Introduction
Treatment of congestive events remains an important aspect of modern treatment of heart failure (HF) and is mainly limited to taking loop diuretics. The European Society of Cardiology suggests using early and repeated assessment of sodium content in urine in patients admitted with HF to evaluate diuretic therapy [1]. However, these recommendations are based mainly on the results of observational studies and the experts’ opinion [1, 2].
Taking into account the mechanism of action of loop diuretics, natriuresis can be a sensitive, objective and reliable marker for evaluating the response to diuretic therapy. A number of studies have shown that insufficient natriuretic response in patients with acute decompensation of chronic heart failure (ADCHF) was associated with an increased risk of adverse outcomes [3, 4, 5]. Moreover, an early assessment of natriuresis (1–2 hours after the start of taking loop diuretics) is an accurate marker of insufficient use of diuretics during hospitalization [6]. The PUSH-AHF study showed that enhanced diuretic therapy under the control of natriuresis, compared with standard treatment, improves natriuresis and diuresis within 48 hours, without affecting all-cause mortality and/or the frequency of hospitalization with HF for 180 days in patients with CHF [7].
Objective
Evaluation of the effectiveness of the algorithm for diuretic therapy under the control of natriuresis in patients with acute decompensation of chronic heart failure (ADCHF) in the intensive care unit (ICU).
Materials and methods
A prospective controlled non-randomized single-center study was conducted in the Intensive Care Unit (ICU) of the Clinical Hospital named by V.V. Vinogradov. The study was approved by the local Ethics Committee of Peoples' Friendship University of Russia named by Patrice Lumumba (Protocol No. 3 dated December 23, 2021). In a population of patients hospitalized in the ICU (n = 150) with acute decompensation of chronic heart failure (ADCHF), the effectiveness of the algorithm for prescribing diuretic therapy under the control of natriuresis (n = 50) was studied in comparison with the standard therapy group (n = 100). CHF decompensation was diagnosed based on current recommendations: the appearance or rapid deterioration of symptoms and signs of HF was considered, requiring emergency hospitalization of the patient and intensive therapy in the presence of objective signs of heart damage, which included systolic and/or diastolic dysfunction, left ventricular hypertrophy, left atrial dilation according to echocardiographic examination and increased levels of natriuretic peptide (NT-proBNP).
The study did not include patients with severe liver and kidney diseases, immobilization, terminal somatic and malignant diseases, edematous syndrome of other etiology, the presence of an electrocardiostimulator, exacerbation of obstructive pulmonary disease, bronchial asthma, acute infectious diseases (including pneumonia and COVID-19), known hepatitis/cirrhosis of the liver.
All patients included in the study, upon hospitalization and on day 3, underwent a standard physical, laboratory and instrumental examination, which included the determination of NT-proBNP, an ultrasound examination of the lungs and an ultrasound assessment of venous congestion according to the VExUS protocol (a new doppler ultrasound classification system for quantifying venous congestion), which includes an assessment the diameter of the inferior vena cava (IVC), as well as with a diameter of IVC ≥ 2.0 cm, assessment of the shape of hepatic blood flows, portal and interlobular veins of the kidneys in the mode of pulse-wave dopplerography. A step-by-step assessment of venous congestion and its severity is shown in fig. 1.
Fig. 1. Step-by-step assessment of venous congestion according to the VExUS protocol
Therapy of patients at the outpatient stage was represented by loop diuretics 72.5 %, mineralocorticoid receptor antagonists (MRAs) — 53.2 %, angiotensin converting enzyme inhibitors (ACE inhibitors)/angiotensin II receptor blockers (ARBs)/angiotensin receptor/neprilysin inhibitor (ARNI) — 77.2 %, beta blockers — 70.1%, cardiac glycosides — 17.0 %, oral anticoagulants — 55 %. All patients in the hospital received loop diuretics, MRAs — 72.5 %, ACE/ARB/ARNI — 92.3 %, beta blockers — 96.4 %, cardiac glycosides — 17.0 %, oral anticoagulants — 62 %.
