ORIGINAL RESEARCH published: 08 July 2022 doi: 10.3389/fcvm.2022.847450 Venous Leg Compression for Tissue Decongestion in Patients With Worsening Congestive Heart Failure Jose Civera 1,2† , Gema Miñana 1,2,3† , Rafael de la Espriella 1,2 , Enrique Santas 1,2 , Clara Sastre 1,2 , Anna Mollar 1,2 , Adriana Conesa 1,2 , Ana Martínez 1,2 , Eduardo Núñez 1,2 , Antoni Bayés-Genís 3,4,5 and Julio Núñez 1,2,3* 1 Cardiology Department, Hospital Clínico Universitario de Valencia, INCLIVA Instituto de Investigación Sanitaria, Valencia, Spain, 2 Department of Medicine, Universitat de València, Valencia, Spain, 3 CIBER in Cardiovascular Diseases (CIBERCV), Edited by: Madrid, Spain, 4 Heart Failure Unit, Cardiology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain, Carlos Garcia Santos-Gallego, 5 Department of Medicine, Autonomous University of Barcelona, Barcelona, Spain Mount Sinai Hospital, United States Reviewed by: Kenichi Hongo, Aims: Venous leg compression (VLC) with elastic bandages has been proposed as a Jikei University School of potentially useful strategy for decreasing tissue congestion. We aimed to evaluate the Medicine, Japan Juan Badimon, effect of VLC on short-term changes on intravascular refill, assessed by inferior vena Icahn School of Medicine at Mount cava (IVC) diameter in patients with worsening heart failure (WHF) requiring parenteral Sinai, United States furosemide. Additionally, we sought to evaluate whether early changes in IVC were related *Correspondence: Julio Núñez to short-term decongestion. yulnunez@gmail.com; Methods: This is a prospective study in which we included 20 consecutive ambulatory juenuvi@uv.es orcid.org/0000-0003-1672-7119 patients with WHF treated with subcutaneous furosemide and VLC for at least 72 h. The † These endpoints were (a) short-term changes in IVC, (b) the association between decongestion authors share first authorship and 3-h IVC changes following VLC. Changes in continuous endpoints and their Specialty section: longitudinal trajectories were estimated with linear mixed regression models. All analyses This article was submitted to were adjusted for multiple comparisons. Heart Failure and Transplantation, a section of the journal Results: Following administration of subcutaneous furosemide and VLC, we found a Frontiers in Cardiovascular Medicine significant increase in 3-h IVC diameter (1IVC = 1.6 mm, CI 95%: 0.7–2.5; p < 0.001), Received: 02 January 2022 with a greater increase in those with baseline IVC≤21 mm (2.4 vs. 0.8 mm; p < 0.001). Accepted: 17 June 2022 Published: 08 July 2022 3-h intravascular refill (increase in IVC≥2 mm) was associated with greater decongestion Citation: (natriuresis, weight, peripheral edemas, and dyspnea) in those with baseline IVC≤21 mm Civera J, Miñana G, de la Espriella R, but not when IVC>21 mm (p < 0.05 for all comparisons). Santas E, Sastre C, Mollar A, Conesa A, Martínez A, Núñez E, Conclusions: In this cohort of patients with congestive WHF treated with subcutaneous Bayés-Genís A and Núñez J (2022) furosemide and VLC, we found a greater increase in short-term IVC in those with Venous Leg Compression for Tissue Decongestion in Patients With IVC ≤21 mm at baseline. In this subset of patients, a 3-h increase in IVC≥2 mm was Worsening Congestive Heart Failure. associated with greater short-term decongestion. Front. Cardiovasc. Med. 9:847450. doi: 10.3389/fcvm.2022.847450 Keywords: worsening heart failure, congestion, diuretic efficiency, inferior vena cava, venous leg compression Frontiers in Cardiovascular Medicine | www.frontiersin.org 1 July 2022 | Volume 9 | Article 847450 Civera et al. Venous Leg Compression in Heart Failure INTRODUCTION Procedures Subcutaneous Administration of Furosemide Fluid overload explains most of the symptoms and signs Subcutaneous furosemide was administered by using a single- of patients with worsening heart failure (WHF) (1, 2). use, continuous infusion pump system (DOSI-FUSER R , Diuretics constitute the mainstay armamentarium in these Leventon, S.A.U, Barcelona, Spain) and a standard commercial patients, although the evidence endorsing the optimal subcutaneous infusion set. The infusion pump system consists of diuretic strategy (intensity and sequence of the diuretic an elastomeric balloon inside a rigid container, an infusion line prescription) is scarce (3, 4). Optimal decongestion should with the capillary device, and a Luer-lock connector that attaches imply tissue and vascular decongestion. However, at least in to the standard subcutaneous infusion set. After the balloon is the short-term, most used interventions, such as parenteral inflated, the medication flows through the capillary device due diuretics, have a predominant effect by reducing intravascular to the pressure from the elastomeric balloon, which determines congestion (3, 4). Several strategies have been postulated the flow rate. We used an infusion pump containing a 250 mL to mobilize extravascular volumes, such as infusion of loop balloon reservoir with a nominal continuous flow rate of 2.1 diuretics and hypertonic solutions (sodium or albumin), mL/h over 72 h. without