under target values, the flowchart in Figure 1 was applied backwards, unless the above-mentioned no-go criteria were fulfilled. All patients had a central venous line, an arterial line, and electrocardiogram monitoring for hemodynamic control. Volume and catecholamine therapy to achieve an adequate perfusion pressure and volume loading were performed according to the ICU standard protocol.[18] After adequate fluid therapy, norepinephrine was titrated to maintain the mean arterial pressure (MAP) at > 70 mmHg. The catecholamine therapy regarding therapy of low-output-failure was performed primarily with dobutamine or dopamine at the discretion of the physician on duty. Additional therapy, if necessary, e.g., sedation or mechanical ventilation, was started according to the ICU standard protocol.[18] Patient urine output was measured hourly, and every 24 h, a fluid balance was calculated.

Figure 1 Flowchart for drug dosage if diuresis < 0.8 mL/kg/h or > 1.5 mL/kg/h every 2 h. If diuresis was in the range of 0.8–1.5 mL/kg/h, the dosage was kept.

Laboratory Parameters

Every 12 h, serum creatinine and blood urea nitrogen were measured (Hitachi 744 E, Roche Diagnostics, Mannheim, Germany), and every 6 h, a blood gas analysis and electrolyte measurements (ABL 500, Radiometer, Copenhagen, Denmark) were performed. Every 24 h, serum creatinine clearance was calculated. Every 12 h, blood samples for renin (two-site immunoradiometric assay, DRG Instruments GmbH, Germany) and aldosterone (coated tube radioimmunoassay, DRG Instruments GmbH, Germany) concentration measurements were withdrawn and centrifuged and serum was stored at − 80°C until analysis. The observation time was 72 h.

Costs

The costs for diuretic therapy were calculated as the mean cost/patient/day in the furosemide and the torsemide groups, respectively.

Statistical Analysis

Data were expressed as median and range. Baseline data were measured at inclusion in the study. Overall data were measured over the whole study period. Baseline intergroup statistical analysis was performed using the Mann-Whitney-U test, for dichotomous variables using the Pearson Chi-Square and Fisher exact test, respectively. Intragroup statistical analysis for determined time intervals was performed with the Wilcoxon matched-pairs signed rank sum test. For intergroup and intragroup statistical analysis over the whole study period, the two-factorial nonparametric (ANOVA)-type rank variance analysis for longitudinal data and small sample sizes was performed using the SAS System software (SAS Institute Inc., Cary, NC, USA). A p value of < 0.05 was considered statistically significant.

Results

Fourteen patients were included in the furosemide group and 15 patients in the torsemide group. Basic patient characteristics and outcome data are presented in Table 1. Serum creatinine and blood urea nitrogen values preoperatively, before CRRT and before study start are presented in Table 2. Baseline hemodynamic related parameters are presented in Table 3. Baseline sodium, potassium, renin, and aldosterone concentrations are presented in Table 4. With the exception of age, the baseline data did not differ significantly between both groups (Tables 1, 2, 3, 4). In three patients in the furosemide group, the study had to be interrupted after 48 h because of blood urea nitrogen > 42 mmol/L, after 21 h because of urine output < 0.8 mL/kg/h, and after 48 h because of death. In the torsemide group, the study had to be stopped in five patients. In three patients, it was stopped after 25, 48, and 66 h because of blood urea nitrogen > 42 mmol/L, after 48 h because of transfer to another hospital, and in the last case, after 8 h because of urine output < 0.8 mL/kg/h. No significant difference was found between groups regarding study interruption (p = 0.65). A dosage of 29 (0–160) mg torsemide and a dosage of 60 (0–240) mg furosemide were given every 6 h in each group, respectively. Figure 2 shows the dosages given over time. The dosage given between the first time interval after the study began and the last time interval was significantly reduced in furosemide- and torsemide-treated patients (Table 3). The urine output, 24 h balance, and serum creatinine clearance did not differ significantly between the groups (Tables 2, 3). However, the intragroup comparison of the first time interval after study start with the last time interval and the analysis of variance over the study time (p < 0.01) showed a significant decrease in urine output for the furosemide group and a not significant decrease for the torsemide group (Table 3, Figure 3). The central venous pressure (CVP) and the MAP were not significantly different between the groups (Table 3). The statistical analysis did not show significant differences between the groups regarding serum creatinine and blood urea nitrogen concentrations (Table 2). The intragroup comparison of the first time interval after study start with the last time interval showed a significant increase in serum creatinine and blood urea nitrogen in the furosemide group, but not in the torsemide group (Table 2). The statistical analysis for sodium, potassium, and potassium substitution was not significantly different between the groups (Table 4). The intragroup analyses for sodium between the first time interval after study start and the last time interval were significantly different in the furosemide-treated group (Table 4). The analysis between groups and the intragroup first to last time interval analysis for the renin and aldosterone concentrations did not show any significant differences (Table 4). The mean cost/patient/day for furosemide was $10 (8 €), and the mean cost/patient/day for torsemide was $8.8 (7 €).

