Strategy for monitoring decompensated heart failure treated by an oral ...

Journal of Cardiology Cases 14 (2016) 185–188

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Case Report

Strategy for monitoring decompensated heart failure treated by an oral vasopressin antagonist with special reference to the role of serum chloride: A case report Hajime Kataoka (MD)1,*, Yu Yamasaki (PhD)1 Division of Internal Medicine and Pharmacy, Nishida Hospital, Oita, Japan

A R T I C L E I N F O

A B S T R A C T

Article history: Received 12 May 2016 Received in revised form 3 July 2016 Accepted 15 August 2016

Compared with conventional diuretic therapy, monitoring decompensated heart failure (HF) under treatment with a vasopressin antagonist is problematic because (1) use of this medication usually allows the patient free water intake to prevent drug-induced hypernatremia and (2) this medication often induces only minimal changes in the hemodynamics and blood concentration. In a 68-year-old female HF patient, use of tolvaptan did not induce much change in the urine output, presumably because of the low water intake due to a lack of thirst, but she did achieve a profound weight loss. Both the changes in chloride and sodium were negatively correlated with changes in the hemoglobin and serum creatinine, and positively correlated with changes in the mean red blood cell volume, but changes in the serum chloride were better correlated with each variable than were changes in the serum sodium. ß 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Keywords: Heart failure Chloride Diuretics Tolvaptan Vasopressin antagonist

Introduction In heart failure (HF) patients with hypervolemic hyponatremia, an oral vasopressin V2-receptor antagonist, such as tolvaptan, induces aquaresis in the kidney and a subsequent increase in the serum sodium concentration [1]. Fluid removal with a vasopressin receptor antagonist beneficially occurs with sparing or improvement of renal blood flow and the glomerular filtration rate, relative to treatment with a loop diuretic [2]. Compared with conventional diuretic therapy, monitoring of decompensated HF patients under treatment with a vasopressin antagonist is problematic, however, because this medication (1) usually allows a patient free water intake to prevent drug-induced hypernatremia and (2) often induces minimal changes in hemodynamics and blood concentration [3,4]. Therefore, it is important to elucidate suitable methods for monitoring HF patients during treatment with a vasopressin antagonist. In HF status, alterations in body fluid accompany

* Corresponding author at: Department of Internal Medicine, Nishida Hospital, Tsuruoka-Nishi-Machi 2-266, Saiki-City, Oita 876-0047, Japan. Fax: +81 972 23 3053. E-mail address: [email protected] (H. Kataoka). 1 These authors contributed equally to this work.

changes in both the extracellular and intracellular fluid volumes. Treatment of HF patients requires clinical evaluation and monitoring of changes in each volume. We recently demonstrated that, in HF patients, serum chloride (Cl) is a key osmolyte for the regulation of intracellular volume [5] and distribution of body fluid between each compartment of extracellular and intravascular spaces [6]. Herein, we report the case of an HF patient treated with a vasopressin antagonist that highlights the importance of monitoring changes in serum Cl concentration in relation to changes in plasma hemoglobin to evaluate intravascular volume and changes in mean red blood cell volume (MCV) to estimate intracellular volume. Case report A 68-year-old female, being treated for hypertension by another clinic, first visited (October, 2014) our outpatient clinic 9 months prior to the present admission because of the onset of decongestive HF. Cardiac examination revealed diastolic dysfunction of the preserved left ventricular ejection fraction (49%), nondilated diastolic volume (133 cc), and moderate mitral and tricuspid regurgitation. A 12-lead electrocardiogram revealed atrial fibrillation with a heart rate of 110 beats/min. She was

http://dx.doi.org/10.1016/j.jccase.2016.08.005 1878-5409/ß 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

H. Kataoka, Y. Yamasaki / Journal of Cardiology Cases 14 (2016) 185–188

186 Table 1

Findings of the study patient. Out patient

Body weight (kg) Urine output (cc) Blood pressure (mmHg) Heart rate (bpm) HF related symptoms Dyspnea Physical findings Wheezing on lung auscultation Distribution of edema Pleural effusion by ultrasound Peripheral blood findings Hemoglobin (g/dL) Hematocrit (%) Mean red cell volume (fL) Total protein (g/dL) Albumin (g/dL) Electrolytes (mEq/L) Sodium Potassium Chloride Blood urea nitrogen (mg/dL) Creatinine (mg/dL) B-type natriuretic peptide (pg/mL) Loop diuretic Azosemide Mineralocorticoid antagonist Spironolactone Vasopressin antagonist Tolvaptan