The algorithm of diuretic therapy in the intensive care unit under the control of natriuresis in patients with ADCHD is shown in fig. 2.
Fig. 2. Algorithm for diuretic therapy under the control of natriuresis in patients with CHF in the intensive care unit
The starting dose of furosemide was 20 mg i/v in patients in the natriuresis group who did not receive loop diuretics on an outpatient basis, if received, the starting dose was equal to the oral dose. After 2 hours, a quantitative assessment of sodium in urine was performed. If the natriuresis was ≥ 70 mmol/l, furosemide was continued at the same dose every 12 hours. If the natriuresis was < 70 mmol/L, the dose of furosemide was doubled. Natriuresis was monitored every 12 hours.
| Parameter | ICU (n = 150) | Natriuresis group n = 50 (34 %) |
Standard therapy group n = 100 (66 %) |
|---|---|---|---|
| Demographic characteristics | |||
| Gender, male/ female, n (%) |
84 (56 %)/ 66 (44 %) |
29 (58 %)/ 21 (42 %) |
55 (55 %)/ 45 (45 %) |
| Age, years (M±SD) | 70.6 ± 13,8 | 70.2 ± 14.1 | 71.9 ± 10.8 |
| BMI ≥ 30 kg/m2 | 75 (50 %) | 24 (48 %) | 51 (51 %) |
| BMI, kg/m2 (M±SD) | 32,3 ± 7.7 | 30.5 ± 12.3 | 32.1 ± 9.6 |
| Anamnesis | |||
| IHD, n (%) | 71 (47 %) | 23 (46 %) | 48 (48 %) |
| AH, n (%) | 150 (100 %) | 50 (100 %) | 100 (100 %) |
| ФП, n (%) | 102 (68 %) | 34 (68 %) | 68 (68 %) |
| Stroke, n (%) | 30 (20 %) | 12 (24 %) | 18 (18 %) |
| CKD3 st, n (%) | 41 (27 %) | 14 (28 %) | 27 (27 %) |
| COPD/BA, n (%) | 35 (23 %) | 12 (24 %) | 23 (23 %) |
| DM 2 type, n (%) | 54 (36 %) | 17 (34 %) | 37 (37 %) |
| Hemodynamic parameters | |||
| SBP, mm Hg | 139.6 ± 27.5 | 136.7 ± 24.2 | 140.4 ± 26.9 |
| DBP, mm Hg | 79.1 ± 15.9 | 80.6 ± 12.5 | 79.3 ± 11.2 |
| HR, beat/min | 102.8 ± 26.3 | 94.2 ± 18.6 | 104.6 ± 23.5 |
| SpO2, % | 90.5 ± 6.6 | 89.6 ± 6.2 | 92.3 ± 5.2 |
| Functional status | |||
| LVEF < 50%, n (%) | 59 (39 %) | 19 (38 %) | 40 (40%) |
| LVEF, % | 37.4 ± 12.9 | 36.2 ± 15.4 | 37.4 ± 12.2 |
| SHOCK, points | 8.2 ± 2.5 | 8.4 ± 2.1 | 8.0 ± 3.2 |
The criteria for transfer from the ICU to the cardiology department were the absence of signs of significant impairment of vital functions, including: relief of pulmonary edema, cardiogenic shock; absence of signs of hypoxemia (blood oxygen saturation > 95 % in the air); the presence of adequate diuresis in the absence of signs of hypovolemia; absence of signs of increasing acute renal damage; lack of need for inotropic maintenance or intravenous administration of vasodilators during the last 6 hours.
The software tools MedCalc Software's VAT Version 19.0 and IBM SPSS Statistics (version 26.0) were used for statistical data processing. Quantitative variables were described as the arithmetic mean (M) and standard deviation of the mean (SD) (with a normal distribution) or as the median (Me) and interquartile interval (IQR) (with an asymmetric distribution). The nature of the data distribution was determined by the Kolmogorov—Smirnov criterion. Qualitative variables were represented by absolute (n) and relative (%) values. Pearson's ꭓ2 criterion was used to compare groups by frequency of qualitative variables. The differences were considered statistically significant at a value of p < 0.05 (taking into account the Bonferroni correction).