Table 1. Baseline characteristics and outcome data

	Torsemide (n = 15)	Furosemide (n = 14)	p^*
Age (years)	69 (45–78)	75 (62–83)	0.01
Sex (m/f)	13/2	8/6	0.10
Body mass index (kg/m^2)	80 (65–104)	67 (57–90)	0.47
Operation:
CABG	7	11	0.26
Valve replacement	2	1	0.60
CABG + valve replacement	4	2	0.39
Aortic valve and root replacement	1	1	> 0.99
Ejection fraction	35 (10–63)	48 (12–82)	0.23
ICU stay (days)	20 (6–49)	16 (6–77)	0.67
Hospital mortality (n)	4	3	> 0.99
APACHE III	63 (42–87)	77 (48–125)	0.06

Abbr.: values in median (range); baseline data: measured at inclusion; APACHE: acute physiology and chronic health evaluation score; p^*: Mann-Whitney-U test and Pearson Chi-Square and Fisher exact test.

Table 2. Serum creatinine, serum creatinine clearance, and blood urea nitrogen values

	Torsemide (n = 15)	Furosemide (n = 14)	p
Serum creatinine preoperative (µmol/L)	106 (85–176)	117 (73–149)	0.54^*
Blood urea nitrogen preoperative (mmol/L)	9 (3–15)	10 (6–29)	0.30^*
Serum creatinine before CRRT (µmol/L)	230 (115–389)	203 (106–345)	0.29^*
Blood urea nitrogen before CRRT (mmol/L)	13 (8–35)	17 (11–31)	0.60^*
Serum creatinine before study start (µmol/L)	177 (47–314)	181 (80–345)	0.75^*
Blood urea nitrogen before study start (mmol/L)	21 (10–33)	19 (11–27)	> 0.99^*
Serum creatinine clearance/study course (mL/min)	21 (1–73)	20 (1–55)	0.65^+
	0.98^α	0.42^α
Serum creatinine/study course (µmol/L)	212 (35–469)	221 (80–654)	0.84^+
	0.24^α	0.02^α
Blood urea nitrogen/study course (mmol/L)	24 (10–52)	29 (2–57)	0.38^+
	0.17^α	< 0.01^α

Abbr.: values in median (range); study course: data over the whole study period; APACHE: acute physiology and chronic health evaluation score; p^*: Mann-Whitney-U test; p^α for intragroup first time interval after baseline to last time-interval comparison: Wilcoxon matched-pairs signed rank sum test; p⁺ for intergroup study course data: two-factorial nonparametric analysis of variance for longitudinal data.

Table 3. Hemodynamic data, dosage, 24-hour balance, and urine output

		Torsemide (n = 15)	Furosemide (n = 14)	p
Dosage (mg)	Study course	29 (0–160)	60 (0–240)
		< 0.01^α	< 0.01^α
CVP (mmHg)	Before study start	13 (6–22)	14 (7–24)	0.53^*
	Study course	12 (5–23)	12 (5–24)	0.89^+
		0.88^α	0.19^α
MAP (mmHg)	Before study start	75 (60–100)	76 (59–97)	0.83^*
	Study course	77 (42–118)	75 (59–105)	0.84^+
		0.64^α	0.62^α
24-hour-balance	Study course	0 (3079–3330)	0 (2785–5046)	0.54^+
		0.47^α	0.41^α
Urine output (mL)	6 h before study start	660 (260–930)	436 (220–650)	0.07^*
	Every 6 h	750 (163–2470)	770 (10–1950)	0.98^+
		0.24^α	0.03^α

