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Vasopressin antagonist efficacy and safety in volume-overloaded critically ill patients: a new therapeutic alternative
  1. Jesús Ruiz-Ramos1,
  2. Paula Ramírez2,
  3. María Jesús Broch2,
  4. Mónica Gordon2,
  5. Esther Villarreal2,
  6. Armando Pinos2,
  7. Manuel Sosa2,
  8. Álvaro Castellanos-Ortega2
  1. 1 Pharmacy Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain
  2. 2 Intensive Care Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain
  1. Correspondence to Dr Paula Ramírez, Intensive Care Unit, Hospital Universitario y Politécnico La Fe, Valencia 46026, Spain; ruiz_jesram{at}


Objectives To assess tolvaptan’s efficacy and safety in critical care patients with volume overload.

Methods Prospective observational study. Twenty-eight patients in the recovery phase from multiple organ failure and with volume overload refractory to conventional therapy treated with tolvaptan were included.

Results Patients received an initial daily dose of 3.75 (n=1), 7.5 (n=8) and 15 (n=19) mg of tolvaptan. Median treatment duration was 2 days (range: 1 to 12). All patients presented an increase in 24 hours diuresis after the first dose (median increase from baseline (IQR)=1114 (285–1943) mL), with a median net daily fluid loss of 1007 mL (456–2380) mL after 24 hours. High diuretic efficacy (daily fluid loss higher than 0.5 L with tolvaptan first dose) was detected in 18 patients (64.3%). Initial hyponatraemia was present in 16 (57.1%) patients, while overly rapid correction with tolvaptan treatment occurred in two patients without clinical consequences. Two patients presented hypophosphataemia after treatment.

Conclusion Tolvaptan is an effective therapeutic option in critically ill patients with volume overload refractory to conventional diuretics. Further studies are required to evaluate its safety profile and its effect on short-term outcomes and mortality.

  • tolvaptan
  • critical care
  • fluid balance
  • diuretics
  • edema
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Fluid therapy plays an essential role in the acute resuscitation phase of critically ill patients.1 2 Almost all intensive care unit (ICU) patients receive considerable amounts of fluid therapy during an episode of critical illness, either intentionally through a strategy of aggressive volume expansion or secondarily as carriers for vasopressors, antibiotics or nutrition. Two circumstances often concur with this situation. First, acute kidney injury that impairs free water and solute excretion, and almost universally contributes to the development of a positive water balance. Second, oncotic pressure reduction and increase of capillary permeability in the critically ill patient will determine the appearance of generalised oedema that hampers water management.2

Different studies have shown that tissue oedema could potentially contribute to a progressive organ dysfunction.3 4 In fact, different authors have found a relationship between negative fluid balance and an improvement in survival rates in critically ill patients.5–8 Therefore, after an initial resuscitation phase, the efforts of the medical team are directed towards taking out fluid overload. Loop diuretics are considered a key treatment in controlling fluid overload in these patients. However, these drugs are not always effective and several side effects have been described, including renal dysfunction, metabolic alkalosis or electrolyte abnormalities due to losses in the urine.9 Due to treatment failure some volume overload patients are finally subjected to renal replacement therapies.

Vaptans are vasopressin V2-receptor antagonists, yielding to an increased electrolyte-free water excretion.10 Tolvaptan has been approved for the treatment of adult patients with hyponatraemia due to inappropriate antidiuretic hormone secretion syndrome (SIADH). However, some studies have reported good results in patients with volume overload (chronic heart failure) resistant to conventional diuretic treatment.11 12

The aim of this report is to describe our initial experience with tolvaptan in terms of effectiveness and safety in critically ill patients with volume overload resistant to conventional diuretic treatment.


Study design and inclusion criteria

We performed a prospective observational study in a 24-bed medical ICU of a 1200-bed university hospital during 18 months. Patients fulfilling the following criteria were eligible for the study: patients admitted to the ICU and in the recovery phase from multi-organ failure; volume overload refractory or intractable with conventional diuretic treatment; patients older than 18 years old; and informed consent obtained. Patients with one or more exclusion criteria were excluded, including: hypernatraemia (>145 mEq/L); and renal replacement therapy.

Data collection protocol

The following data were collected at study inclusion: sex, co-morbidities, severity scores (Acute Physiology and Chronic Health Evaluation Score-II (APACHE-II)) and Sepsis-related Organ Failure Assessment Score (SOFA)), fluid balance and organ function. Tolvaptan duration and dosage, treatment response, ICU length of stay and ICU and in-hospital mortality were recorded. Analytical control of ions and renal function parameters were performed before starting treatment with tolvaptan and daily until 7 days after receiving tolvaptan.


Volume overload: As in previous studies, we defined volume overload as a cumulative fluid balance that would be expected to increase the patient’s body weight by 10% or more in relation to ICU admission weight.4 13 14 For example, if the patient’s weight at ICU admission was 60 kg and the patient had a positive fluid balance of 6 L or more, they would meet volume overload criteria.