consistent evidence about their utility (5, 6). Subcutaneous furosemide dose was calculated based on the Venous leg compression (VLC) by using elastic bandages subject’s outpatient oral dose using a 1:1.25 conversion (80 mg has been proposed as another potentially useful strategy of oral furosemide = 100 mg of subcutaneous furosemide). for decreasing tissue congestion. However, its efficacy and Therefore, for administering a daily dose of 100 mg of safety in heart failure (HF) patients require a profound subcutaneous furosemide, a 2 mg/mL drug concentration was evaluation (7). required (dilution: 500 mg of non-formulated furosemide in In this work, we sought to evaluate the association 250 mL of 0.9% sodium chloride). Specialized HF nurses filled the between VLC and short-term changes in intravascular refill infusion system following the manufacturer’s instructions, placed and whether these changes are related to decongestion the subcutaneous catheter, and thoroughly explained general parameters in patients with WHF that require parenteral guidelines and troubleshooting to study participants. furosemide administration. Venous Leg Compression MATERIALS AND METHODS Compression of the lower limbs was performed with a multi- component layer compression bandage system at a pressure of 20 Study Design and Eligibility Criteria mmHg (UrgoK2 LITE R ) consisting of two dynamic components: This is a one-arm open-label prospective study in which an inelastic and elastic bandage. When combined, the two layers we included 20 consecutive ambulatory patients with WHF constitute one compression bandaging system that provides both treated with subcutaneous furosemide and VLC for at least a dynamic static stiffness profile and tolerable resting pressures. 72 h between January 1st, 2020, and June 1st, 2021, at an The first layer, KTech R , is an inelastic bandage (approximately outpatient HF-Clinic in Spain (Hospital Clinic Universitari, 75% extensibility), consisting of viscose and polyester wadding Valencia-Spain). All patients received a subcutaneous with a knitted layer made of polyamide and elastane. When furosemide infusion for the treatment of WHF. Patients in contact with the skin, the KTech R layer distributes the were eligible if they presented with WHF with peripheral pressure uniformly over the surface of the leg and provides edema (at least grade 1+) that required parenteral ambulatory compression, along with protection and absorbency when needed administration of furosemide. All patients had an established (9). Ktech R provides a high working pressure with a low diagnosis of HF according to ESC guidelines (8). Exclusion resting pressure, which in combination with the action of the criteria consisted of (a) acute decompensated HF requiring calf muscle creates a massage effect, assisting venous return hospital admission (acute pulmonary edema, evidence of and reducing edema levels. The second layer, KPress R , is an hypoxemia, defined as an oxygen saturation <90% in pulse elastic cohesive bandage of approximately 160% extensibility, oximetry or oxygen partial pressure <80 mmHg in arterial made from synthetic components, such as acrylic, polyamide, blood gas analysis), (b) cardiogenic shock, (c) symptomatic and elastane. This outer bandage provides the additional hypotension or any systolic blood pressure (SBP) <90 compression necessary to achieve the required therapeutic mmHg, and d) index event triggered by an uncontrolled pressure and, more critically, maintains the recommended arrhythmia (advanced heart block without a pacemaker, resting pressures necessary to maintain improved blood flow sustained ventricular tachycardia, therapeutic defibrillator (9). These pressures are consistently maintained over time shock, or atrial fibrillation/flutter with sustained ventricular (during 7 days) (10). Each bandage layer displays an oval response >150 bpm), infection/sepsis, or severe anemia indicator (the PresSure R system, also known as the etalonnage) (hemoglobin <7 g/dL), and patient that require hospitalization that expands into a circle when stretched correctly. Proper at clinician judgment. Patients on renal replacement therapy application is further enhanced by guides for appropriate overlap or ultrafiltration were also excluded. This study complied with of layering. There are two different sizes of UrgoK2 LITE R the Declaration of Helsinki and was approved by the local according to the ankle perimeter (18–25 or 25–32 cm). For each institutional review committees. All patients signed an informed patient, the ankle perimeter was measured, and the right size consent form. was selected. Frontiers in Cardiovascular Medicine | www.frontiersin.org 2 July 2022 | Volume 9 | Article 847450 Civera et al. Venous Leg Compression in Heart Failure Assessment of Inferior Vena Cava Diameter Software, Release 15 [2017]; StataCorp LP, College Station, The inferior vena cava (IVC) diameter was visualized by TX, USA). echography (11), with patients in the supine position, using subcostal 4 chamber view (midline, inferior to the xiphoid, RESULTS angling to the right). The maximum IVC diameter