Why Do Patients with Heart Failure Retain Fluid?
The development of peripheral oedema in patients with HF is related to fluid excess. As the heart starts to fail, renal perfusion falls. The kidneys respond by increasing the production of renin, leading to more aldosterone production, which is consequently followed by sodium and water retention.7 Arginine vasopressin (AVP) is also released,8,9 further enhancing fluid retention and stimulating thirst. The activation of the renin–angiotensin–aldosterone and AVP systems maintain cardiac preload (more fluids) and afterload (vasoconstriction, mainly due to angiotensin II), thereby maintaining the homeostasis of the cardiovascular system but at a cost of increased systemic venous pressure (VP). The heart itself tends to worsen with time as the failing LV tends to dilate, as does the left atrium, particularly if mitral regurgitation develops. The elevated VP can further reduce renal blood flow as the gradient between mean renal arterial pressure (often itself decreased by the HF process) and VP declines. Glomerular filtration rate falls, enhancing and perpetuating the vicious cycle.10
How Do We Identify Congestion?
The accumulation of fluids is a gradual process. In normal circulation, there is continuous filtration of fluid from the intravascular space into the tissues at a rate dependent on the gradient between the intravascular and extravascular hydrostatic pressure. Any filtered fluid is then drained by the lymphatics. Overt cardiogenic peripheral oedema develops because the fluid retention results in an increase in intravascular hydrostatic pressure and a commensurate increase in the filtration rate, which eventually exceeds the capacity of the lymphatics to drain fluid away (see Figure 1).
Some patients do not present until they have developed widespread peripheral oedema. In such cases the need for medical intervention is obvious. However, a substantial number of cases of subclinical congestion will not be clinically recognised, despite the presence of symptoms (i.e. breathlessness). In patients with no known cardiac 
disease, particularly in older people,11,12 the identification of subclinical congestion (and underlying cardiac dysfunction) at an earlier stage might change the trajectory of the disease. In patients who are already known to have HF, whether subclinical congestion is important is not clear.
It used to be said that assessment by an experienced clinician is probably adequate to determine fluid status.13 However, the art of clinical examination is declining, partly because of the widespread availability of echocardiography and other functional or biochemical tests, partly because accurate assessment can take a long time, particularly in patients with poor mobility, and partly because clinical signs are not often specific for the disease; all of this leads to doctors being less skilled in clinical assessment.14 Moreover, clinicians often disagree when faced with typical signs of HF, which may have an unreliable relationship to diagnostic findings, including chest X-rays.15 Nevertheless, a well-conducted clinical examination in patients with suspected HF is still a powerful tool to identify sicker patients who have a worse prognosis, irrespective of their LVEF.16
The most reliable clinical sign indicating volume overload is a raised jugular venous pressure (JVP), which also provides powerful prognostic information.17 However, the clinical assessment of the JVP is often challenging and subjective18 and its assessment by ultrasound might thus be useful. In the vast majority of cases, assessing the jugular vein by ultrasound is possible and allows the identification of patients with more advanced congestion and higher natriuretic peptides (NPs),19 who are at higher risk of adverse outcomes.20 Assessing the inferior vena cava diameter by echocardiography provides complementary information to clinical examination, is validated against invasively measured haemodynamics and is readily available in echocardiographic departments.21,22
The use of NPs as a measure of cardiac dysfunction is advised by current guidelines. NPs are one of the body’s defences against congestion.23 Any stretch of the myocardium leads to an increase in NP level, and raised levels in a treated patient suggests that there is residual congestion, regardless of LVEF. It is important to remember that circulating plasma levels should be adjusted for age and that co-morbidities, including atrial fibrillation, renal dysfunction and obesity, may influence NP levels.24 In clinical settings without easy access to echocardiography, measuring the NP level is a simple and reliable tool, efficient in terms of patient and staff time. Serial NP assessment at home is feasible with a finger-stick test and this approach in high-risk patients might detect possible decompensation early.25
Invasive devices have potential as tools to predict congestion.26 Possible variables that can be measured include trans-thoracic impedance, pulmonary artery pressure and left atrial (LA) pressure. Implantable devices, such as cardiac resynchronisation therapy (CRT) pacemakers and/or defibrillators (ICDs) can measure intrathoracic impedance, thus estimating pulmonary congestion, but their predictive value is still uncertain.27
In the HOMEOSTASIS trial, measurements of LA pressure were taken twice daily in 40 patients with advanced HF. After the first 3 months, treatment was personalised based on the readings, which led to a fall in LA pressure (17.6 mmHg in the first 3 months to 14.8 mmHg; p=0.003), the prescription of higher doses of angiotensin-converting-enzyme inhibitors (ACE-I) and beta-blockers, a lesser need for high doses of loop diuretics and improvement in both New York Heart Association (NYHA) class and LVEF.28
In the CHAMPION trial, pulmonary arterial pressure was measured daily using wireless devices permanently implanted into the pulmonary artery. There was a 37 % decrease in the number of hospitalisations for HF over the 15 months of follow-up.29
An objective measure of ‘congestion’ might be helpful not only to allow physicians to tailor treatments to specific targets, but also to allow more reproducible randomised controlled trials designed to assess decongestive strategies, particularly when markers of cardiac dysfunction (such as LVEF) are not significantly impaired. For example, the ALDO-DHF and TOPCAT trials in patients with HeFNEF suggested that while spironolactone might worsen renal function and anaemia in patients with low circulating NPs (and thus, presumably, little congestion), it significantly reduced HF hospitalisations in patients with higher N-terminal of the prohormone brain natriuretic peptide (NT-proBNP).30,31 The majority of HF trials nowadays include raised NPs as a major criterion for enrolment.