Refractoriness to conventional diuretic treatment: Those patients who do not reverse volume overload status despite conventional diuretic treatment (at least 40 mg of intravenous furosemide daily or equivalent).15

Tolvaptan responders (diuretic efficacy): Consensus definition for diuretic response is lacking.16 As in the studies of Testani et al,15 we considered as ‘high responders’ those patients with an average net daily fluid loss higher than 0.5 L after the first dose of tolvaptan.

Safety parameters

The rate of hyponatraemia correction was examined. An overly rapid hyponatraemia correction was defined as an increase in plasmatic (Na+)≥12 mmol/L after 24 hours.17 We also searched for adverse reactions resulting from hypovolaemia such as haemodynamic compromise and effects on serum analytical parameters and renal function.

Statistical analysis

Data are represented as mean values (SD) or median (IQR). The Wilcoxon signed-rank test was used for the comparison of variables between baseline and 24 hours, 3 and 7 days after tolvaptan administration.

Data were collected from the medical charts. Statistical analysis was performed with Stata/SE 12.0 (StataCorp, College Station, TX, USA) statistical software. For all comparisons, P<0.05 value was considered statistically significant.

The study had the approval of the Biomedical Research Ethics Committee of the Hospital La Fe (Ref: PGR-TOV-2018–01). An internal protocol for the use of tolvaptan ‘off-label’ in these patients was previously approved by the local Pharmacy and Therapeutic Committee.


Description of the population and tolvaptan treatment

From June 2014 to January 2016, 28 patients were included in the study. Characteristics and outcomes of patients are shown in table 1. All patients met volume overload criteria. Shock (septic or cardiogenic) was the mean diagnosis at ICU admission (n=19; 67.9%). Patients had been admitted to ICU for a mean of 12 days (range: 1–58)) before tolvaptan was started. Twenty-four (85.7%) patients received intravenous furosemide previous to tolvaptan treatment (median dose: 66 mg (40–250 mg)). In the other four patients, furosemide treatment was contraindicated, three of them due to previous nephropathy and one of them due to allergic reaction.

Table 1

Characteristics and outcomes of patients receiving tolvaptan

Tolvaptan initial daily dose was 3.75 (n=1), 7.5 (n=8) or 15 (n=19) mg. Dose was increased in five (17.8%) patients from 7.5 mg to 15 mg. Median treatment duration was 2 days (range: 1 to 12).

Clinical efficacy of tolvaptan

Eighteen patients (64.3%) were classified as high responders. Eight (28.6%) patients had an average net daily fluid loss <0.5 L and in two (7.1%) patients' positive fluid balance was observed despite tolvaptan administration. Fluid loss (negative fluid balance) was present not only at day 1 (mean fluid balance variation (IC95%): −1066(−1905 to −350) mL), but also at day 3 (-1013 (−1881 to −144) mL), and at day 7 (-475 (−1805 to +855) mL) (figure 1), reaching statistically significant differences between day 0 and day 1.

Figure 1

Time-course of change in daily fluid balance (mL/24 hours). *:P<0.01 (Wilcoxon signed-rank test).

Twenty-four hours' urinary volume was significantly increased compared with baseline in 25 patients (89.3%) at day 1 (+1069 (627–1511) mL), in 21 patients (75.0%) at day 3 (+1138 (505–1772) mL), and in 19 patients (67.9%) at day 7 (+745 (229–1171) mL).

Change in the serum sodium concentration

Serum sodium increased from baseline at day 1 (median (IQR):+3.5 (−0.8 to 5.5) mEq/L; P=0.091), at day 3 (+6.5 (4.0–9.5); P=0.019) and at day 7 (+8.0 (1.3–10.5) mEq/L, P=0.017)). Hyponatraemia was present in 16 (57.1%) patients (defined as serum sodium levels<135 mEq/L) at baseline. In 10 of them, hyponatraemia was corrected at the end of treatment. Two (7,1%) patients with initial hyponatraemia presented a rapid correction of serum sodium levels after a 15 mg tolvaptan dose without neurological symptoms sequels.

Time-course of changes in serum sodium levels in patients with and without hyponatraemia at the baseline is shown in figure 2. In patients with normonatraemia, serum sodium levels did not change significantly at the end of treatment compared with the baseline (mean (SD): 140.4 (1.2) vs 144.6 (2.7) mEq/L; P=0.103), whereas in patients with hyponatraemia, serum sodium levels significantly increased after treatment (126.9 (5.6) vs 136.3 (2.5) mEq/L; P=0.009).

Figure 2

Time-course of changes in serum sodium levels (mEq/L). Values are shown as mean ±SD deviation.

No significant differences were found in 24 hours' fluid balance variation between patients with and without baseline hyponatraemia (−1528 (827) vs −1165 (496) mL, P=0.283).