Results
The effectiveness of the algorithm for prescribing diuretic therapy depending on the control of natriuresis was studied in the population of patients hospitalized in the ICU (n=150). There were no significant differences between the groups with natriuresis and standard treatment in clinical and demographic parameters and ejection fraction (table 1), as well as in initial laboratory and instrumental signs of congestion and sodium in urine (table 2). It was noteworthy that the group with natriuresis was characterized by significantly more pronounced manifestations of venous congestion according to the VEXUS protocol compared with the standard therapy group (diameter of the inferior vena cava 2.4 ± 0.6 cm vs. 2.2 ± 0.3 cm, p = 0,01, 23 % of patients without venous congestion vs. 8 %, p < 0,001).
| Parameter | Natriuresis group n = 50 (34 %) |
Standard therapy group n = 100 (66 %) |
р |
|---|---|---|---|
| Duration of stay in the ICU | 3 (2; 3) | 5 (3; 16) | 0.01 |
| Clinical evaluation of congestion | |||
| Dyspnea, n (%) At admission 3 day |
50 (100 %) 27 (54 %) |
100 (100 %) 78 (78 %) |
1.0 0.003 |
| Wheezing in the lungs, n (%) At admission 3 day |
48 (96 %) 25 (50 %) |
97 (97 %) 70 (70 %) |
0.75 0.02 |
| Orthopnea, n (%) At admission 3 day |
47 (94 %) 24 (48 %) |
95 (95 %) 67 (67 %) |
0.80 0.03 |
| Swollen cervical veins, n (%) At admission 3 day |
24 (48 %) 22 (44 %) |
50 (50 %) 46 (46 %) |
0.81 0.81 |
| Edema of the legs, n (%) At admission 3 day |
48 (96 %) 26 (52 %) |
97 (97 %) 76 (76 %) |
0.75 0.003 |
| Laboratory and instrumental assessment of congestion | |||
| NT-proBNP, pg/ml At admission 3 day |
5044 (3100; 10134) 3896 (2060; 8876) |
4540 (2603; 9808) 3342 (2928; 7246) |
0.92 0.90 |
| Diameter of the inferior vena cava, sm At admission 3 day |
2.4 ± 0.6 2.1 ± 0.3 |
2.2 ± 0.3 2.1 ± 0.2 |
0.01 0.88 |
| GRADE (congestion degree) At admission |
0: 4 (8 %) 1: 10 (20 %) 2: 14 (28 %) 3: 22 (44 %) |
0: 23 (23 %) 1: 22 (22 %) 2: 15 (15 %) 3: 40 (40 %) |
0.06 |
| GRADE (congestion degree) 3 day |
0: 28 (56 %) 1: 10 (20 %) 2: 12 (24 %) 3: 0 (0 %) |
0: 20 (20 %) 1: 35 (35 %) 2: 18 (18 %) 3: 27 (27 %) |
< 0.001 |
| B-lines At admission 3 day |
33.0 ± 9.2 9.6 ± 1.2 |
31.2 ± 9.6 23.4 ± 2.5 |
0.74 < 0.001 |
| Laboratory assessment of kidney function | |||
| eGFR, ml/min/1.73 m At admission 3 day |
56 [36; 78] 53 [34; 77] |
58 [35; 82] 56 [34; 80] |
0.72 0.69 |
| eСКФ < 60, ml/min/1,73 m, n (%) At admission 3 day |
24 (48 %) 26 (52 %) |
45 (45 %) 49 (49 %) |
0.73 0.73 |
| Sodium dynamics | |||
| Sodium in blood, mmol/l At admission 3 day |
139.3 ± 4.6 139.4 ± 6.5 |
137.07 ± 6.8 138.27 ± 5.3 |
0.89 0.86 |
| Natriuresis, mmol 24 h 48 h |
402 ± 165 626 ± 202 |
382 ± 198 534 ± 285 |
0.01 0.03 |
| Parameters of diuretic therapy | |||
| The starting dose of furosemide, mg | 40 [20; 80] | 60 [40; 80] | 0.69 |
| The daily dose of furosemide, mg | 120 [80; 160] | 80 [40; 100] | < 0.05 |
| The total dose of furosemide for 3 days | 420 [240; 620] | 240 [120; 360] | < 0.05 |
| Diuresis, ml (day 1) |
2750 [1500; 3350] |
1500 [1000; 2000] |
< 0.05 |
| Diuresis, ml (day 2) |
3350 [2975; 3950] |
1700 [1300; 2000] |
< 0.05 |
| Diuresis, ml (day 3) |
3300 [2975; 3700] |
1800 [1400; 2000] |
< 0,05 |
| Sodium in single dose of urine, mmol/l, (Me [IQR]) | 103 [79; 131] |
107 [77; 131] |
0.92 |
| The frequency of achieving euvolemia | |||
| The frequency of achieving euvolemia (VEXUS GRADE 0, В-lines < 5, absence of clinical signs of congestion) |