Why Does Congestion Matter?
Congestion is an important cause of symptoms in patients with HF. The discomfort of swollen legs and ascites precipitates hospitalisation. Congestion is associated with the sensation of breathlessness, particularly when patients develop pulmonary oedema and pleural effusions. Congestion reduces hepatic function, and the congested liver can itself be a source of discomfort. As described above, congestion causes renal dysfunction by reducing the transrenal pressure gradient. Anaemia, which is highly prevalent among HF patients, can be made worse by congestion through dilution, and can further exacerbate symptoms and cardiac dysfunction.32
The commonest cause for hospitalisation in patients with CHF is fluid retention and congestion.4 Hospitalisation itself is associated with an adverse prognosis, and repeated hospitalisations are associated with increasingly poor survival.33 Congestion itself, and not just reduced cardiac function, thus appears to be associated with a poor prognosis.Congestion is a powerful marker of an adverse prognosis and it is thus potentially an important therapeutic target.
How Do We Treat Congestion in Chronic Heart Failure Patients?
Inducing a Diuresis
Diuretics are the mainstay of management for patients with congestion. It has become a truism to state that their use is based on empirical judgement and subjective clinical evaluation, rather than evidencebased medicine.
Different classes of diuretics are used in patients with chronic HF, although loop diuretics (furosemide, bumetanide and torasemide) are the most widely prescribed. They exert their effect primarily by inhibiting the sodium–potassium–chloride co-transporter in the thick ascending limb of the Loop of Henle, by preventing the re-absorption of these ions, a subsequent diuresis occurs. The loop diuretics mediate their effect from the luminal side of the tubule, and so some glomerular filtration is essential to allow them to work.
The beneficial effects of a loop diuretic on JVP, pulmonary congestion, peripheral oedema and body weight have been known for years; diuretics also improve cardiac function, symptoms, and exercise tolerance in patients with HF.34–36 However, no randomised prospective study has ever evaluated their impact on the outcome of chronic HF patients. Particularly in patients with severe renal dysfunction, a reduced response to them is frequently observed and their use alone may be insufficient.
For those responding poorly to a loop diuretic alone, the combination with a thiazide (or thiazide-like) diuretic can be very potent. Although metolazone is often used in this scenario, there is little evidence that it is superior to other agents, such as bendroflumethiazide.37 The trial experience of combining several classes of diuretics is still limited to just above 300 patients enrolled in small, mechanistic studies.38
Mineralocorticoid receptor antagonists (MRAs) are, of course, also diuretics. Two large trials39,40 have shown that adding spironolactone or eplerenone to standard treatment in symptomatic patients with reduced LVEF (either chronically or after a recent myocardial infarction) produces morbidity and mortality benefits. Whether the beneficial effects are due to a reduction in congestion is not at all clear given the wide range of actions of MRAs.41 The dose of MRA used to induce a diuresis is typically much higher than that used to treat chronic HF.
The clinical benefits observed following the introduction of loop diuretics are counterbalanced by a more marked activation of the renin– angiotensin system.42 An important matter to be considered is thus whether adding a diuretic in patients who are not clinically congested has any benefit. It is not at all clear whether diuretics lead to improved exercise capacity and/or improvement in biochemical measures of subclinical congestion (including NPs). Francis and colleagues showed that the acute injection of a loop diuretic (furosemide 1.3 ± 0.6 standard deviation [SD] mg/kg body weight) in patients who are not congested can provoke transient adverse haemodynamic effects, with an increase in LV filling pressures and a fall in stroke volume index,43 with restoration of better haemodynamics and neurohumoral variables only after several hours. Other reports suggest that using diuretics unnecessarily (when there is no evidence of congestion) for a longer period of time might decrease systolic and diastolic blood pressure and increase circulating levels of renin compared with placebo.44
Retrospective studies have raised concerns about a possible detrimental effect of the long-term use of loop diuretics in HF patients, possibly caused by chronic and sustained adverse neuroendocrine activation.45,46 However, it is also logical to think that patients with more severe HF will be prescribed more loop diuretics, which would have then been associated with the adverse outcome.47 The relation between diuretic dose and outcome needs more clarification, but there is the general belief that achieving the lowest tolerated dose, or even a definite withdrawal from loop diuretics, might be beneficial.
A small number of studies have attempted to identify patients who might be able to tolerate diuretic withdrawal. Perhaps a third of patients with HF can tolerate loop diuretic withdrawal, particularly if LVEF is above 27 % or the baseline dose of loop diuretics is ≤40 mg furosemide/ day;48 this proportion significantly increases in patients who are not clinically considered at high risk of deterioration49 and might reach up to 90 % success at 3 months follow-up when the LVEF is normal.50