causes and treatment of oedema.pdf

156 | MARCH 2013 | VOLUME 10 www.nature.com/nrcardio

Department of Cardiology, Hull York Medical School, University of Hull, Castle Hill Hospital, Cottingham HU16 5JQ, UK (A.L. Clark, J.G.F.Cleland).

Correspondence to: A.L. Clark [email protected]

Causes and treatment of oedema in patients with heart failureAndrew L. Clark and John G.F. Cleland

Abstract | Oedema is one of the fundamental features of heart failure, but the pathophysiology of oedema varies. Patients present along a spectrum ranging from acute pulmonary oedema to gross fluid retention and peripheral oedema (anasarca). In patients with pure pulmonary oedema, the problem is one of acute haemodynamic derangement; the patient does not have excess fluid, but pulmonary venous pressure rises such that the rate of fluid transudation into the interstitium of the lung exceeds the capacity of the pulmonary lymphatics to drain away the fluid. Conversely, in patients with peripheral oedema, the problem is one of fluid retention. Understanding the causes of oedema will enable straightforward, correct management of the condition. For patients with acute pulmonary oedema, vasodilatation is important to reduce cardiac filling pressures. For patients with fluid retention, removing the fluid, using either diuretics or mechanical means, is the most important consideration.

Clark, A.L. & Cleland, J.G.F. Nat. Rev. Cardiol. 10, 156170; published online 15 January 2013; doi:10.1038/nrcardio.2012.191

IntroductionA striking feature of most patients presenting with heart failure (HF) is the presence of pulmonary oedema, peripheral oedema, or both. Cardiogenic congestion usually responds well to diuretic therapy, leading to neglect of both its importance and its cause. The term congestive heart failure has fallen out of favour as patients do not usually have congestion other than during acute episodesof HF. Improved understanding of the patho physiology of oedema might allow treatments to be used more e ffectively, and point the way to new therapeutic targets.

The clinical behaviour of patients with oedema falls along a spectrum ranging from pulmonary oedema at one end to peripheral oedema at the other. Patients with predominant pulmonary oedema are breathless puffers and those with predominant peripheral oedema are fluidloaded bloaters. Most patients presenting with severe HF will lie somewhere along this spectrum. Importantly, many patients have both pulmonary and peripheral oedema, but the pathophysiology of the two conditions is distinct.

HF is a common reason for admission to hospital. In England and Wales in 20062007, there were more than 250,000 deaths and hospital discharges for HF.13 Data from the national audit of HF hospital admissions in the UK suggest that breathlessness at rest, presu mably indicating pulmonary oedema, was present in 28% of patients on admission, with greatly limited exercise capacity present in a further 40%, and 43% had moderate or severe oedema.2,3 Many trials of patients with acute HF

have included patients with little evidence of breathlessness at rest (Table1); thus, the evidencebased information for treating acute pulmonary oedema in particular is limited. A lot is now known about the best management of patients with chronic HF, but little attention has been paid to the management of oedema since the advent of loop diuretics in the 1960s. New pharmaceutical developments have reawakened interest in oedema and acute HF. In this Review, we aim to describe what is known about the pathophysiology of cardiogenic oedema, and to discuss how knowledge of the pathophysiology can guidetreatment.

Pulmonary oedemaPathophysiology and presentationAcute pulmonary oedema usually presents as a dramatic medical emergency. The typical patient presents with a short history (measured in minutes or hours) of very severe breathlessness. Fluid accumulation in the lungs results in impaired gas exchange and consequent hypoxia. Generally, the patient coughs up the oedema fluid as pink, frothy sputum, and will struggle to speak. The patient usually needs to sit upright and any attempt to lay them flat might cause further distress and can be fatal. Generalized sympathetic nervous system activation results in tachycardia, cold skin, pallor, sweating and, often, in systemic (and if measured, pulmonary) hypertension.