21 (42 %) | 12 (12 %) | < 0.05 |
The data are presented as the mean±standard deviation (M±SD) (with a normal distribution) or as the median (Me) and interquartile interval (IQR) (with an asymmetric distribution).
In the natriuresis group, in contrast to the standard therapy group, the duration of patients' stay in the ICU was significantly shorter (3 vs. 5 days, p = 0.01), the frequency of achieving euvolemia was significantly more frequent (42 % vs. 12%, p < 0.05), the daily diuresis in patients was significantly higher against the background of higher daily (120 mg vs. 80 mg, p < 0.05) and the total dose of furosemide (420 mg vs. 240 mg, p < 0.05). There was a more pronounced decrease in congestion in the group of patients with natriuresis in the form of a decrease in pulmonary (number of B-lines 9.6 ± 1.2 versus 23.4 ± 2.5) and venous congestion (GRADE 0–56%, 1–20%, 2–24%, 3–0% against 0–20%, 1–35%, 2–18%, 3–27%) on the 3rd day of hospitalization (table 2).
Thus, the inclusion of an algorithm for prescribing diuretic therapy under the control of natriuresis in patients with CHF in the intensive care unit is effective and contributes to a more pronounced and rapid reduction of congestion, as well as a 1.5-fold reduction in the duration of stay in the ICU.
Discussion
In our study, the effectiveness of the algorithm for prescribing diuretic therapy depending on the control of natriuresis was studied in patients with heart failure (HF) hospitalized in the ICU. The hypothesis of the superiority of prescribing diuretic therapy under the control of natriuresis to patients with HF in achieving euvolemia and reducing congestion according to instrumental examination data, such as ultrasound of the lungs and assessment of venous congestion according to the VExUS protocol compared with standard diuretic therapy, has been confirmed. It was shown that in the natriuresis group, in contrast to the standard therapy group, the duration of stay of patients in the ICU was significantly shorter. The results obtained can be explained by a higher daily diuresis against the background of furosemide dose optimization.
Volume overload is a characteristic symptom of HF, which can seriously disrupt organ function and is an important goal of treatment [8]. Changes in hemodynamics and neurohormonal activation lead to salt and fluid retention [9]. For a long time (more than 50 years), excess fluid volume in acute heart failure (AHF) was treated with loop diuretics. However, despite many years of experience, their dosage and type of administration are mainly based on the experts’ opinion.
According to current recommendations, loop diuretics should be administered intravenously in patients with AHF, 20-40 mg of furosemide in patients who did not receive loop diuretics, and in patients with chronic HF, an equivalent dose that the patient took orally at home (class I, evidence level B) [10].
The DOSE (Diuretic Strategies in Patients with Acute Decompensated Heart Failure) study showed that patients who were prescribed intravenous loop diuretics in high doses (2.5 times higher than the oral dose) compared to patients receiving a low intravenous dose (equivalent to an oral dose at home) showed no differences in their condition and symptoms of HF after 72 hours [11]. In addition, data on the association between high doses of loop diuretics and increased mortality were extremely contradictory [12, 13].