during the respiratory cycle was measured approximately 3 cm before the The median age was 80 years (73–85), 8 (40%) patients were merger with the right atrium. An IVC maximum diameter female, 15 (75%) showed a prior history of NYHA III, and of >21 mm was defined as dilated IVC. IVC diameter was all of them were previously admitted for acute HF, all of evaluated at baseline and 3, 24, 48, and 72 h after applying them were on treatment with oral loop diuretics [median the compression bandage. A change in IVC at 3-h >2 mm was furosemide equivalent doses 80 mg/day (40–120)] and showed considered significant. peripheral edema at presentation (90% with grades 3+ to 4+). The median (p25–p75%) SBP, heart rate, eGFR, NT- Clinical Monitoring and Biomarkers Assessment proBNP and carbohydrate antigen (CA125) at presentation were All patients were physically visited on the day of presentation, at 127 mmHg (110–139), 74 bpm (64–82), 44 ml/min/1.73 m2 24, 48, and 72-h. At these encounters, we registered the New York (33–61), 2,738 pg/ml (1,290–8,585), and 34 U/mL (15–125), Heart Association (NYHA) class, pedal edema, weight, and vital respectively. The median (p25–p75%) of LVEF and tricuspid signs. The pedal edema was assessed by 1+ to 4+ grade (grade annular plane systolic excursion (TAPSE) were 52% (36–60) and 1+: slight pitting 2 mm depth, grade 2+: somewhat deeper pit 17.5 mm (14–19), respectively. A total of 12 (60%) patients had 4 mm, grade 3+: noticeably deep pit 6 mm, and grade 4+: very LVEF ≥50%. The median (p25–p75%) of IVC diameter was deep pit 8 mm), and by measuring the diameter of lower limbs 22.5 mm (15–27). Half of the patients displayed IVC diameter 10 cm above the external malleolus. The mean diameter between ≤21 mm. Patients were treated with homogenous doses of both limbs was registered. subcutaneous furosemide [median 100 mg/day (min: 80, and We also assessed dyspnea visual analog scale (VAS) and max: 120)]. standard plasma laboratory data [estimated glomerular filtration Baseline characteristics across IVC status (≤21 vs. rate (eGFR), plasma electrolytes (sodium and potassium), and >21 mm) are summarized in Table 1. Patients with IVC amino-terminal pro-brain natriuretic peptide (NT-proBNP)] at ≤21 mm showed lower NYHA class, NT-proBNP, and jugular presentation and 72-h. The dyspnea VAS scale of 0 corresponds engorgement (Table 1). There were no differences in the to the patient’s subjective feeling of “I can breathe normally,” and severity of peripheral edema or other clinical parameters a dyspnea VAS score of 10 corresponds to “I can’t breathe at of congestion. all.” Spot urinary sodium was assessed each 24-h after treatment intervention, at 24, 48, and 72 h. Changes in IVC Following Venous Leg Compression Endpoints Following administration of subcutaneous furosemide and VLC, The endpoints were: a) changes in short-term IVC following we found a significant increase in 3-h IVC diameter (1IVC = administration of subcutaneous furosemide and VLC, and b) 1.6 mm, 95% CI: 0.7 to 2.5; p < 0.001). A total of 9 patients the relationship between 3-h changes in IVC and parameters (45%) displayed a 3-h increase in IVC ≥2 mm. Afterward, a of decongestion (natriuresis, pedal edema, weight, dyspnea stepwise decrease of IVC diameter was noticed at 24, 48, and VAS, and NT-proBNP). In addition, safety endpoints included 72-h (Figure 1). However, the effect of VLC on the short- changes in eGFR, SBP, electrolytes, and the proportion of term trajectory of IVC diameter was heterogeneous across IVC patients that symptomatically did not tolerate the 72-h leg status at baseline (p-value for interaction <0.001). In patients venous compression. in which IVC was below or equal to the median (≤21 mm), we found a greater increase in 3-h IVC diameter (1IVC = Statistical Analysis 2.4 mm, 95%CI: 1.0 to 3.8; p < 0.001). In those with IVC Continuous baseline variables were expressed as median >21 mm, IVC did not significantly increase at 3-h (1IVC [interquartile interval (IQI)]. Discrete variables were presented = 0.8 mm, 95% CI:−0.6–2.2; p = 0.611), as is shown in as numbers (percentages). Changes in continuous endpoints and Figure 2. The number of patients that increased IVC at least their longitudinal trajectories were estimated with linear mixed 2 mm at 3-h was higher in those with baseline IVC ≤21 mm regression models (LMRMs). Continuous exposures with a [7 (70%) vs. 2 (20%), p = 0.025]. At later time-points (24, non-parametric distribution were log-transformed [NT-proBNP 48, and 72-h), and compared to baseline values, we found a (lnNT-proBNP)]. Multivariate estimates were adjusted for age, greater decrease in IVC diameters in those with dilated IVC sex, baseline eGFR, left ventricular ejection fraction (LVEF), (>21 mm), but a neutral effect in those with IVC ≤21 mm and the baseline endpoint value regardless of their p-value. (Figure 2). The LMRMs are presented as least square means (LSM) with their respective 95% confidence intervals. P-values were adjusted Decongestion Following Leg Compression for multiple comparisons (Sidak procedure). A 2-sided p-value In the whole sample, and