Usually, acute pulmonary oedema has a precipitantacute ischaemia or myocardial infarction and arrhythmias (particularly atrial fibrillation) are common contributors, and acute mitral regurgitation is less so. Chest infection can both cause, and be a complication of, pulmonary oedema.46 Other causes include a high dietary salt load and uncontrolled hypertension.

Competing interestsJ.G.F. Cleland declares associations with the following companies: Amgen and Novartis. A.L. Clark declares an association with Novartis. See the article online for full details of the relationships.

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NATURE REVIEWS | CARDIOLOGY VOLUME 10 | MARCH 2013 | 157

The pathophysiology of acute pulmonary oedema is best understood as a haemodynamic phenomenon. In the normal circulation, the FrankStarling mechanism holds: As the load on the left ventricle increases prior to the onset of systole, so does the work of the heart during the subsequent contraction (Figure1). The preload is equivalent to the enddiastolic (or filling) pressure in the left ventricle, and is the same as the left atrial pressure and pulmonary venous pressure at the end of diastole (in the absence of mitral valve stenosis).

Another relationship described by Starling explains the net flow of fluid across a capillary in terms of the forces acting across the capillary wall.7 Although the balance of forces changes along the length of the capillary, the major factor causing the fluid to move out of the capillary is the difference between the hydrostatic pressure within the capillary and the lower pressure in the surrounding interstitial fluid. Opposing this movement is the colloid osmotic pressure within the capillary, which is mainly provided by albumin. The colloid osmotic pressure is higher than the osmotic pressure in the interstitium and thus tends to keep the fluid in the capillary. A protective mechanism is provided by lymphatic washout of any albumin that reaches the interstitium, resulting in an increase in the osmotic pressure gradient between the capillary and the interstitium, which seems to reducetransudation of fluid.8 In addition, some resistance to transudation of fluid is provided by the alveolarc apillary basement membrane.

In the normal circulation, fluid is continuously transu ded from the capillaries into the interstitium, and fluid crossing into the interstitial space is removed by the lymphatic system. The pulmonary capillary wall is relatively impervious to fluid, and the tight apposition of the pulmo nary capillary and alveolar membranes (the alveolar capillary basement membrane) enables efficient gas transfer. Even if fluid escapes from the capillaries into the interstitium, provided that it does not spill over into the alveoli, lymphatic drainage will clear the fluid and the patient is unlikely to experience breathlessness at rest.

In the failing left ventricle, the curve relating the enddiastolic pressure to left ventricular work moves down and to the right. The filling pressure (preload) in the left ventricle required to deliver a given amount of work increases. As the left ventricular filling pressure rises, so does the pressure in the left atrium and pulmonary capilla ries. As hydrostatic pressure increases, capillary wall tension increases as the fourth power of the radius of the capillaries, increasing the rate of transmural filtration. At the same time, lymphatic drainage into the systemic veins could be impeded by increases in systemic venous pressure. Eventually, a tipping point is reached when the capacity of the lymphatic system to remove fluid from the interstitium is exceeded, and fluid starts to a ccumulate in the airspaces of the lungs (alveolaroedema).

Elegant experiments in dogs have demonstrated the presence of such a critical tipping point. Beyond the threshold, there is a nearlinear relation between the increase in left atrial pressure and the rate of oedema formation (Figure2).9 A reduction in plasma protein levels reduces the threshold at which oedema starts to accumulate. Notably, in acute pulmonary oedema the total amount of fluid in the body does not increase and the effect of impaired cardiac function leading to haemodynamic changes results in fluid moving to the wrong body compartment. Indeed, some evidence suggests that the fluid extravasation into the alveoli results in a reduction in blood volume during acute pulmonary oedema, which then increases back to normal levels during s uccessful treatment.10

Key points

Oedema is one of the fundamental features of heart failure Clinical trial data to guide best practice in managing cardiac oedema arelacking Acute pulmonary oedema is characterized by accumulation of fluid in the air

spaces, not by fluid overload Acute pulmonary oedema is best treated as a haemodynamic problem

usingvasodilators Peripheral oedema is characterized by an excess of total body water Peripheral oedema is best treated by removing fluid, either with diuretics

ormechanically

Table 1 | Trials of patients with acute heart failure

Study name

Intervention Mode of action

Mean patient age (years)