Recently, a position on the use of diuretics for HF was published by the Heart Failure Association (HFA) of the European Society of Cardiology [14]. In this document, emphasis was placed on the early administration of intravenous diuretics in high doses, 1–2 times higher than the oral home dose, and early titration of the dose based on an assessment of the diuretic effect using as markers sodium concentration in urine and/or diuresis.
An early assessment of natriuresis (1-2 hours after the start of taking loop diuretics) is an accurate marker of insufficient use of diuretics during hospitalization [6]. Determination of the amount of sodium in a single portion of urine is recommended in patients with HF 2 hours after the start of diuretic therapy. Urine sodium values < 50–70 mmol/l 2 hours after taking a diuretic or hourly diuresis < 100–150 ml during the first 6 hours, identifies patients with an insufficient reaction to a diuretic and further it is recommended to double the dose of an intravenous loop diuretic or add another diuretic to obtain additional diuresis /natriuresis [1].
The PUSH-AHF study showed that enhanced diuretic therapy under the control of natriuresis, compared with standard treatment, improves natriuresis and clinical outcomes in patients with ADCHF [7], which is also confirmed by the results of our study. It was found that in the group of patients, with the inclusion of the algorithm for prescribing diuretic therapy under the control of natriuresis, in contrast to the group of standard therapy, there was a more pronounced decrease in congestion in the form of a decrease in pulmonary (number of B-lines 9.6 ± 1.2 versus 23.4 ± 2.5) and venous congestion according to the VEXUS protocol (GRADE 0– 56%, 1–20%, 2–24%, 3–0% against 0–20%, 1–35%, 2–18%, 3–27 %) on the 3rd day of hospitalization, there was a significantly higher incidence of euvolemia (42 % vs. 12 %, p < 0.05) and a shorter duration of stay in the ICU (3 vs. 5 days, p = 0.01).
As in the PUSH-AHF study, treatment with diuretics according to the natriuresis algorithm was safe and did not lead to electrolyte disturbances, despite significantly higher total doses of loop diuretics used. Thus, in our study, in patients in the natriuresis group, daily diuresis was significantly higher against the background of higher daily doses (120 mg vs. 80 mg, p < 0.05) and total doses of furosemide (420 mg vs. 240 mg, p < 0.05). It has been shown that the increased venous pressure observed in patients with congestive heart failure is the strongest predictor of impaired renal function, and therefore treatment of congestive events potentially has a renoprotective effect [4, 15, 16]. The difference between our study and the PUSH-AHF study was that we performed furosemide dose adjustment every 12 hours, and in the PUSH-AHF study every 6 hours. There are isolated pilot studies devoted to this problem in the Russian literature [17, 18, 19]. The results obtained indicate that an individual approach to treatment based on the use of an algorithm for prescribing diuretic therapy under the control of natriuresis makes it possible to identify patients who need additional therapy with loop diuretics in high doses to achieve euvolemia without worsening kidney function.
Study limitations
The limitations of this study are the small sample size, the brevity of patient follow-up, which is limited by the time they stay in the ICU, the lack of assessment of long-term outcomes such as general and cardiovascular mortality and hospitalization for heart failure.
Conclusion
In patients with ADCHF in the intensive care unit, the effectiveness of using the algorithm for prescribing diuretic therapy under the control of natriuresis was demonstrated, which was accompanied by a more pronounced and rapid decrease in congestion, a higher frequency of achieving euvolemia and a shorter duration of stay in the ICU.
Disclosure. The authors declare no competing interests.
Author contribution. All authors according to the ICMJE criteria participated in the development of the concept of the article, obtaining and analyzing factual data, writing and editing the text of the article, checking and approving the text of the article.
Ethics approval. This study was approved by the local Ethical Committee of RUDN University (reference number: 3-23.12.2021).
Funding source. This study was not supported by any external sources of funding.
Data Availability Statement. The data that support the findings of this study are available from the corresponding author upon reasonable request.
