Estimation of the plasma volume status of elderly patients with acute decompensated heart failure using bedside clinical, biological, and ultrasound parameters

Assessment of intravascular volume status to ensure optimization before hospital discharge could significantly reduce readmissions. It is difficult to evaluate congestion on clinical signs during an episode of acute heart failure (ADHF) in elderly patients.


| INTRODUCTION
Heart failure is a common disease, with a prevalence of estimates 1,130,000 people in France, with an incidence of more than 120,000 new cases per year. 1 It is a serious disease, burdened with decompensation, with significant consequences on quality of life and soaring costs of public health. 2 Its incidence and prevalence increase considerably with age, making it the most common cause of hospitalization in the elderly, with more than 50,000 hospitalizations per year in people over 75 in France. 3 The assessment of intravascular congestion is paramount in treating acute decompensated heart failure (ADHF) in elderly patients, as it helps optimize diuretic therapy. Such assessment is based on clinical presentation. Elevated jugular venous pressure is a specific sign of overload, 4 though not a very sensitive one. 5,6 Natriuretic peptides and chest X-ray are difficult to interpret in the elderly. 7,8 Transthoracic echocardiography (TTE) remains a method of choice to assess congestion by analyzing left ventricular filling pressures and the inferior vena cava (IVC) variations. 4 However, access to TTE is limited and it is performed less than one in five patients in geriatric departments. 9,10 IVC diameter and compliance as assessed by echocardiography is a fast and effective way to obtain the right-atrial pressure with a threshold of 21 mm and respiratory variation <50% to define hypervolemia. 11,12 The IVC can guide the clinician in administering effective decongestive treatment and achieving euvolemia. 13,14 In a frail, multimorbid and poly-medicated patient, an ultra-portable ultrasound device at bedside is a valuable, easy-to-use tool. 14 Other parameters have been proposed for the diagnosis and monitoring of volume overload in ADHF patients. The indirect estimation of plasma volume status (ePVS) by the Duarte formula 15 could be useful in diagnosing ADHF. 16 The occurrence of renal failure under diuretic treatment is frequent and increases the length of hospital stay. The use of a blood volumemonitoring tool might be helpful to avoid renal failure [17][18][19] (Appendix A).
The aim of the study was to determine the relationship between various parameters of blood volume assessment (clinical and laboratory parameters, IVC ultrasound exam, and instantaneous plasma volume) in patients over 75 years of age admitted for ADHF. Then, to determine whether IVC parameters enable identifying patients at risk of functional acute renal failure related to excessive depletion.

| Study presentation
Our study is an observational, longitudinal, prospective, single-center cohort study that was conducted in the cardiology department of Bicêtre hospital between January 1, 2019, and May 1, 2020. Consecutive patients older than 75 years, hospitalized for ADHF and discharged alive were eligible for the study. The ADHF diagnosis was based on a combination of clinical signs and symptoms, admission N terminal pro brain natriuretic peptide (NT-proBNP) >1500 pg/ml and echocardiographic structural abnormalities (left ventricular ejection fraction [LVEF], filling pressures). 4,20 The study excluded patients with NT-proBNP <300 pg/ml, cardiogenic shock, acute MI < 1 week, acute pulmonary edema, acute anemia requiring red blood cell transfusions, severe liver failure not related to heart failure with liver enzymes aspartate-amino-transférase and alanine aminotransferase > 4 N, severe chronic kidney disease (CKD) with estimated glomerular filtration rate (eGFR) < 15 ml/min on admission, or on dialysis.
The study complied with the declaration of Helsinki and was approved by the local ethics committee (#20181128163709). All patients gave their informed consent.