Women (%)

Systolic blood pressure (mmHg)

Heart rate (per min)

Respiratory rate (permin)*

LVEF (%)*

-blocker use (%)

Digoxin use (%)

Time to study inclusion

30-day mortality (%)

VERITAS63 Tezosentan Endothelin antagonist

70 40 131 81 26 [>24] 29 [


A patient with acute pulmonary oedema classically presents with a high left ventricular filling pressure and high systemic vascular resistance.11 Some patients present with pulmonary oedema owing to uncontrolled hypertension. In these cases, the problem is an increase in the left ventricular afterload and consequent rise in filling pressure required to maintain cardiac output. Hypertension, which can occur as a result of an acute salt load or a phaeochromocytoma, might cause recurrent episodes of flash pulmonary oedema; that is, very abrupt onset of episodes. Such events are commonly associated with hypertension

and, in particular, with renal artery stenosis.12 Flash pulmonary oedema often happens in the presence of normal left ventricular systo lic function, highlighting the involvement of the neuro hormonal system in the genesis of acute pulmonary oedema.13 AngiotensinII seems to have a particularly important role in flash pulmonary oedema. When infused into renal arteries at a low perfusion pressure (mimicking renal artery stenosis), angiotensinII causes marked systemic hypertension, salt and water retention, and pulmonary oedema.14

The role of abnormalities in the pulmonary vasculature, the alveolarcapillary membrane, and the alveolar wall itself in the development of acute pulmonary oedema is not clear. Some evidence suggests that high catecholamine levels, as seen in patients with a phaeochromocytoma, may cause an increase in pulmonary capillary permeability resulting in pulmonary oedema without a great increase in left ventricular filling pressure.15 In highaltitude pulmonary oedema, capillary stress fracture can contribute to the development of oedema, although the major cause of pulmonary oedema is excessive hypoxiainduced pulmonary hypertension.16 In adult respiratory distress syndrome, damage to the alveolarcapillary membrane caused by inflammation, infection, trauma, or toxins might cause pulmonary oedema to develop even if the left atrial pressure is not increased.17 Some researchers have drawn attention to the possible contribution of a generalized inflammatory state, resulting in endothelial dysfunction in patients with chronic HF.18 However, there is no good evidence that such mechanisms have a major role in the d evelopment of acute cardiogenic pulmonary oedema.

Another potential contributor to pulmonary oedema formation is sleepdisordered breathing, which is very common in patients with HF.19 Recurrent airway obstructions have been shown to precipitate pulmonary oedema in a dog model.20 In addition, patients with sleep apnoea have a higher salt intake than those without.21 The induction of negative alveolar pressure during airway obstruction could increase transudation of fluid into airspaces. Distinguishing between arousal from sleep apnoea and paroxysmal nocturnal dyspnoea is difficult; the relationship between the two conditions is not yet clear.

Intriguingly, some patients with chronic HF can tolerate extremely high left atrial pressures that would provoke severe pulmonary oedema in an otherwise healthy person. This observation might indicate increased pulmo nary lymphatic drainage,22 particularly in patients with mitral stenosis.23 Alternatively, the alveolar capillary membrane may become thickened, reducing pulmonary microvascular permeability.24,25 Such changes are consistent with the observation that the diffusing capacity of the alveolar capillary membrane is reduced in patients with chronic HF.26 Increases in pulmo nary arteriolar tone could reduce pulmonary blood flow and capillary distension, protecting the lung from oedema. In healthy individuals, little smooth muscle is present in the precapillary pulmonary arterioles, but in the setting of chronic disease, smooth muscle cell hypertrophy occurs, enabling powerful vasoconstriction.25

Left ventricular preload

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Figure 1 | The FrankStarling law of the heart. In the healthy heart (blue line), increasing preload results in greater ventricular work. In the failing heart (red line), the curve moves down and to the right. Thus, to attain a particular amount of left ventricular work, the required filling pressure is greater (indicated by arrow).

