spironolactone (50 mg od), allopurinol (50 mg od), and bronchodilators (theophylline, tiotropium, and formoterol). The patient also used nocturnal noninvasive positive pressure ventilation. The last Brain natriuretic peptide and left ventricular ejection fraction obtained in the absence of signs and symptoms of congestion were 805 pg/mL and 45%, respectively.

On hospital admission, orthopnea, Pitting edema bilater- ally to the knees, and jugular vein distension were observed. The weight was 91 kg, blood pressure was 119/76 mm Hg, respiratory rate was 22 breaths per minute, and body temperature was normal.

At the cardiopulmonary auscultation, the tones were rhythmical with systolic murmur of 2/6 in the aortic area; rhonchi, diffuse wheezing, crepitations, and a reduction of murmur in pulmonary bases were also listened on.

Arterial blood gas analysis, hematology, and blood chemistry at baseline are shown in Table 1. Glomerular filtration rate (GFR) calculated by Cockroft-Gault formula was 94 mL/min.

The electrocardiography showed sinus tachycardia at 114 beats per minute with incomplete Right bundle branch block and left axis deviation (Fig. 1). The chest x-ray revealed bilateral Pleural effusions and signs of vascular redistribu- tion. Central fluid overload was also observed by thoracic ultrasound (Fig. 2). Echocardiography was of poor quality and showed the following abnormalities: severe aortic stenosis, estimated left ventricular ejection fraction of 35%, right ventricular enlargement, and inferior vena cava dilatation with impaired collapsibility. A whole-body impedance evaluation [1] (CardioEFG; Akern, Firenze, Italy) according to Biavector analysis (Akern, Firenze, Italy) was performed to assess patient’s fluid content as described by Piccoli et al [2] (Fig. 3). This examination revealed a severe fluid overload.

Initially, the patient was treated with intravenous administration of Loop diuretic (furosemide, 250 mg daily continuous) and intravenous aldosterone receptor antago- nist (spironolactone, 50 mg daily). The oral administration of ramipril and allopurinol was continued at dosages previously taken.

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During the first 3 days of treatment, we did not observe improvement in hemodynamic status. Consequently, we added intravenous methylprednisolone (60 mg/d) to diuretics based on few previous researches. After 3 days from the onset of glucocorticoids, we progressively observed an increase in daily urine volume, a decrease in weight, and a relief of signs and symptoms of congestion. Simultaneously, BNP at first increased and thereafter decreased (Fig. 4).

At discharge, GFR improved to 128 mL/mL (+26%), BNP fell from 1805 to 980 pg/mL (-45%), weight decreased to 84 kg, and Biavector showed a significant reduction of fluid status and the achievement of the normohydration state (Fig. 3). Moreover, creatinine and acid uric levels decreased, whereas urea nitrogen and serum glucose levels increased, and no changes on electrolytes were observed (Table 1).

It is well known that glucocorticoids may induce fluid and sodium retention by promoting sodium reabsorption at the level of renal tubule. In fact, they should, therefore, be used with caution in patients with ADHF, as recommended by guidelines. Conversely, few studies have demonstrated that fluid retention and renal function can improve after glucocorticoid or corticotropin administration in addition to Standard therapy [3-7]. In particular, the infusion of prednisone has been shown to exert a beneficial effect in patients with refractory ADHF [8-10].

Already, in 1959, Mickerson and Swale [7] studied 13 patients with ADHF resistant to digitalis and diuretics. They reported an enhanced response to diuretics and an improved clinical status after 3 or 4 days from the onset of prednisolone

administration. Bayliss [5] has also shown that glucocorti- coids can enhance natriuresis in congestive HF on constant sodium diet and induce the restoration of normal serum sodium levels.

The aforementioned beneficial effects seem mainly because of the improvement in renal function by a 30% to 50% increase of renal blood flow [11,12], which is mediated by largely investigated direct and indirect mechanisms.

Table 1 Arterial blood gas analysis, hematology, and blood chemistry

Baylis and Brenner [13] demonstrated that glucocorti- coid administration causes vasodilatation of the afferent and efferent arterioles in rats, resulting in an increased renal blood flow and, as a consequence, in an increase of GFR. De Matteo and May [14,15] found, in Experimental models, that the direct action of these drugs on the vascular kidney is mediated by the release of nitric oxide and vasodilator prostaglandins. Intriguingly, the vasodilatory response to glucocorticoids appears limited to the kidney, whereas it is not present in coronary, mesenteric, or iliac vascular beds [16].

