The Effect of Continuous Infusion Loop Diuretics in Patients With Acute Decompensated Heart Failure With Hypoalbuminemia

Abstract

Purpose:

Hypoalbuminemia is believed to decrease diuretic effectiveness and contribute to diuretic resistance that is observed in patients with nephrotic syndrome. Hypoalbuminemia is also seen in patients with acute decompensated heart failure (ADHF). However, the role of hypoalbuminemia on the effectiveness of continuous infusion diuretics in patients with ADHF is not known.

Methods:

To evaluate hypoalbuminemia (albumin ≤3 g/dL) and diuretic effectiveness, we performed a retrospective study in 162 patients admitted to a tertiary care center for treatment of ADHF over a 3-year period. All patients received continuous infusion diuretic for at least a 2-day time period.

Results:

A total of 33 patients were determined to have hypoalbuminemia. Average net urine output over a 2-day study period was similar between patients with and without hypoalbuminemia (−1462 ± 1734 vs −1233 ± 1560 mL, P = .46, respectively). In addition, diuretic doses (furosemide equivalent/24 hours) were similar between the 2 groups (788 ± 671 vs 778 ± 713 mg, P = .91, respectively) as was baseline serum creatinine (1.6 ± 0.6 vs 1.6 ± 0.6 mg/dL, P = .5, respectively).

Conclusion:

Overall, hypoalbuminemia did not decrease the diuretic effectiveness when measured by the net urine output in patients receiving continuous infusion diuretics for the treatment of ADHF.

Keywords

diuretics heart failure hypoalbuminemia continuous infusion

Introduction

One factor that is thought to contribute to diuretic resistance is hypoalbuminemia. Loop diuretics are highly protein bound (>95%) and reach their target site at the loop of Henle through active secretion into the tubular lumen.¹ Hypoalbuminemia is thought to contribute to decreased diuretic effect in part by decreased delivery of drug to the kidneys.

The concept that hypoalbuminemia leads to decreased diuretic effect has mainly come from the nephrotic syndrome literature where there is both a decrease in serum albumin concen-trations and increased albumin excretion.^2–5 Data regarding hypoalbuminemia and diuretic effect in heart failure patients are extremely limited. To our knowledge, data are nonexistent in regard to the effect of continuous infusion diuretic in hypoalbuminemic patients with heart failure. The purpose of this study is to compare the effect of continuous infusion loop diuretic therapy in the treatment of acutely decompensated heart failure (ADHF) in patients with and without hypoalbuminemia.

Methods

We performed a retrospective observational analysis to determine the role of hypoalbuminemia on the effect of continuous infusion diuretic therapy in patients with ADHF. Review of our institution experience with continuous infusion diuretics was approved by the University of Michigan Institutional Review Board.

All patients admitted to the University of Michigan Health System with ADHF and who received continuous loop diuretic infusions from January 2006 through June 2009 were included. Patients with serum creatinine levels >3 mg/dL or on dialysis were excluded. In addition, patients with incomplete medical records, less than 24 hours of loop diuretic infusion treatment, concurrent nephrotoxic agents (aminoglycosides, tacrolimus, cyclosporine, and sirolimus), patients transferred already given loop infusions, and those less than 18 years of age were excluded. Heart failure diagnosis was confirmed by admitting note and past medical history. Choice of diuretic and dose adjustments was made based upon the clinical judgment of the medical team.

The primary outcome of this study was to evaluate net urine output and diuretic dose over 48 hours (day 1 and 2) of continuous infusion therapy in patients with and without hypoalbuminemia. Hypoalbuminemia was defined as serum albumin levels ≤3 g/dL. Furosemide equivalents were determined by multiplying the daily bumentanide dose by 40. For evaluation of baseline parameters continuous variables were assessed using unpaired t test and categorical data by chi-square analysis. A P < .05 was considered significant. An unpaired test with unequal variance (Welch test) was employed to evaluate the differences in net urine output and diuretic dose between the 2 groups. Since we evaluated these parameters over time a Bonferroni correction was applied; P < .025 was considered significant. Data are reported as mean and standard deviation.

