Strategy for monitoring decompensated heart failure treated by an oral vasopressin antagonist with special reference to the role of serum chloride: A case report

Abstract

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.

<Learning objective: The present case of heat failure therapy using a vasopressin antagonist highlights the importance of monitoring serum chloride concentration in relation to changes in the hemoglobin (to evaluate intravascular volume) and mean red cell volume (to estimate intracellular fluid status) in addition to changes in body weight.>

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 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%), non-dilated 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 initially treated with loop diuretics (60 mg azosemide and 25 mg spironolactone every morning) to control body fluid retention and β-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 β-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 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 re-administer 60 mg azosemide every morning and the patient's symptoms improved gradually thereafter.

Table 1.

Findings of the study patient.

	Out patient		In hospital
	July 10	31	August 21	24	25	26	28	Sept 4	7	11
Body weight (kg)	38.2	38.1	39.6	–	–	–	36.4	39	38.8	–
Urine output (cc)	–	–	–	1150	1200	1000	980	1200	600	1820
Blood pressure (mmHg)	97/68	109/73	98/78	107/77	117/79	109/68	111/69	96/71	97/75	103/79
Heart rate (bpm)	–	61	82	55	85	79	84	62	92	54
HF related symptoms
Dyspnea	NYHA II	NYHA II	NYHA III	–	–	–	NYHA II	NYHA III	–	NYHA II
Physical findings
Wheezing on lung auscultation	Absent	Absent	Mild	Mild	–	–	Absent	Absent	Mild	Absent
Distribution of edema	Pedal	Pedal	Systemic	Systemic	–	–	Absent	Systemic	Systemic	Absent
Pleural effusion by ultrasound	Absent	–	–	–	–	–	Absent	–	Moderate	–
Peripheral blood findings
Hemoglobin (g/dL)	14.2	14.1	14.1	15.1	–	13.9	13.1	12.3	11.9	12.7
Hematocrit (%)	41.5	40.3	39.7	42.5	–	40.1	39	37.2	36	37.6
Mean red cell volume (fL)	87	85	83	83	–	85	88	89	91	89
Total protein (g/dL)	–	6.3	5.7	–	–	–	5.8	–	5.4	5.6
Albumin (g/dL)	–	3.6	3.1	–	–	–	3.1	–	2.8	2.7
Electrolytes (mEq/L)					–
Sodium	134	–	125	126	–	135	140	136	140	140
Potassium	4.2	–	5	4.3	–	4	4.3	5	4.6	3.9
Chloride	96	–	87	85	–	98	104	102	108	104
Blood urea nitrogen (mg/dL)	25	17	23	39	–	44	32	27	21	27
Creatinine (mg/dL)	1.13	0.91	1.01	1.15	–	1	0.91	0.91	0.85	0.91
B-type natriuretic peptide (pg/mL)	573	–	661	–	–	–	593	–	1014	749
Loop diuretic
Azosemide	Azosemide 60 mg								Azosemide 60 mg
Mineralocorticoid antagonist
Spironolactone	Spironolactone 25 mg
Vasopressin antagonist
Tolvaptan					Tolvaptan 7.5 mg → 15 mg

HF, heart failure.

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.

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.

	r	p value
Chloride (mEq/L)
Hemoglobin (g/dL)	−0.898	0.0025
Serum creatinine (mg/dL)	−0.826	0.012
Mean red cell volume (fL)	0.946	0.0004
Sodium (mEq/L)
Hemoglobin (g/dL)	−0.795	0.018
Serum creatinine (mg/dL)	−0.729	0.04
Mean red cell volume (fL)	0.901	0.002

Fig. 1.

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

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 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 as-yet 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 re-distribution 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 Table 1, Table 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.