The indirect effects of glucocorticoids on natriuresis and diuresis seem to be related to their influence on the natriuretic peptide system [17]. Glucocorticoids up-regulate atrial natriuretic peptide (ANP) receptors on vascular Endothelial cells [18], potentiate the response of cyclic guanosine monophosphate to ANP [19], and increase the release and synthesis of ANP [20]. In addition, they could induce plasma Volume expansion, because of sodium retention, leading to a reduction of tissue edema (shifting of tissue water along the osmotic gradient) and vasodilatation of peripheral arteries, thus, further increasing blood renal flow and GFR.

Furthermore, in the clinical setting, Liu et al [8-10] performed several studies to assess the diuretic efficacy of prednisone (1 mg/kg with maximum dosage of 60 mg/d) in patients with congestive HF with diuretic resistance and demonstrated an improvement of congestive symptoms and global clinical status. The patients treated with glucocorti- coids compared with placebo group showed an enhance- ment of renal function and an increase of urine volume output, sodium excretion, and GFR [10]. It is worth noting that the treatment was safe and that a diuretic effect was obtained after 3 days of treatment, and it kept increasing with time [10].

All these beneficial effects of corticosteroids in ADHF have been confirmed in our patient. In fact, from the clinical point of view, we confirm that glucocorticoids added to diuretic therapy improve congestion with a lag time of 3 days and that this effect is time-dependent, inducing potent diuresis with subsequent urine output of more than 4 L/d. The glucocorticoid administration also enhanced GFR and reduced creatinine. Moreover, we also found that, after starting therapy, the BNP increased and then fell at the highest urine output. This suggests that the initial effects of glucocorticoids on diuresis are indirect and mediated by the stimulation of natriuretic peptide production. In accordance with Khang et al [8], we found a decrease in uric acid and an increase in urea nitrogen and, as expected, in plasma glucose.

Fig. 1 Electrocardiogram.

It can not be excluded that an additional mechanism of the effect of glucocorticoids on renal function could be mediated by the osmotic effect of hyperglycemia.

Finally, some of these considerations suggest that the mechanisms mediating the beneficial effects of glucocorti- coids are similar to those obtained by a new therapeutical

approach to diuretic-resistant ADHF, based on the infusion of Hypertonic saline solution [21].

This report, in addition to little clinical studies, supports the potential usefulness of glucocorticoids in ADHF, suggesting its use in such diuretic-resistant cases before to think invasive treatment (ultrafiltration). In fact, this old class

Fig. 2 Lung ultrasound shows sonographic B lines, also known as lung comets, and pleural effusion.

of drugs, usually contraindicated in HF, does not have a negative impact on fluid overload in this patient. Further- more, it can paradoxically induce, with a latency of 3 days, a potent diuretic effect in addition to diuretic therapy, thus, improving clinical congestion. These effects are related to the enhanced renal function caused by several direct and indirect mechanisms, which could merit further investiga- tions with particular attention on the induced activation of

BNP. A novelty of this report is also to document the utility of glucocorticoids to achieve the normal hydration status as evaluated by Biavector. So, as well as ?-blockers in chronic HF, we ask whether glucorticoids are Dr Jekyll or Mr Hyde in Acute HF.

We hope that based on these considerations, future large, randomized, double-blind studies are evaluating the effects of these drugs on morbidity and mortality in patients with

Fig. 3 Bioimpendance vector analysis of the patient at admission (?) and discharge (?). The Biavector nomogram shows 3 tolerance ellipses, plotting resistance (R) and reactance (Xc) standardized by height (H), and includes 50%, 75%, and 95% of healthy individual points, respectively [2]. When the calculated point falls out of the lower pole of the 75% tolerance, ellipse indicates hyperhydration. At admission, the Biavector shows a severe fluid overload with estimated hydration of free fat mass of 88.4%. At discharge, the calculated point falls in the 50% tolerance ellipse, indicating a normal tissue hydration (73.6% of free fat mass).

ADHF. Further researches are also needed to discover the Pathophysiologic mechanisms of the glucocorticoid effec- tiveness on the intricate cardiorenal interactions.

Acknowledgment

We would like to thank Paolo Berloco for his technical assistance.

Fig. 4 Trends of diuresis, weight, and BNP. Dashed line indicates the start of intravenous glucocorticoid.