In hospital

July 10

31

August 21

24

25

26

28

Sept 4

7

11

38.2 – 97/68 –

38.1 – 109/73 61

39.6 – 98/78 82

– 1150 107/77 55

– 1200 117/79 85

– 1000 109/68 79

36.4 980 111/69 84

39 1200 96/71 62

38.8 600 97/75 92

– 1820 103/79 54

NYHA II

NYHA II

NYHA III

–

–

–

NYHA II

NYHA III

–

NYHA II

Absent Pedal Absent

Absent Pedal –

Mild Systemic –

Mild Systemic –

– – –

– – –

Absent Absent Absent

Absent Systemic –

Mild Systemic Moderate

Absent Absent –

14.2 41.5 87 – –

14.1 40.3 85 6.3 3.6

14.1 39.7 83 5.7 3.1

15.1 42.5 83 – –

13.9 40.1 85 – –

13.1 39 88 5.8 3.1

12.3 37.2 89 – –

11.9 36 91 5.4 2.8

12.7 37.6 89 5.6 2.7

134 4.2 96 25 1.13 573

– – – 17 0.91 –

125 5 87 23 1.01 661

126 4.3 85 39 1.15 –

– – – – – – – – – – – –

135 4 98 44 1 –

140 4.3 104 32 0.91 593

136 5 102 27 0.91 –

140 4.6 108 21 0.85 1014

140 3.9 104 27 0.91 749

Azosemide 60 mg

Azosemide 60 mg Spironolactone 25 mg Tolvaptan 7.5 mg ! 15 mg

HF, heart failure.

initially treated with loop diuretics (60 mg azosemide and 25 mg spironolactone every morning) to control body fluid retention and b-blockade (10 mg carvedilol twice daily) for control of heart rate and blood pressure. The subsequent clinical course was uneventful up to the present admission and her serum B-type natriuretic peptide (BNP) levels fluctuated between 241 and 573 pg/mL without worsening of HF status except for occasional mild pedal edema. Owing to worsening of the HF and progressive hyponatremia, she was admitted to our hospital on August 21, 2015. Clinical course and physical signs, peripheral blood, serum electrolytes, and measurement of BNP are shown in Table 1. Upon admission, she complained of a mild dyspneic sensation at rest and her body weight had increased by 1.5 kg compared to that at a recent outpatient clinic visit (July 31, 2015). Physical examination revealed mild systemic edema and bronchial wheezing on chest auscultation. Upon admission, the dosage of a b-blocker was reduced (2.5 mg carvedilol twice daily) due to progressive hypotension. To correct the overhydrated hyponatremia, we discontinued the azosemide and initiated oral administration of tolvaptan on August 25. The dose of tolvaptan was 7.5 mg on day 1, and increased the following day to 15 mg every morning. This

Table 2

Correlations between changes in serum chloride or sodium and changes in hemoglobin, serum creatinine, and mean red cell volume during the clinical course.

Chloride (mEq/L) Hemoglobin (g/dL) Serum creatinine (mg/dL) Mean red cell volume (fL) Sodium (mEq/L) Hemoglobin (g/dL) Serum creatinine (mg/dL) Mean red cell volume (fL)

r

p value

0.898 0.826 0.946

0.0025 0.012 0.0004

0.795 0.729 0.901

0.018 0.04 0.002

medication did not noticeably increase the patient’s urine volume, but modestly reduced her body weight by 3 kg and resolved the systemic edema within 3 days of beginning the treatment. During this period, the serum sodium and Cl concentrations concomitantly increased to a normal range and the hemoglobin concentration gradually decreased. The patient’s dyspneic sensation improved, but her serum BNP level did not change significantly (from 661 to 593 pg/mL). Seven days after initiating the tolvaptan treatment (September 4), she complained of dyspnea and presented with systemic edema, a concomitant body weight gain of 2.6 kg, and an increase in the serum BNP level to 1014 pg/mL. We began to readminister 60 mg azosemide every morning and the patient’s symptoms improved gradually thereafter. Table 2 shows the correlations between changes in serum Cl or sodium and changes in hemoglobin, serum creatinine, and MCV during the clinical course. Both the changes in Cl or sodium were negatively correlated with changes in the hemoglobin and serum creatinine, and positively correlated with changes in the MCV, but changes in the serum Cl (Fig. 1) were better correlated with each variable than were changes in the serum sodium. Discussion Under the usage of a vasopressin receptor blockade in HF patients, monitoring of urine volume alone may have a limited value because this medication allows for the patient’s free water intake to prevent drug-induced hypernatremia. In such cases, monitoring the change in body weight would be more advantageous because fluid is the body component with the ability to undergo the most rapid change, so a substantial change in body weight over a short period would relate most directly to fluid status [7]. In our patient, use of tolvaptan did not induce much change in the urine output, presumably because of the low water intake due to a lack of thirst, but she did achieve a profound weight loss, indicating that monitoring changes in body weight is more


Fig. 1.

