Glucocorticoids are known to have pronounced physiologic effects in the kidney. Conventional teaching dictates that it should be used with caution in patients with congestive heart failure because of its fluid and sodium retention effects. It is surprising that, despite the widespread prevalence of this belief within the medical community, there are few data to support it. In fact, several animal studies have documented their striking diuretic effects. Animal studies showed that glucocorticoids could increase renal plasma flow and glomerular filtration rate (GFR) without changes in the glomerular filtration fraction.1-3 Animal studies also showed glucocorticoids might have an important effect on atrial natriuretic peptide (ANP), a potent endogenous diuretic peptide. Glucocorticoids may regulate synthesis and release of ANP,4 may upregulate ANP receptors on vascular endothelial cells, and thus may have an important effect on diuresis and natriuresis in patients with fluid overload.
In our clinical practice, we observed that adding prednisone to standard care in patients with CHF and refractory diuretic resistance resulted in a striking diuretic effect. To corroborate our postulation, we designed this randomized, double-blind, placebo-controlled pilot clinical study to determine the potentiating diuretic efficacy of prednisone, a glucocorticoid, in patients with CHF.
PATIENTS AND METHODS
The inclusion criteria included adult patients with CHF (age ≥18) from any cause, with normal cortical function, receiving diuretic therapy, and clinically stable and whose body weight maintained the same for at least 3 days without overt signs of fluid retention. Exclusion criteria were patient refusal and having signs of infection, diabetes mellitus, acute coronary syndrome, or uncontrolled hypertension. The diagnosis of congestive heart failure was based on clinical, echocardiogram, or radiologic evidence of pulmonary edema and a jugular venous pressure higher than 10 cm H2O. After a written confirmation form was obtained, prednisone (1 mg/kg/day with a maximum dose of 60 mg/day was given for 7 days) was added, leaving other medical treatments unchanged.
The total daily output of urine was collected during a 7-day study period, and urine electrolytes were examined. Blood electrolytes were compared between 2 treatment groups both at baseline and at the end of the study. During the whole study period, all diuretics and their dosages remained unchanged. Change from baseline in body weight was also recorded during the study to reflect changes in volume status of the patients.
The study was conducted according to ethical principles stated in the Declaration of Helsinki (1996) and in adherence to local guidelines for good clinical practice. The protocol was approved by a local institutional ethics review committee, and written informed consent was obtained from all patients.
Continuous variables were expressed as mean ± standard deviation (SD) unless otherwise stated. A Mann-Whitney U test was used to analyze differences of parameters between the 2 treatment groups. All statistical tests were performed with 2-sided alternatives, a type I error of 0.05, and SPSS software (version 13.0).
From November 2005 to April 2006, we enrolled 20 stable patients with congestive heart failure. Baseline characteristics were similar among patients in the study groups with regard to age, etiology of heart failure, severity of left- ventricle dysfunction, medical therapy, electrolyte status, and renal function (Table 1).
Figure 1 depicts the detailed changes of urine volume and urine electrolyte changes. There was no significant difference between the 2 treatment groups during the first 3 days; however, the urine volume significantly increased from the 4th day and kept increasing with time. Sodium and chloride excretion also increased with time, which was consistent with the change of urine volume. As compared with the placebo group, urine volume peaked at the 6th day (2655.0 mL/24 h), which was 810.5 mL larger than those in the placebo group (95% CI 276.25 to 1344.86, P < 0.05). The maximum of sodium and chloride excretion peaked at the 7th day. Sodium excretion was 368.8 mmol/24 h, which was 123.8 mmol/24 h higher than those patients given placebo (95% CI 11.4 to 236.2, P < 0.05) on the 7th day. Similarly, chloride excretion was 341.7 mmol/24 h in patients receiving prednisone, which was 123.8 mmol/24 h higher than the placebo group (95% CI 11.4 to 236.24, P < 0.01) on the 7th day.
Effects on Renal Function
The creatinine excretion was consistently higher during the study period in the prednisone group compared with the placebo group. The mean difference was 1404.7 μmol/24 h (95% CI 492.2 to 2317.3, P = 0.003) during the study period, which translated into a slight improvement of renal function. The effect on change from baseline in serum creatinine was −19.5 μmol/L (95% CI −7.4 to −31.6, P < 0.01) when compared with placebo, favoring prednisone.
Effects on Serum Electrolytes
At the end of the study, there was no significant difference with regard to serum electrolytes (Table 2).
Overall, prednisone was well tolerated in the patients enrolled in the study, and no overt adverse effects were observed, which may be a result of the relatively short study period. Of note, prednisone appeared to have no impact on heart rate and blood pressure. At the end of study, the heart rate was 70.5 ± 9.4 BPM in the prednisone group versus 72.0 ± 8.6 BPM in the placebo group; systolic blood pressure was 107.5 ± 10.3 mm Hg in the prednisone group versus 108.5 ± 20.9 mm Hg in the placebo group; diastolic blood pressure was 71.0 ± 10.7 mm Hg in the prednisone group versus 68.5 ± 6.2 mm Hg in the placebo group. During the study, there was a trend that patients in the prednisone group lost slightly more body weight than those given placebo. However, the difference was not statistically significant (Fig. 1F).
To our knowledge, this is the first randomized clinical study to explore the feasibility of using prednisone as a potentiating diuretic agent in patients with stable congestive heart failure. Prednisone resulted in a striking diuresis and natriuresis and improvement of renal function.
Medical text books dictate that glucocorticoids increase tubule secretion of potassium and hydrogen ions, as well as renal tubule Na+ reabsorption, leading to fluid and sodium retention, and thus suggest that it should be used with caution in patients with heart failure. However, May and Bednarik reported that glucocorticoids had a specific renal vasculature vasodilator feature,5 which could vasodilate both the afferent and efferent resistances and resulted in an increase in glomerular plasma flow.3 Vasodilation of renal vessel by glucocorticoids was possible through enhancing NO production,6 activating endogenous renal dopaminergic mechanism.1 Animal studies also showed that glucocorticoids might have an important effect on ANP. Animal studies suggest that glucocorticoids might regulate synthesis and release of ANP4; may upregulate ANP receptors on vascular endothelial cells7; and may, at least in part, potentiate the response of cyclic guanosine monophosphate to ANP.8 A human study also suggested glucocorticoids might have a permissive effect on human ANP-mediated natriuresis and diuresis.9 Therefore, glucocorticoids might have an important effect on diuresis and natriuresis after volume expansion.2 Those mechanisms may explain the different effects of prednisone between normal subjects and patients with heart failure because patients with heart failure usually have renal vasoconstriction (from low cardiac output and sympathetic excitation) and elevated ANP levels.
There are several limitations in this study. The sample size was relatively small and the study population was clinically stable with no overt signs of fluid overload. Thus, our results should not be extrapolated to the patients with decompensated heart failure with significant volume expansion. Its role in this population remains unclear.
Our early clinical experience (unpublished observational data) showed that the effect of prednisone was dose-dependent. The dosage of prednisone we used in the study was from our clinical experience. A dose-comparison study, therefore, needs to be done to determine the preferable dose. Whether a loading dose could shorten the time to diuresis is still waiting to be confirmed in the future study.
Nevertheless, this pilot study showed that prednisone might have a striking diuresis and natriuresis in patients with congestive heart failure. Prednisone may be a promising drug in the management of patients with decompensated CHF with overt fluid retention (an example is shown in Figure 2), especially for those patients with diuretic resistance. A randomized, placebo-controlled clinical study is under way to determine its efficacy and safety profile in patients with decompensated congestive heart failure.
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