compared to baseline values, of < 0.05 was set as a criterion for statistical significance. we found a significant increase in natriuresis, weight All analyses were performed in Stata 15.1 (Stata Statistical reduction, and decreased peripheral edema during the first Frontiers in Cardiovascular Medicine | www.frontiersin.org 3 July 2022 | Volume 9 | Article 847450 Civera et al. Venous Leg Compression in Heart Failure TABLE 1 | Baseline characteristics. Total population (N = 20) IVC at baseline ≤21 mm (N = 10) IVC at baseline >21 mm (N = 10) p-value Demographics and medical history Age, years 80.0 (72.5–84.5) 82.0 (68.0–85.0) 78.0 (74.0–83.0) 0.705 Male, n (%) 12 (60.0) 5 (50.0) 7 (70.0) 0.650 Hypertension, n (%) 17 (85.0) 9 (90.0) 8 (80.0) 1.000 NYHA class, n (%) 5 (25.0) 5 (50.0) 0 II III 15 (75.0) 5 (50.0) 10 (100.0) Diabetes mellitus, n (%) 13 (65.0) 7 (70.0) 6 (60.0) 1.000 Weight, Kg 83.0 (77.4–89.5) 80.2 (77.3–89.0) 85.4 (77.5–89.9) 0.597 COPD, n (%) 3 (15.0) 1 (10.0) 2 (20.0) 1.000 Renal failure, n (%) 14 (70.0) 8 (80.0) 6 (60.0) 0.628 Atrial fibrillation, n (%) 15 (75.0) 6 (60.0) 9 (90.0) 0.303 Vital signs and physical examination SBP, mmHg 127 (110–138) 123 (102–137) 129 (112–140) 0.406 DBP, mmHg 70.5 (62.5 −75.5) 69.5 (65–73) 71 (60–78) 0.597 Heart rate, bpm 73.5 (64–2) 68.5 (62–75) 81 (70–86) 0.059 Peripheral edema, n (%) 1+ (slight) 2 (10.0) 1 (10.0) 1 (10.0) 2+ (moderate) 0 0 0 3+ (marked) 12 (60.0) 6 (60.0) 6 (60.0) 4+ (serious) 3 (15.0) 1 (10.0) 3 (30.0) Pleural effusion, n (%) 3 (15.0) 1 (10.0) 2 (20.0) 1.00 Jugular engorgement, 15 (75.0) 5 (50.0) 10 (100.0) 0.033 n (%) Lower limb perimeter, 27.5 (25.5 – 29.5) 26.8 (25.0 – 29.0) 28.0 (26.0 – 29.5) 0.438 cm Echocardiography LVEF, % 51.5 (36–60) 55 (37–60) 48 (35–60) 0.678 PASP, mmHg 44.5 (35–50) 39.5 (35–45) 50 (35–52) 0.109 TAPSE, mm 17.5 (14–19) 17 (15–19) 18 (14–21) 1.000 Inferior vena cava, mm 22.5 (14.5–27) 14.5 (14–20) 27 (25–28) < 0.001 Laboratory tests Serum sodium, mmol/L 139.5 (137–142.5) 140.5 (139–143) 138 (137–142) 0.212 Serum potassium, 4.4 (4.1–4.6) 4.5 (4.3–4.7) 4.3 (4.0–4.5) 0.102 mmol/L eGFR, mL/min/1.73 m2 31.3 (23.0–40.7) 23.0 (15.1–48.8) 37.3 (25.3–40.7) 0.513 Hematocrit, % 35 (31–43) 37 (31–43) 35 (33–41) 0.775 Urine creatinine mmol/L 68 (43–94) 73 (65–94) 39.5 (27–95.5) 0.131 Urine sodium, mmol/L 64 (49–86) 64 (56–83) 64 (33–87) 0.935 Urine potassium 35.5 (28–45) 35 (31–42) 37 (23–51) 0.894 mmol/L NT-proBNP, pg/mL 2738 (1290–8585) 1950 (880–4246) 8585 (2588–11765) 0.018 CA125, U/mL 33.5 (15–125) 32 (15–379) 34 (14.5–87) 0.790 Pharmacological heart failure therapy at baseline Loop diuretics (oral), 20 (100) 10 (100) 10 (100) 1.000 n (%) FED, mg 80 (40–80) 70 (40–80) 80 (80–120) 0.186 Furosemide sc dose, 100 (90–120) 100 (80–100) 110 (100–120) 0.054 mg Chlorthalidone, n (%) 13 (65.0) 4 (40.0) 9 (90.0) 0.057 Acetazolamide, n (%) 1 (5.0%) 0 1 (10.0) 1.000 (Continued) Frontiers in Cardiovascular Medicine | www.frontiersin.org 4 July 2022 | Volume 9 | Article 847450 Civera et al. Venous Leg Compression in Heart Failure TABLE 1 | Continued Total population (N = 20) IVC at baseline ≤21 mm (N = 10) IVC at baseline >21 mm (N = 10) p-value MRA, n (%) 12 (60.0) 4 (40.0) 8 (80.0) 0.170 Sacubitril-valsartan, n 6 (30.0) 3 (30.0) 3 (30.0) 1.000 (%) ACEI/ARB, n (%) 7 (35.0) 4 (40.0) 3 (30.0) 1.000 iSGLT-2, n (%) 9 (45.0) 5 (50.0) 4 (40.0) 0.656 Betablockers, n (%) 18 (90.0) 9 (90.0) 9 (90.0) 1.000 ACEI, angiotensin converting enzyme-inhibitors; ARB, angiotensin receptor blockers; CA125, carbohydrate antigen 125; COPD, chronic obstructive coronary disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; FED, furosemide equivalent dose; iSGLT-2, sodium-glucose co-transporter-2 inhibitors; LVEF, left ventricle ejection fraction; MRA, mineralcorticoid receptor antagonists; NT-proBNP, amino-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; PASP,: pulmonary arterial systolic pressure; SBP, systolic blood pressure; TAPSE, tricuspid annular plane systolic excursion. Continuous variables are expressed as median (p25–p75%). FIGURE 1 | Changes in IVC diameter following administration of subcutaneous furosemide and venous leg compression. IVC, inferior vena cava. 72 h (Supplementary Figure 1). Likewise, dyspnea VAS Urinary Sodium significantly decreased at 72-h (1VAS = −3.4, 95% CI: −4.1– A 3-hour increase in IVC ≥2 mm was associated with a greater −2.6; p < 0.001). We did not find significant changes in 72-h natriuresis in those with IVC ≤21 mm but not in those with IVC NT-proBNP (1LnNT-proBNP = −0.05, 95% CI: −0.23–0.34; >21 mm, in which most of the comparisons were neutral (p-value p = 0.718). Renal function decreased at 72-h (1GFR = −4.2, for interaction=0.012) (Figure 3A). 