Results

A total of 162 patients were included in the study, and 33 patients were defined as hypoalbuminemic. Baseline charac-teristics are shown in Table 1. No significant differences were observed for any variable except for baseline albumin levels. Overall, the patient population was a relatively sick patient population with heart failure as demonstrated by presence of low blood pressure, low serum sodium, elevated serum creatinine, and blood urea nitrogen and consistent with an inpatient population with ADHF in a tertiary care setting. In the control group (patients without hypoalbuminemia) 97 (75%) patients received bumentanide and in the hypoalbuminemia group 28 (85%) patients received bumentanide. For patients with hypoalbuminemia, mean albumin level was 2.7 ± 0.3 mg/dL and ranged from 1.7 to 3.0 g/dL. For the control group, the mean albumin level was 3.7 ± 0.4 mg/dL and ranged from 3.1 to 4.5 g/dL.

Table 1.

Baseline Variables (Mean ± Standard Deviation).

Variable^a	Albumin ≤3.0 g/dL (N = 129)	Albumin <3.0 g/dL (N = 33)
Age, years	61 ± 15	60 ± 16
Men	77 (60%)	22 (67%)
Caucasian	94 (73%)	21 (64%)
Bumetanide infusion	97 (75%)	28 (85%)
Ischemic cardiomyopathy	56 (43%)	19 (58%)
Systolic heart failure	98 (76%)	24 (73%)
Ejection fraction, %	31 ± 20	31 ± 19
Systolic blood pressure, mm Hg	109 ± 21	110 ± 20
Diastolic blood pressure, mm Hg	63 ± 11	60 ± 12
Serum sodium, mEq/L	136 ± 5	136 ± 5
Serum creatinine, mg/dL	1.6 ± 0.5	1.6 ± 0.6
Blood urea nitrogen, mg/dL	49 ± 25	48 ± 24
Vasoactive medication and other diuretics
Inotropes/vasopressors	40 (41%)	14 (42%)
Thiazide diuretic	25 (19%)	10 (30%)
Spironolactone	37 (29%)	7 (33%)

^aP > .05 for all variables.

The effect of continuous infusion loop diuretic on net urine output for patients with and without hypoalbuminemia is shown in Table 2. Overall, there was no difference in net urine output (24 hour fluid intake−24-hour urine output) or diuretic dose between the 2 groups. The range in net urine output for the normal albumin group was between (−)5660 mL/24 h to (+)7028 mL/24 h. For the hypoalbuminemic group, the range was (−)8486 mL/24 h to (+)2113 mL/24 h.

Table 2.

Net Urine Output (24-Hour Urine Output − 24-Hour Fluid Intake) and Diuretic Dose.

Variables	Day 1		Day 2
Patients	Albumin >3 g/dL	Albumin <3 g/dL	Albumin >3 g/dL	Albumin <3 g/dL
Net UO, mL/24 h	1258 ± 1615	1422 ± 1996 (P = .64)	1204 ± 1502	1507 ± 1412 (P = .30)
Bumentanide dose, mg/24 h	24 ± 17	23 ± 13 (P = .26)	25 ± 22	23 ± 21 (P = .72)
Furosemide dose, mg/24 h	267 ± 165	184 ± 122 (P = .23)	189 ± 153	211 ± 174 (P = .79)

Abbreviation: UO, urinary output.

Although not statistically different, the percentage of patients receiving either thiazide diuretics or vasoactive drugs was higher in patients with low albumin levels. When evaluating the effect of these drugs they did not significantly enhance the overall net urine output. Specifically, for patients with low albumin levels and receiving a thiazide diuretic, the mean net urine output over 48 hours was 955 ± 1229 versus 1687 ± 1885 mL (P = .073) for patients not receiving a thiazide diuretic. For patients with low albumin receiving a vasoactive drug, the mean net urine output over 48 hours was 1578 ± 2120 versus 1378 ± 1418 (P = .68) for patients not receiving a vasoactive drug.

Discussion

Hypoalbuminemia is often cited as a factor in decreasing diuretic effectiveness. However, the role of hypoalbuminemia and diuretic effectiveness in the setting of continuous infusion diuretic in patients with ADHF is not known. The results of this retrospective analysis demonstrated that there was no difference in net urine output or diuretic dose between patients with or without hypoalbuminemia. These data showed that when administered by continuous infusion, diuretic effectiveness is not decreased in the presence of hypoalbuminemia in patients with ADHF.

The belief that hypoalbuminemia may decrease loop diuretic effectiveness is based on the observation of diuretic resistance in patients with nephrotic syndrome and the pharmacokinetic and pharmacodynamic properties of loop diuretics.^1–7 Loop diuretics are highly protein bound (>95%), mainly to albumin. For loop diuretics to work they need to be present in the tubular lumen of the nephron. To reach the tubular lumen, loop diuretics are actively secreted into the lumen by organic acid secretary pumps located near the proximal tubules. Since loop diuretics are highly protein bound, conditions that alter albumin levels may affect delivery of the diuretic to the kidney as discussed below.