187

Correlation of serum chloride (Cl) to: (a) hemoglobin (Hb); (b) serum creatinine (Cr); and (c) mean red cell volume (MCV) during the clinical course.

useful than monitoring urine volume. Of course, monitoring urine output is always important, and, in conjunction with body weight monitoring, would give more valuable information regarding the clinical course of HF [8]. When the intended effects of conventional diuretics are achieved, hemoconcentration often occurs as well, so the diuretic effect can be monitored by measuring indexes of plasma volume, such as hemoglobin, hematocrit, and %plasma volume [9]. The ‘‘aquaretic’’ effect of vasopressin receptor blockade, however, is accompanied by minimal changes in the plasma volume by an asyet unknown mechanism and therefore a persistent burden may be placed on the failing heart after therapy [3], thus making it difficult to monitor the HF patient based on the changes in the serum BNP [2] and indexes of plasma volume and hemodynamics [4], so we emphasize again the importance of body weight monitoring under HF treatment by vasopressin receptor blockade. As for the pharmacologic effects, it is appropriate to consider the mechanism(s) of the persistent burden to the failing heart after aquaresis using a vasopressin V2-receptor antagonist. We recently demonstrated that vascular expansion during worsening HF is associated with the changes in the serum Cl concentration. As a key osmolyte, greater accumulation of Cl in the blood vessels might act to increase or maintain intravascular volume [6]. This relationship was also observed in the patient reported here, as shown in Table 2 and Fig. 1(a). Ordinarily, use of tolvaptan induces aquaresis and results in the elevation of serum sodium and, presumably elevation of serum Cl concentrations [10]. Considering the role of serum Cl that we have reported [6], the consequence of serum Cl concentration elevation induced by tolvaptan would cause a redistribution of body fluid after diuresis, such as an increase or maintenance of plasma volume, and probably drainage of fluid from the interstitial space due to changes in the serum osmolality [11]. Thus, while maintaining plasma volume might be beneficial for preserving blood supply to the kidney (Fig. 1(b)) and other organs, the persistent burden to the failing heart should be kept in mind when monitoring HF patients based on changes in serum BNP and hemodynamic parameters. Indeed, during tolvaptan administration in our patient, hemoconcentration did not occur and the change in BNP was minimal even after drug-induced optimal diuresis determined by the body weight reduction and concomitant resolution of HF-related symptoms and signs [8], indicating that the burden to the failing heart persisted after adequate aquaresis. In the case of a persistent cardiac burden after suitable diuretic therapy, other strategies for reducing cardiac burden would be required in addition to treatment of intrinsic heart disease and kidney dysfunction. We recently reported that MCV serially changes according to the transition of HF status, presumably reflecting the intracellular fluid status, and that serum Cl is the key osmolyte for the regulation of MCV [5]. Thus, it is necessary to pay attention to changes in the MCV during HF monitoring and treatment, as shown in Tables 1 and 2 and Fig. 1(c). On the basis of our recent

observations [5], MCV under transition of HF is affected by serum Cl. If changes in MCV reflect total body fluid movement between the intracellular and transcellular spaces, a substantial fluid shift might be induced by changes in the serum Cl concentration under diuretic therapy. Finally, the present case report suggests that, considering the possible central role of Cl in the distribution of body fluid in HF status [5,6,12], modulation of the serum Cl concentration could become an attractive therapeutic target for HF treatment, such as for reducing serum Cl concentration using conventional diuretics [13], and for enhancing serum Cl concentration using a V2-receptor antagonist [1,10] and hyperosmotic saline infusion [14]. Modulation of serum chloride could induce not only vascular volume changes, but also a fluid shift between the extracellular and intracellular spaces. In conclusion, on the basis of our recent observations [5,6,12], the present case highlights the importance of monitoring serum Cl concentration in HF patients treated with a vasopressin V2-receptor antagonist. Of course, the notion reported here should be confirmed in many HF patients under various situations such as differences in the sex, age, etiology, and type of HF. It is also reasonable to explore the HF pathophysiology, including effects of a V2-receptor antagonist for HF, based on the Cl dynamics because Cl is an established key electrolyte for tubuloglomerular feedback in the kidney [15].

Conflict of interest None.

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