95% CI: −7.7–−0.7; p = 0.019). We also found a significant SBP and heart rate reduction at 24-h with posterior recovery Weight (Supplementary Figure 1). An increase in IVC ≥2 mm at 3-h was associated with a greater weight reduction when IVC ≤21 mm compared to those with Short-term Increase in Intravascular IVC >21 mm (p-for interaction <0.001). In this latter group, Volume and Decongestion/Safety: The intravascular refill was associated with higher weight (Figure 3B). Role of Baseline IVC Diameter Overall, a short-term increase in IVC ≥2 mm was Peripheral Edema differentially associated with diuretic efficacy across The increase in IVC was borderline differentially associated baseline IVC diameter. An increase in IVC ≥2 mm was with the resolution of edemas (p-value for interaction = 0.061). associated with a greater decongestion in those with Intravascular refill led to a significant decrease in leg diameter in baseline IVC ≤21 mm compared to those with dilated those with IVC ≤21 mm. Conversely, higher leg diameters were IVC (Figures 3, 4). All patients tolerated 72-h venous found in those with an increase in IVC ≥2 mm and baseline IVC leg compression. >21 mm (Figure 3C). Frontiers in Cardiovascular Medicine | www.frontiersin.org 5 July 2022 | Volume 9 | Article 847450 Civera et al. Venous Leg Compression in Heart Failure FIGURE 2 | Effect of venous compression on the trajectory of IVC diameter across IVC status at baseline. IVC, inferior vena cava. FIGURE 3 | Changes in decongestion parameters across baseline IVC diameter and the presence of IVC increase at 3-h. (A) Urinary sodium. (B) Weight. (C) Leg circumference. IVC, inferior vena cava. Dyspnea VAS NT-ProBNP IVC increase ≥2 mm at 3-h was associated with resolution of The relationship between an increase in IVC and 72-h NT- dyspnea in those with IVC ≤21 mm at 72-h, but not in those proBNP did not significantly differ across IVC status at baseline with IVC >21 mm (p-value for interaction=0.020). In this latter (p-value for interaction=0.131). However, we found higher group, IVC increase ≥2 mm was associated with greater dyspnea LnNT-proBNP values in those with increased 3-h IVC and at 72 h (Figure 4A). plethoric IVC at baseline (Figure 4B). Frontiers in Cardiovascular Medicine | www.frontiersin.org 6 July 2022 | Volume 9 | Article 847450 Civera et al. Venous Leg Compression in Heart Failure FIGURE 4 | Changes in VAS and the logarithm of NT-proBNP across baseline IVC diameter and the presence of IVC increase at 3-h. (A) Visual analog scale. (B) Amino-terminal pro-brain natriuretic peptide. NT-proBNP, amino-terminal pro-brain natriuretic peptide, IVC, inferior vena cava; VAS, visual analog scale. Estimated Glomerular Filtration Rate limited ability for profiling the congestive phenotype in WHF IVC 3-hour increase ≥2 mm was not differentially related to 72-h (16), a fact that may easily explain the disappointing findings in eGFR across baseline IVC (p-value for interaction = 0.835), as is several randomized clinical trials. Thus, there is consensus about presented in Figure 5A. the need to improve the assessment of HF congestion by using a multiparametric approach, including imaging, biomarkers, and Systolic Blood Pressure clinical parameters (15, 16). Short-term IVC increase ≥2 mm was not associated with a Most of the volume overload, especially at more advanced differential effect across baseline IVC (p-value for interaction = phases of the disease, corresponded to tissue and not circulatory 0.776) (Figure 5B). congestion (17). Patients with predominant tissue congestion Summary of the main findings is presented in a identified a subset of patients with lower diuretic efficiency central illustration. and at higher risk of diuretic resistance (3, 4). Traditional depletive strategies mainly play a role in controlling intravascular DISCUSSION congestion (3, 4), while effective treatment strategies for targeting tissue/extravascular congestion remain a clinical challenge (3, We found that short-term VLC using elastic bandages may be 4). To manage tissue congestion, different approaches aiming useful for enhancing diuretic response in patients with congestive to facilitate the intravascular volume recruitment (transferring WHF treated with subcutaneous furosemide and absence of water from extravascular to an intravascular compartment) intravascular congestion (IVC ≤21 mm) at baseline. Conversely, by increasing plasmatic osmolarity are used without robust it seems to have no role in those with intravascular congestion evidence. These strategies included the infusion of loop diuretic (Figure 6). together with a saline hypertonic solution or albumin (5, 6, 18, 19). Another approach consists of using pharmacological Diuretic Response: The Role of agents such as SGLT2i or tolvaptan that increase urine-free water Extravascular Congestion and elimination (4, 20). Intravascular Refill This study postulates that VLC in patients with WHF, evident Parenteral loop diuretic agents are the mainstay of the treatment tissue congestion, and absence of intravascular congestion, of patients with congestive WHF (3, 4, 8). Despite their might be a widely available therapeutic alternative for short- ubiquitous use in daily clinical practice, the evidence base for term intravascular compartment expansion. Interestingly, we the appropriate use of these agents remains largely empirical found that intravascular expansion following VLC was greater (3, 4, 8). Clinical trials are scarce, and most of them have resulted in those with normal-low intravascular