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Figure 2 | The correlation between increasing left atrial pressure and the rate of development of pulmonary oedema. No oedema forms until left atrial pressure reaches a critical threshold (around 25 mmHg), and thereafter, left atrial pressure is directly related to the rate of oedema development. Permission obtained from Walters Kluwer Health Guyton, A.C. & Lindsey, A.W. Effect of elevated left atrial pressure and decreased plasma protein concentration on the development of pulmonary oedema. Circ. Res. 7, 649657 (1959).9

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TreatmentAn Xray of the chest shows why acute pulmonary oedema is a medical emergency. Fluid initially collects in the interstitial spaces, resulting in stiff lungs and an increase in the work of breathing. Subsequently, the air spaces are filled with fluid, leading to gross impairment of pulmonary gas exchange (Figure3).The prognosis is bleak following acute pulmonary oedema, with an inhospital mortality of 1020%, varying greatly with age and presence of comorbidity.6 The 1year mortality is at least 20% in patients with the lowest blood pressure (systolic


an increase in mortality and the need for intubation.36 In a retrospective study of nearly 150,000 patients admitted to hospital for acute decompensated HF, opiate use (in >20,000 patients) was associated with poor outcomes and an odds ratio for mortality of 4.84.37 Although no definitive evidence of harm with opiate use exists, the data do not support the routine use of opiates in acute pulmonary oedema, and these drugs should be used with caution, if at all.

Oxygenation and ventilatory supportPatients with hypoxia should be given oxygen. No studies have shown that oxygen helps patients without hypoxia.38 The breeze caused by high air flow and the oxygen mask might be a comfort for some patients and a source of anxiety for others. Care should be taken not to overdose patients with oxygen if they have chronic lung disease and are at risk of CO2 retention. Ventilatory support might be necessary. Patients can get tired, or their gas exchange worsen, despite medical therapy. Invasive venti lation temporarily reverses the situation,39 immediately removes the work of breathing, can directly reduce alveolar oedema by applying positive airway pressure, and improves gas exchange.40

Ventilatory support falling short of endotracheal intubation and invasive ventilation can be helpful. Continuouspositive airway pressure (CPAP) ventilation and bilevel positive airway pressure (BiPAP) ventilation, in which positive pressure is applied to the airway both during inspiration and expiration, have been the most widely studied types of ventilatory support. The two modes of ventilation are collectively known as noninvasive positive pressure ventilation (NIPPV). The evidence to support the use of prehospital noninvasive ventilation is limited, but suggests that preadmission CPAP improves the clinical state of patients arriving at hospital, and reduces the need for invasive ventilation.41 Importantly, CPAP might reduce cardiac output by squeezing pulmonary capillaries and increasing resistance to pulmonary blood flow, but metaanalyses suggest that NIPVV might be beneficial for patients once they have arrived in hospital.42 However, in the 3CPO trial,43 almost 1,000 patients were randomly allocated to CPAP, BiPAP, or routine oxygen therapy and no difference was found in shortterm mortality or the need for intubation among the three groups, although a small improvement was observed in dyspnoea at 1 h with NIPPV. The 3CPO study is, to date, the largest study of ventilation techniques and the only large clinical trial conducted primarily among puffers.

DiureticsStandard practice in the management of acute pulmonary oedema has been the use of intravenous loop diure tics, as the ensuing diuresis is understood to remove the fluid in the lungs. Certainly, loop diuretics reduce circulating fluid volume and, consequently, filling pressure, but they may also have bradykininmediated vaso dilator effects. The notion that loop diuretics reduce preload through venodilatation, and that

the veno dilatation occurs before any increase in urine flow, is firmly entrenched, but the data are weak and controversial.44 Some investigators have reported rapid reductions in filling pressure follow ing intravenous furosemide,44 others report slow changes45 and emphasize that changes in haemodynamic variables are seen only in patients with a subsequent diure sis.46 One small study suggested that furosemide does not relieve symptoms in acute pulmonary oedema.47 In anuric patients undergoing haemo dialysis, neither lowdose nor highdose furosemide had an effect on central haemodynamic variables.48 Others have found that furosemide causes an increase in peri pheral vascular resistance and a decrease in stroke volume when adminis tered acutely.45,49 Part of the difficulty in sifting through the data on haemodynamics with furosemide is that most patients included in studies had had an acute myocardial infarct and thus their condition was i nherently unstable.