Abbr.: values in median (range); study course: data over the whole study period; CVP, central venous pressure; MAP, mean arterial pressure, p^* for intergroup baseline data: Mann-Whitney-U test and Pearson Chi-Square and Fisher exact test; p^α for intragroup first time interval after baseline to last time-interval comparison: Wilcoxon matched-pairs signed rank sum test; p⁺ for intergroup study course data: two-factorial nonparametric analysis of variance for longitudinal data.

Table 4. Laboratory data

		Torsemide (n = 15)	Furosemide (n = 14)	p
Sodium (mmol/L)	Before study start	137 (133–142)	136 (130–149)	0.48^*
	Study course	137 (132–152)	139 (130–152)	0.20^+
		0.32^α	< 0.01^α
Potassium (mmol/L)	Before study start	4.7 (4.0–5.2)	4.7 (4.2–5.4)	0.39^*
	Study course	4.6 (3.2–5.8)	4.6 (3.3–6.4)	0.97^+
		0.45^α	0.79^α
Potassium substitution every 6 hours (mval)	Study course	17 (0–80)	15 (0–90)	0.73^+
Aldosterone (pg/mL)	Before study start	36 (10–1770)	69 (18–575)	0.39^*
	Study course	47 (10–1770)	71 (10–635)	0.11^+
		0.75^α	0.22^α
Renin (pg/mL)	Before study start	35 (3–497)	69 (7.4–531)	0.98^*
	Study course	29 (1–607)	70 (5–552)	0.15^+
		0.21^α	0.84^α

Abbr.: values in median (range); study course: data over the whole study period; p^* for intergroup baseline data: Mann-Whitney-U test and Pearson Chi-Square and Fisher exact test; p^α for intragroup first time interval after baseline to last time-interval comparison: Wilcoxon matched-pairs signed rank sum test; p⁺ for intergroup study course data: two-factorial nonparametric analysis of variance for longitudinal data.

Figure 2 Median and interquartile ranges for torsemide and furosemide doses applied over the study period.

Figure 3 Median values for urine output over the study period of furosemide and torsemide groups as percentage of median urine output at inclusion (100%).

Discussion

To our knowledge, this is the first study comparing furosemide and torsemide in critically ill patients recovering from ARF after CRRT. The dosage applied for furosemide was chosen according to the standard ICU protocol[18] and the publication of Brater.[6] The dosage for torsemide was adjusted according to the previously described pharmacological characteristics of torsemide.[6], [8] The double potency of torsemide is reflected in this study, because furosemide was dosed twice as high as torsemide in almost every time interval. In ARF, continuous infusion versus high boluses of loop diuretics have been shown to be potentially superior regarding effectiveness and toxicity.[4], [6&7], [19&20] The initial dosages led to an excessive rise in urine output, especially in the furosemide group. It appears that the initial continuous dosage was too high. Urine output decreased markedly in the torsemide group after dosage reduction. Torsemide might have a better dose–response relationship than furosemide. The dosage could be reduced significantly during the study period in both groups. Urine output over the time and in comparison of first to last time interval was significantly decreased in the furosemide group. This effect and the apparently better dose–response relationship of torsemide could be attributed to the longer half-life of torsemide. However, furosemide is eliminated renally and has a longer half-life in patients with renal insufficiency in comparison to torsemide, which is eliminated mainly through the liver.[6&7] In CRF and ARF, both diuretics, in a bolus dosage of 100–250 mg intravenously, have shown to significantly increase urine output.[8&9], [15&16], [20] This effect was more pronounced for torsemide in some studies.[8] Shilliday et al.[17] compared the use of furosemide, torsemide, and placebo in a bolus intravenous application of 3 mg/kg every 6 h in ARF patients who were, however, at the same time treated with mannitol and dopamine infusion. Urine output was significantly higher in the diuretics group, whereas the need for dialysis and outcome were not different between the groups.[17] These results on the immediate potential beneficial effects (volume control without dialysis and turning oliguric in nonoliguric ARF) could also be shown by other authors.[17], [20] A recent cohort study by Metha et al.[5] could even show an increased mortality when loop diuretics, indistinctive of which one, were applied in ARF. Noteworthy is the fact that study patients were in ARF before the decision to initiate CRRT and were not recovering from ARF after CRRT, as in our study. Outcome data were not different in our study groups. To the best of our knowledge, nobody has investigated patients recovering from ARF after CRRT. Especially in patients with cardiac insufficiency, like the patients in this study, diuretic therapy is mostly unavoidable.