volume, and, in in non-conclusive results (3, 4, 8, 12, 13). Although congestion this subset of patients, it was positively associated with a explains most symptoms and signs in decompensated patients, greater decongestion. On the contrary, this maneuver appears the severity and body distribution are largely heterogeneous futile or even not recommended in cases with circulatory (1, 2, 14, 15). Clinical proxies of congestion have also shown a volume overload. Frontiers in Cardiovascular Medicine | www.frontiersin.org 7 July 2022 | Volume 9 | Article 847450 Civera et al. Venous Leg Compression in Heart Failure FIGURE 5 | Changes in eGFR and SBP across baseline IVC diameter and the presence of IVC increase at 3-h. (A) Estimated glomerular filtration rate. (B) Systolic blood pressure. eGFR, estimated glomerular filtration rate; IVC, inferior vena cava; SBP, systolic blood pressure. FIGURE 6 | Central illustration. The use of venous leg compression in congestive heart failure. IVC, inferior vena cava. Previous Studies edema (7, 22). However, a contemporary report has suggested To date, studies of VLC mainly focused on the treatment of this strategy as safe in patients with venous ulcers and HF (23). chronic lower limb edema and ulcer, and few studies have been Among available studies in patients with HF, different performed in congestive HF (7). Moreover, VLC in patients with populations have been analyzed. Dereppe et al. performed an severe and WHF appears as a contraindication in the guidelines invasive measurement of venous pressures using a Swan-Ganz dedicated to leg ulcer treatment (21), as a sudden movement of catheter in 11 patients with HF (5 with chronic HF and 6 with a large amount of blood from lower limbs veins could lead to a acute myocardial infarction). After VLC, a significant increase rapid increase in preload and afterload, precipitating pulmonary in right auricular, pulmonary artery, and pulmonary wedge Frontiers in Cardiovascular Medicine | www.frontiersin.org 8 July 2022 | Volume 9 | Article 847450 Civera et al. Venous Leg Compression in Heart Failure pressures was observed, and the values returned to baseline CONCLUSIONS 30 min after finishing compression (24). Brain et al. also reported, in 15 patients with moderate to severe HF, that pneumatic VLC VLC treatment is safe in patients with congestive WHF. was associated with an increase in both mean right atrial pressure Treatment with VLC and subcutaneous furosemide was and pulmonary pressure, which did not translate into significant associated with a greater 72-h decongestion when IVC at changes in left-sided heart function (25). However, Wilputte et baseline is within normal values. Conversely, it appears not to al. observed, in 5 patients with HF and NYHA class III and IV have a role in increasing diuretic response in those with WHF that simultaneous bandage VLC and muscle contraction induced and dilated IVC at presentation. a significant increase in the right arterial pressure and a transient deterioration of the right and left ventricular function (26). More recently, the effects of VLC with elastic bandages DATA AVAILABILITY STATEMENT compared to hypertonic albumin on diuretic efficiency were evaluated in a large retrospective cohort of patients (N = The raw data supporting the conclusions of this article will be 1147) with volume overload and diuretic resistance during the made available by the authors, without undue reservation. de-escalation phase of sepsis resuscitation (27). The use of elastic bandages was associated with superior diuretic efficiency than hypertonic albumin solution, despite lower baseline ETHICS STATEMENT serum albumin levels in those receiving elastic bandages (27). The studies involving human participants were reviewed Unfortunately, none of the prior works evaluated the effect of and approved by Comité de Investigación del Instituto de VLC across the intravascular status. investigación del Hospital Clínico Universitario de Valencia. Written informed consent to participate in this study was Clinical Feasibility provided by the participants’ legal guardian/next of kin. In case of safety and efficacy confirmation, VLC by using elastic bandages is a widely available, simple, well-tolerated, and cheap intervention that may be easily translated into daily clinical practice. AUTHOR CONTRIBUTIONS JC and GM: conceptualization, data curation, investigation, Further Studies methodology, project administration, validation, visualization, These findings underscore (a) the heterogeneous writing–original draft, and writing–review and editing. RE, ES, pathophysiology of congestion in WHF, (b) the complexity and AB-G: data curation, investigation, methodology, validation, of managing congestion in HF, and (c) the need for moving visualization, and writing–review and editing. CS, AMo, AC, toward a more precise medicine when tackling congestion in and AMa: data curation, visualization, and writing–review HF. Larger and more controlled studies are required to confirm and editing. EN: formal analysis, investigation, methodology, current findings and unravel whether VLC may have a