| Management
On admission, patients were treated with loop diuretics such as Furosemide according to the DOSE trial-inspired protocol. 21 Doses were adjusted according to the doctor's clinical judgment and the patient's frailty. 22 The motive for switching to oral diuretic and the cumulative IV dose were recorded.
During hospitalization, a daily clinical examination provided data on weight, heart rate (HR), blood pressure (BP), and the presence of hepatojugular reflux (HJR) or jugular vein distention (JVD) if any. The occurrence of lower limb edema (LLE) was graded according to extent (none, ankles, knees, and thighs), and similarly for lung crackles (none, lung base, half of the lungs, more than 2/3 of the lungs). Biological data collected daily-included plasma protein levels, hemoglobin, hematocrit, urea and creatinine, with estimated renal function (eGFR according to the CKD-EPI formula) until discharge or up to Day 8. NT-proBNP and plasma albumin were measured at admission. IVC status was defined according to the guidelines 23 as five possibilities: "thin," "non-dilated with diameter (D) < 21 mm and respiratory variation (RV) > 50%," "dilated with D < 21 mm or RV < 50%," "dilated with D > 21 mm and RV < 50%," "dilated with D > 21 mm and RV < 50% and dilated hepatic veins." Estimated plasma volume status was estimated using the Duarte formula: Hypervolemia was defined by echo by a "dilated IVC > 21 mm and/or RV < 50%." 24,25 The biological definition of hypervolemia was an ePVS score > In the acute phase, the mean duration of intravenous Furosemide treatment was 4.8 ± 1.7 days with a mean dose of 775 ± 1132 mg.
Acute renal failure (>30% increase from baseline creatinine) was found in 8% of patients.  To our knowledge, our study is one of the first to analyze the association between clinical, biological, and IVC variations, as well as to use both parameters to monitor diuretic treatment of acute heart failure in an elderly patients.

| Blood volume analysis
Our findings are consistent with previous studies. The clinical evaluation of blood volume showed a good performance of the examination of JVD, which has a class IB recommendation according to American Heart Association (AHA) guidelines. 27 In Miller JB's 2012 study, 28 the inspiratory collapse of IVC < 33% has a Se of 80% and Sp of 81% to define hypervolemia. In our study, an IVC > 21 mm and an RV < 50% on admission is superior to clinical evaluation alone and identifies 100% of acutely decompensated patients.
The estimation of plasma volume as a parameter guiding ADHF management has inspired several studies following K. Duarte's 2015 publication 15 of the results on the EPHESUS study database. 29 A study by Chouihed 26 suggests that an ePVS value above 5.12 × 10 −4 dL/g at the first blood test in patients presenting with acute dyspnea at the emergency department could help diagnose ADHF. In Kobayashi's study, ePVS is associated with hemodynamic markers of congestion. 29 In our study, we did not find any correlation between the selected ePVS value and clinical or ultrasound (IVC) signs of congestion. As for the change in ePVS after the onset of depletion, the results lack differential value. A possible explanation may be that the ePVS may not be as reliable in elderly patients and that the threshold needs adjusting.
In our study, NT-proBNP correlated only slightly with other criteria for hypervolemia. This is consistent with previous studies 27 and invites us to retain the use of NT-proBNP for ADHF diagnosis and prognosis only, but not for monitoring patients' congestive states.
Other criteria such as plasma protein levels and hematocrit vary little in the first few days and are poorly correlated with other signs of hypervolemia. This has been shown in other studies. 28

| Managing diuretic therapy
In the study by Yavaşi et al, the authors show that the analysis of IVC collapsibility is useful to manage diuretic therapy. 28 In our study, we investigated four ways to monitor patients' blood volume during diuretic therapy, and we found that the combined evaluation of daily clinical signs (JVD) and the ultrasound assessment of IVC was the best method. The combined practice of clinical and ultrasound assessment of congestion allows for early detection of patients whose

| Limitations of the study
Our study represents a descriptive analysis of the volume status of elderly subjects hospitalized for decompensated HF and explores the combination of different monitoring parameters. The limitations of the study are a small number of patients and the absence of a control group. Therefore, we could not measure diagnostic performance markers (Se, Sp, positive predictive value, negative predictive value).

| CONCLUSION
In ADHF patients older than 75 years, clinical evaluation of congestion and the ultrasound examination of IVC correlate well. Evaluation of IVC measurement with an ultraportable device is feasible by a geriatrician.
The correlation between JVD/HJR and IVC measurement is good. The combined clinical and ultrasound analysis identifies patients at risk of functional renal failure and should facilitate the adjustment of diuretic doses in elderly patients with acute decompensated HF.

ACKNOWLEDGMENT
Not applicable.