Serum creatinine and blood urea nitrogen levels were slightly elevated or in the upper normal range preoperatively. Increased incidence of preoperative renal dysfunction has often been described in the literature in cardiac surgery patients, also as a risk factor for adverse events postoperatively.[2], [21&22] Despite adequate diuresis, serum creatinine and blood urea nitrogen levels were elevated before study start and increased further in the median over the study period. However, only three patients in the torsemide group versus one patient in the furosemide group had to be reinitiated on CRRT because of high blood urea nitrogen values. The comparisons of serum creatinine and blood urea nitrogen levels at study start with end of study levels showed a significantly higher increase in the furosemide group. A possible influencing effect in the furosemide group could have been the significantly older age, as it is known that kidneys of older patients take longer to recover after ARF. However, diuretics primarily have an influence on urine output and not on serum creatinine and blood urea nitrogen clearance. Taking these points into consideration and the fact that clearance was not significantly different between groups, the difference in blood urea nitrogen and serum creatinine elimination may not have been a torsemide effect. Boesken et al.[9] treated patients with advanced CRF with 200 mg torsemide (intravenous) every day and found no significant increase in renal function judged by serum creatinine clearance and serum creatinine. In studies investigating patients with nephrotic syndrome and CRF by Allison et al.[23] and Russo et al.,[16] however, decreases for serum creatinine and blood urea nitrogen clearance were observed for torsemide and furosemide. In a case study, 250 mg/day torsemide was given intravenously in ARF patients without an effect on serum creatinine and blood urea nitrogen clearance.[16]

The 24-h balance in this study was highly influenced by the clinical needs of the patient. What remains out of question is the importance of an adequate volume and perfusion status.[4&5], [20&21] Adequate intravascular volume and perfusion pressure can be assumed, because the hemodynamic parameters did not show any differences in the intergroup and intragroup analyses.

Aldosterone concentrations were not significantly different in both groups. The potassium concentration was also constant in study patients, primarily because of accurate substitution therapy, and potassium substitution was not different between groups. Increased aldosterone concentrations could not be found in CRF patients treated with loop diuretics, as shown in this study.[15] In animal experiments and one study done with CHF patients, an increase of aldosterone was found after loop diuretic therapy.[10&11], [13&14] In in vitro, animal, and human studies in CHF patients, torsemide inhibited aldosterone binding to the receptor, causing an anti-aldosteronic effect with reduced kaliuresis.[10-14], [24] The accurate potassium substitution performed in this study could have influenced aldosterone levels, as aldosterone secretion is dependent on potassium levels.[14] Renin concentrations were not significantly different in both groups. Activation of the RAAS by loop diuretics was found to differ in animal studies and in human studies.[10&11], [14&15] In the first time interval to last time interval comparison, sodium increased significantly in the furosemide group. Torsemide was given in equipotent doses to furosemide, and we expected similar natriuresis in both groups, as described in some studies.[8], [10&11], [15] Other studies, however, describe an increased dose-dependent saluretic effect of torsemide.[8], [15] This might have happened in our study.

The total cost/patient/day was slightly lower in the torsemide group, mainly because less diuretic was given in comparison to furosemide.

Conclusions

Torsemide and furosemide were effective in increasing urine output in ARF patients after CRRT treatment. The initial doses required might be lower in this patient population. Torsemide might show a better dose-dependent diuretic effect. Serum creatinine and blood urea nitrogen elimination were less pronounced in the furosemide group. The anti-aldosteronic effect of torsemide could not be proven in this study. Considering the cost analysis, torsemide might show possible advantages compared to furosemide.