clinical resources, software, supervision, validation, and writing– role in managing patients with congestive HF with predominant review and editing. JN: conceptualization, formal analysis, tissue but not intravascular congestion. funding acquisition, investigation, methodology, project administration, resources, software, supervision, validation, Limitations visualization, writing–original draft, and writing–review and First, it is a one-arm small pilot study with the absence editing. All authors contributed to the article and approved the of a control group. Further controlled studies are required submitted version. comparing the effect of VLC plus parenteral administration of furosemide vs. parenteral administration of furosemide only. Second, the patients evaluated were older, with predominant FUNDING preserved ejection fraction and features of advanced HF. Thus, current findings cannot be extrapolated to milder forms of the This work was supported by grants from the Ministry disease and those with predominantly left ventricular systolic of Economy and Competitiveness, Instituto Carlos III dysfunction. Third, this study has the inherent limitations of the (PI20/00392), CIBER Cardiovascular (16/11/00420 and small number of participants. As such, we cannot discard that the 16/11/00403). The authors have no other funding, financial neutral finding on some exposures may be due to low statistical relationships, or conflicts of interest to disclose relative to power (Type II error). Fourth, the patients here included were this work. those with ambulatory WHF. Leg compression’s feasibility, efficacy, and safety should also be tested in hospitalized patients. Finally, the diuretic strategy used here was the subcutaneous SUPPLEMENTARY MATERIAL administration of furosemide. Further studies should confirm current findings using intravenous administration of loop The Supplementary Material for this article can be found diuretics and better define the causal contribution of VLC in online at: https://www.frontiersin.org/articles/10.3389/fcvm. intravascular refilling. 2022.847450/full#supplementary-material Frontiers in Cardiovascular Medicine | www.frontiersin.org 9 July 2022 | Volume 9 | Article 847450 Civera et al. Venous Leg Compression in Heart Failure REFERENCES position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. (2019) 21:137–55. doi: 10.1002/ejhf.1369 1. Chioncel O, Mebazaa A, Harjola VP, Coats AJ, Piepoli MF, Crespo-Leiro 16. Girerd N, Seronde MF, Coiro S, Chouihed T, Bilbault P, Braun F, et al. MG, et al. ESC Heart Failure Long-Term Registry Investigators. Clinical INI-CRCT, Great Network, and the EF-HF Group. Integrative assessment of phenotypes and outcome of patients hospitalized for acute heart failure: the congestion in heart failure throughout the patient journey. JACC Heart Fail. ESC Heart Failure Long-Term Registry. Eur J Heart Fail. (2017) 19:1242– (2018) 6:273–85. doi: 10.1016/j.jchf.2017.09.023 54. doi: 10.1002/ejhf.890 17. Cleland J, Pfeffer MA, Clark AL, Januzzi JL, McMurray J, Mueller C, et al. The 2. Javaloyes P, Miró Ò, Gil V, Martín-Sánchez FJ, Jacob J, Herrero P, et al. ICA- struggle towards a Universal Definition of Heart Failure-how to proceed? Eur SEMES Research Group. Clinical phenotypes of acute heart failure based on Heart J. (2021) 42:2331–43. doi: 10.1093/eurheartj/ehab082 signs and symptoms of perfusion and congestion at emergency department 18. Lee TH, Kuo G, Chang CH, Huang YT, Yen CL, Lee CC, et al. Diuretic effect presentation and their relationship with patient management and outcomes. of co-administration of furosemide and albumin in comparison to furosemide Eur J Heart Fail. (2019) 21:1353–65. doi: 10.1002/ejhf.1502 therapy alone: An updated systematic review and meta-analysis. PLoS ONE. 3. Felker GM, Ellison DH, Mullens W, Cox ZL, Testani JM. Diuretic therapy for (2021) 16:e0260312. doi: 10.1371/journal.pone.0260312 patients with heart failure: JACC state-of-the-art review. J Am Coll Cardiol. 19. Paterna S, Di Gaudio F, La Rocca V, Balistreri F, Greco M, Torres D, et (2020) 75:1178–95. doi: 10.1016/j.jacc.2019.12.059 al. Hypertonic Saline in Conjunction with High-Dose Furosemide Improves 4. Boorsma EM, Ter Maaten JM, Damman K, Dinh W, Gustafsson F, Dose-Response Curves in Worsening Refractory Congestive Heart Failure. Goldsmith S, et al. Congestion in heart failure: a contemporary look Adv Ther. (2015) 32:971–82. doi: 10.1007/s12325-015-0254-9 at physiology, diagnosis and treatment. Nat Rev Cardiol. (2020) 17:641– 20. de la Espriella R, Miñana G, Santas E, Núñez G, Lorenzo M, Núñez 55. doi: 10.1038/s41569-020-0379-7 E, et al. Effects of empagliflozin on CA125 trajectory in patients 5. Paterna S, Di Pasquale P, Parrinello G, Fornaciari E, Di Gaudio F, Fasullo S, with chronic congestive heart failure. Int J Cardiol. (2021) 339:102– et al. Changes in brain natriuretic peptide levels and bioelectrical impedance 5. doi: 10.1016/j.ijcard.2021.06.045 measurements after treatment with high-dose furosemide and hypertonic 21. Andriessen A, Apelqvist J, Mosti G, Partsch H, Gonska C, Abel M. saline solution versus high-dose