Daniele Torres, MD Gaspare Parrinello, MD, PhD

Dipartimento Biomedico di Medicina Interna e Specialistica

Universita degli studi di Palermo

Palermo, Italy E-mail address: [email protected]

doi:10.1016/j.ajem.2011.01.023

Francesco Massari, MD

Cardiologia-UTIC, ASL BA, Altamura, Bari, Italy

Filippo Mastropasqua, MD

Divisione di Cardiologia Fondazione “Salvatore Maugeri“, Cassano Murge

Bari, Italy

Massimo Iacoviello, MD, PhD

Istituto di Cardiologia, Universita di Bari, Italy

Vincenzo Nuzzolese, MD

Cardiologia-UTIC, ASL BA, Altamura, Bari, Italy

References

1. Massari F, Mastropasqua F, Guida P, De Tommasi E, Rizzon B, Pontraldolfo G, et al. Whole-body bioelectrical impedance analysis in patients with chronic heart failure: reproducibility of the method and effects of body side. Ital Heart J 2001;2:594-8.
2. Piccoli A, Rossi B, Pillon L, Bucciante GA. New method for monitoring body fluid variation by bioimpedance analysis: The RXc graph. Kidney Int 1994;46:534-9.
3. Dresdale DT, Greene MA, Guzman SV. Clinical and hemodynamic effects of cortisone in patients with rheumatic heart disease and congestive heart failure. Am Heart J 1958;55:851-66.
4. Gutner LB, Moses JB, Dann S, Kupperman HS. The use of prednisone in congestive heart failure. Am J Med Sci 1957;234: 281-6.
5. Bayliss R. Corticosteroids in heart disease. Br Med J 1966;2: 721-4.
6. Camara AA, Schemm FR. Corticotropin (ACTH) in heart disease: its paradoxical effect on sodium excretion in resistant congestive failure. Circulation 1955;11(5):702-10.
7. Mickerson JN, Swale J. Diuretic effect of Steroid therapy in obstinate heart failure. Br Med J 1959;1(5126):876-83.
8. Khang H, Liu C, Ji Z, Liu G, Zhao Q, Ao Y, et al. Prednisone adding to usual care treatment for refractory decompensated congestive heart failure. Int Heart J 2008;49:587-95.
9. Liu C, Liu G, Zhou C, Ji Z, Zhen Y, Liu K. Potent diuretic effects of prednisone in heart failure patients with refractory diuretic resistance. Can J Cardiol 2007;23:865-8.
10. Liu C, Chen H, Zhou C, Ji Z, Liu G, Gao Y, et al. Potent potentiating diuretic effects of prednisone in congestive heart failure. J Cardiovasc Pharmacol 2006;48:173-6.
11. Raisz LG, Mcneely WF, Saxon L, Rosenbaum JD. The effects of cortisone and hydrocortisone on water diuresis and renal function in man. J Clin Invest 1957;36:767-79.
12. Pechet MM, Bowers B, Bartter FC. Metabolic studies with a new series of 1, 4-diene steroids. II. Effects in normal subjects of prednisone, prednisolone, and 9 alpha-fluoroprednisolone. J Clin Invest 1959;38:691-701.
13. Baylis C, Brenner BM. Mechanism of the glucocorticoid-induced increase in glomerular filtration rate. Am J Physiol 1978;234: F166-1670.
14. De Matteo R, May CN. Glucocorticoid-induced renal vasodilatation is mediated by a direct renal action involving nitric oxide. Am J Physiol 1997;273:R1972-9.
15. De Matteo R, May CN. Inhibition of prostaglandin and nitric oxide synthesis prevents cortisol-induced renal vasodilatation in sheep. Am J Physiol 1999;276:R1125-31.
16. Bednarik JA, May CN. Differential regional hemodynamic effects of corticotropin in conscious sheep. Hypertension 1994;24:49-55.
17. Damjancic P, Vierhapper H. Permissive action of glucocorticoid substitution therapy on the effects of atrial natriuretic peptide (hANP) in patients with adrenocortical insufficiency. Exp Clin Endocrinol 1990;95:315-21.
18. Lanier-Smith KL, Currie MG. Effect of glucocorticoids on the binding of atrial natriuretic peptide to endothelial cells. Eur J Pharmacol 1990; 178:105-59.
19. Kanda K, Ogawa K, Miyamoto N, Hatano T, Seo H, Matsui N. Potentiation of atrial natriuretic peptide-stimulated cyclic guanosine monophosphate formation by glucocorticoids in cultured rat renal cells. Br J Pharmacol 1989;96:795-800.
20. Garcia R, Debinski W, Gutkowska J, Kuchel O, Thibault G, Genest J, et al. Gluco- and mineralocorticoids may regulate the natriuretic effect and the synthesis and release of atrial natriuretic factor by the rat atria in vivo. Biochem Biophys Res Commun 1985;131:806-14.
21. Paterna S, Di Pasquale P, Parrinello G, Fornaciari E, Di Gaudio F, Fasullo S, et al. Changes in brain natriuretic peptide levels and bioelectrical impedance measurements after treatment with high-dose furosemide and hypertonic saline solution versus high-dose furose- mide alone in refractory congestive heart failure: a double-blind study. J Am Coll Cardiol 2005;45(12):1997-2003.