Discontinuation of tolvaptan and adverse reactions

No other significant variations in analytical parameters were observed during treatment (table 2). Two patients (7.1%) presented hypophosphataemia (<2.5 mg/dL) after treatment. Four patients (14.3%) required the application of renal replacement therapy after tolvaptan treatment: one of them was initially considered a ‘high responder’. In all cases, haemofiltration was initiated during the first week after the end of treatment (range: 1 to 5 days) as a result of fluid retention and worsening renal function. No other adverse events were observed during tolvaptan treatment.

Table 2

Patients' laboratory data


Our study demonstrates the aquaretic efficacy and the good safety profile of tolvaptan in critically ill patients with refractory fluid overload.

The administration of large amounts of fluids in the acute phase of critical illness is often unavoidable, leading to a positive fluid balance. Regrettably, fluid overload has been related to higher mortality rates in critically ill patients.7 18 High furosemide dose administration is a common therapy in this situation but in a significant number of patients it is unable to reverse this process and it has been associated with several adverse effects, including renal failure.19 However, nowadays there are no effective alternatives for these patients except for renal replacement therapies.

Tolvaptan’s aquaretic effect has been approved for SIADH treatment (hyponatraemia correction) and also for volume overload conditions such as congestive heart failure (USA) and cirrhosis (Japan).20 21 However, the experience with tolvaptan in critical care patients is still limited. Umbrello et al reported a positive initial experience with tolvaptan in 38 critically ill patients with hyponatraemia.22 In their study, a significant reduction in fluid balance was observed. Similarly we reported a striking increase in diuresis in six volume- overload patients.23

Regardless of initial plasmatic sodium levels we have now observed a safe and potent aquaretic effect of tolvaptan where conventional diuretics had previously failed. As in previous reports we observed an important degree of variability of diuretic response after tolvaptan administration, even though more than half of the patients could be considered as high responders. Treatment duration was short in most of the cases signalling that tolvaptan’s effect was used to get a negative water balance promptly, but not as a continuous treatment. Clinical and prognosis implications of tolvaptan treatment should be investigated in a proper clinical trial.

The small number of patients included did not allow us to investigate potential predictors of tolvaptan response. Initial low plasma and urine sodium levels have been associated with tolvaptan response.22 24 25 This fact has been associated with the degree of arginine vasopressin activation. A negative correlation with urea has also been reported,26 as hypouraemia is a known feature of SIADH.27 The small number of patients included in our study precludes proper analysis of this association.

Two hyponatraemic patients experienced an overly rapid plasma sodium increase (>12 mEq in 24 hours) after a 15 mg dose. Rapid correction of hyponatraemia has been associated with iatrogenic risk of brain damage, especially in those patients with very low initial serum sodium concentration.17 Given the wide variability effect of tolvaptan over diuretic effect as well as increasing sodium levels, a low dose (7.5 mg) should be considered as initial dosage in these patients, especially in those with severe hyponatraemia, and a narrow analytical monitoring is recommended.

The main limitation of the present study is the small and heterogeneous sample population. This fact has prevented a proper evaluation of the potential adverse effects of tolvaptan in this group of patients. However, we have succeeded in our main objective, which was to demonstrate tolvaptan’s efficacy in terms of aquaresis as well as its security profile in a real-life scenario. On the other hand, refractoriness to conventional diuretic was defined with a lower dose of furosemide than usually used in many critically ill patients. As definition of refractoriness is lacking, the dose used by Testani et al15 has been included, defined as the dose that produces maximal instantaneous natriuresis in a healthy volunteer. However, it should be noticed that the mean intravenous furosemide dose previously received to tolvaptan administration was higher than 60 mg, which means that most of the patients received an important dose of loop diuretics without an appropriate response.


According to our short experience, tolvaptan’s aquaretic nature has opened a new possibility in the treatment of fluid overloaded critically ill patients. However, further studies are required to evaluate the effect of tolvaptan on short-term outcome and mortality in critically ill patients with volume overload.

What this paper  adds

What is already known on this subject

  • The administration of large amounts of fluids frequently leads to a positive fluid balance in critically ill patients. Tolvaptan, a vasopressin V2 antagonist, has showed good results in patients with volume overload resistant to conventional diuretic treatment. However, the information about tolvaptan effectiveness in critically ill patients is scarce.

What this study adds

  • In a small number of patients, we demonstrate that tolvaptan has a good effectiveness profile in critically ill patients, without clinical relevant adverse events.

  • Tolvaptan should be considered as an alternative option in patients with volume overload refractory to conventional diuretics.


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  • EAHP Statement 4: Clinical Pharmacy Services.

  • Contributors JR-R participated in the design of the study, data collection and performed the statistical analysis. PR was responsible for the coordination of the study, participated in its design and helped to draft the manuscript. AP and MS participated in data collection. EV and MG participated in the design of the study and statistical analysis. MJB and AC-O participated in its design, coordination and review of the manuscript. All authors read and approved the final manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests PR and MJB have participated in training courses with funding from the laboratory Otsuka Pharmaceutical Europe.

  • Patient consent Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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