Nephrotic syndrome is a nonspecific disorder characterized in part by edema, proteinuria, and hypoalbuminemia. In patients with nephrotic syndrome, there is damage in the kidney which results in leaking large amounts of protein into the urine (>3.5 g of albumin per day). Clinically, it has been observed that patients with nephrotic syndrome have a decreased response to loop diuretics. Theories to explain this observation have been related to hypoalbuminemia and loop diuretic’s high degree of protein binding. Low serum albumin levels as seen in nephrotic syndrome may result in lower drug binding resulting in higher volume of distribution and decrease drug delivery to the kidneys with a corresponding decrease in diuretic effectiveness.^5,7,8 To overcome the diuretic resistance due to low albumin levels, a number of studies have evaluated the role of albumin administration to improve effectiveness with mixed results.^4,5,9–11 An additional mechanism that may decrease diuretic effectiveness may involve high urinary concentrations of albumin. Elevated urinary albumin may bind to loop diuretics in the tubular lumen and result in decreased effect.^2,3,6,7

Unlike what has been observed in nephrotic syndrome, our study did not demonstrate decreased diuretic effectiveness. One reason a decrease in diuretic effectiveness was not seen may relate to the type and degree of hypoalbuminemia and hyperalbuminuria that is present in patients with ADHF when compared to patients with nephrotic syndrome. In patients with nephrotic syndrome, a decrease in serum albumin is most likely due to the loss of albumin in the urine. However, in patients with heart failure, hypoalbuminemia may be more likely related to hemodilution. Although malnutrition, cachexia, and inflammation can also contribute to hypoalbuminemia,¹² in our case malnutrition is not a likely cause since the calculated body mass index for the hypoalbuminemic group was 29 ± 6 kg/m². Although urinary protein was not measured in our study, it is likely that patients with nephrotic syndrome will have a greater degree of hyperalbuminuria. Previous studies have suggested that macroalbuminuria is only present in approximately 5% to 11% of patients with systolic heart failure.^13–15 As previously mentioned, high levels of albumin in the urine as seen in the nephrotic syndrome may theoretically bind loop diuretics and decrease diuretic effects. This interaction is probably less likely to occur in patients with heart failure. Another reason we did not see a decrease in diuretic effect may relate to the mode of administration. Continuous infusion, theoretically, may be more efficacious than bolus administration in part due to greater time spent above diuretic threshold and less rebound effect. However, a recent study suggests that continuous infusion may not be more efficacious than bolus administration.¹⁶ Another factor, and related to the use of continuous infusion, may be the aggressive diuretic approach that is often employed to treat patients with ADHF. Aggressive diuresis (high doses given frequently) may overcome any effect hypoalbuminemia may have on diuretic efficacy by increasing the amount of drug at the site of action.

There are no studies to our knowledge that have directly evaluated the role of continuous infusion diuretics in hypoalbuminemic patients with heart failure. A recent study evaluating the effects of aggressive decongestion in patients with heart failure demonstrated greater net fluid output in patients who experienced hemoconcentration.¹⁷ At baseline, these patients had a significantly lower albumin level when compared to patients who did not experience hemoconcentration (3.4 ± 0.5 vs 3.8 ± 0.5 g/dL, P < .001). In addition, patients who experienced hemoconcentration also received higher amounts of loop diuretics. Although this study did not directly address the question of hypoalbuminemia and diuretic effect, their findings are similar to our study.

There are a number of limitations to this study including its retrospective nature. The study did not evaluate the role of bolus dosing versus continuous infusion and did not measure urinary protein levels. However, in our population of patients with ADHF, it would not be expected to have a high prevalence of nephrotic range proteinuria.^13–15 In addition, in this study there was a limited number of patients with severe hypoalbuminemia (2 patients with albumin levels at or below 2 g/dL). Perhaps, patients with extreme hypoalbuminemia may see a different response to diuretic therapy than what was observed in this study.

Overall, this study evaluated the effect of continuous infusion loop diuretic in patients with hypoalbuminemia and ADHF. In this setting, continuous infusion loop diuretic is similarly effective in patients with or without hypoalbuminemia. Based on our results, diuretic resistance if observed in ADHF, is not likely due to hypoalbuminemia and measures to overcome diuretic resistance by acutely correcting albumin levels does not appear to be warranted.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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