furosemide alone in refractory congestive Compression therapy for venous leg ulcers: risk factors for adverse events and heart failure: a double-blind study. J Am Coll Cardiol. (2005) 45:1997– complications, contraindications - a review of present guidelines. J Eur Acad 2003. doi: 10.1016/j.jacc.2005.01.059 Dermatol Venereol. (2017) 31:1562–8. doi: 10.1111/jdv.14390 6. Kitsios GD, Mascari P, Ettunsi R, Gray AW. Co-administration of 22. Hirsch T. Oedema drainage and cardiac insufficiency–when is there furosemide with albumin for overcoming diuretic resistance in patients a contraindication for compression and manual lymphatic drainage? with hypoalbuminemia: a meta-analysis. J Crit Care. (2014) 29:253– Phlebology. (2018) 47:115–9. doi: 10.12687/phleb2420-3-2018 9. doi: 10.1016/j.jcrc.2013.10.004 23. Attaran RR, Cavanaugh A, Tsay C, Ahmad T, Ochoa Chaar CI, 7. Urbanek T, Juśko M, Kuczmik WB. Compression therapy for leg Persing S, et al. Safety of compression therapy for venous ulcer disease oedema in patients with heart failure. ESC Heart Fail. (2020) 7:2012– in the setting of congestive heart failure. Phlebology. (2020) 35:556– 20. doi: 10.1002/ehf2.12848 60. doi: 10.1177/0268355520905178 8. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et 24. Dereppe H, Hoylaerts M, Renard M, Leduc O, Bernard R, Leduc A. al. Authors/Task Force Members; Document ReviewersDocument Reviewers. Hemodynamic impact of pressotherapy. J Mal Vasc. (1990) 15:267–9. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic 25. Bain RJ, Tan LB, Murray RG, Davies MK, Littler WA. Central haemodynamic heart failure: The Task Force for the diagnosis and treatment of acute changes during lower body positive pressure in patients with congestive and chronic heart failure of the European Society of Cardiology (ESC). cardiac failure. Cardiovas Res. (1989) 23:833–7. doi: 10.1093/cvr/23. Developed with the special contribution of the Heart Failure Association 10.833 (HFA) of the ESC. Eur J Heart Fail. (2016) 18:891–975. doi: 10.1002/ 26. Wilputte F, Renard M, Venner JP. Hemodynamic response to multilayered ejhf.592 bandages dressed on a lower limb of patients with heart failure. Eur J Lym. 9. Young T, Connolly N, Dissemond J. UrgoKTwo R Compression Bandage (2005) 15:1–4. System made easy. Wounds Int. (2013) 4:1–6. 27. Gong S, Dong Y, Gunderson TM, Andrijasevic NM, Kashani KB. 10. Rekha PD, Rao SS, Sahana TG, Prabhu A. Diabetic wound Elastic bandage vs hypertonic albumin for diuretic-resistant volume- management. Br J Community Nurs. (2018) 23 (Suppl 9):S16– overloaded patients in intensive care unit: a propensity-match study. 22. doi: 10.12968/bjcn.2018.23.Sup9.S16 Mayo Clin Proc. (2020) 95:1660–70. doi: 10.1016/j.mayocp.2020. 11. Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran 03.029 K, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography Conflict of Interest: The authors declare that the research was conducted in the endorsed by the European Association of Echocardiography, a registered absence of any commercial or financial relationships that could be construed as a branch of the European Society of Cardiology, and the Canadian potential conflict of interest. Society of Echocardiography. J Am Soc Echocardiogr. (2010) 23:685– 788. doi: 10.1016/j.echo.2010.05.010 Publisher’s Note: All claims expressed in this article are solely those of the authors 12. Felker GM, Lee KL, Bull DA, Redfield MM, Stevenson LW, Goldsmith SR, et al. NHLBI Heart Failure Clinical Research Network. Diuretic strategies and do not necessarily represent those of their affiliated organizations, or those of in patients with acute decompensated heart failure. N Engl J Med. (2011) the publisher, the editors and the reviewers. Any product that may be evaluated in 364:797–805. doi: 10.1056/NEJMoa1005419 this article, or claim that may be made by its manufacturer, is not guaranteed or 13. Wu MY, Chang NC, Su CL, Hsu YH, Chen TW, Lin YF, et al. Loop endorsed by the publisher. diuretic strategies in patients with acute decompensated heart failure: a meta-analysis of randomized controlled trials. J Crit Care. (2014) 29:2– Copyright © 2022 Civera, Miñana, de la Espriella, Santas, Sastre, Mollar, Conesa, 9. doi: 10.1016/j.jcrc.2013.10.009 Martínez, Núñez, Bayés-Genís and Núñez. This is an open-access article distributed 14. Fudim M, Hernandez AF, Felker GM. Role of volume redistribution under the terms of the Creative Commons Attribution License (CC BY). The use, in the congestion of heart failure. J Am Heart Assoc. (2017) distribution or reproduction in other forums is permitted, provided the original 6:e006817. doi: 10.1161/JAHA.117.006817 author(s) and the copyright owner(s) are credited and that the original publication 15. Mullens W, Damman K, Harjola VP, Mebazaa A, Brunner-La Rocca HP, in this journal is cited, in accordance with accepted academic practice. No use, Martens P, et al. The use of diuretics in heart failure with congestion - a distribution or reproduction is permitted which does not comply with these terms. Frontiers in Cardiovascular Medicine | www.frontiersin.org 10 July 2022 | Volume 9 | Article 847450