Anecdotal reports exist on the use of nebulised furosemide in patients with endstage HF.50 Furosemide has also been used to ease breathlessness in patients with terminal cancer.51 Nebulised furosemide seems to have no effect on haemodynamics in patients with chronic, severe HF, although it does have a diuretic effect,52 and might become more widely used in treating people with endstage disease at home.

VasodilatorsAlthough diuretics are the mostwidely prescribed agents for acute HF syndromes,53 the best approach to treating acute pulmonary oedema is to reduce left ventricular filling pressure (and any mitral regurgitation), which is easily accomplished using nitrovasodilators (Figure4). These drugs reduce preload and afterload, increase cardiac output, and help to reduce any myocardial ischaemia. Very little data exist for the direct comparison between vasodilators and loop diuretics, but vasodilators seem to result in morepronounced reductions in filling pressures and an increase in cardiac output, comparedwith no change or a modest decline in cardiac output with furosemide.5456

In a study in which patients were treated in mobile emergency units delivering intensive therapy much more quickly than usual, Cotter and colleagues showed that highdose nitrate therapy (with lowdose furosemide) was probably more effective than highdose furo semide and lowdose nitrate.57 Highdose nitrate therapy was associated with a reduced need for intubation and a lower risk of myocardial infarction. Some studies suggest that a highdose nitrate strategy is of greater benefit and is possibly safer than routine use of NIPPV and lowdosenitrate.58

Some evidence indicates that acute administration of an angiotensinconvertingenzyme (ACE) inhibitor might relieve pulmonary oedema more rapidly than standard therapy alone.59 Tezosentan, an endothelin antagonist, acutely reduces pulmonary vascular resistance,60 but had no effect on outcomes in a study of 84patients with pulmonary oedema.61 In large studies of acute HF, such as the RITZ62 and VERITAS63 trials,

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tezosentan given at a variety of doses had no positive effect on outcome. Tezosentan did reduce left ventricular filling pressure and increase cardiac output, but these apparently beneficial effects were accompanied by pulmonary vasodilatation and a reduction in arterial oxygen saturation, suggesting shunting of blood through unoxygenated lung tissue.64 In a study of 1,613 patients, another endothelin antagonist, bosentan, was shown to have neutral effects in chronic HF.65 Endothelin antagonists are currently mainly used for treating pulmonaryhypertension.

Natriuretic peptides have attracted a great deal of interest as possible agents for the treatment of acute pulmo nary oedema. The recombinant human Btype natriuretic peptide, nesiritide, causes vasodilatation, reducing both afterload and preload and causing natriuresis.66 Nesiritide was approved for use in the USA follow ing publication of a study showing haemo dynamic benefits of the drug in patients with acute HF,67 but the European regulatory authorities were not convinced of its efficacy. Subsequently, in a study involving 7,000 patients with acute HF,68 nesiritide was shown to have no effect on symptoms, or on the rates of rehospitalization or death. Some evidence indicates that natri uretic peptides might increase capillary permeability,69,70 which might c ounteract the other beneficial effects of theseagents.

Other vasodilators that are in development include relaxin, a potent hormone responsible for vasodilatation during pregnancy. Relaxin is an arterial vasodilator that might also have some inotropic effect, but seems not to reduce venous tone.71 The lack of venodilatation might explain why relaxin does not cause syncope to the same extent as other vasodilators. Syncope caused by peri pheral pooling of venous blood is resistant to therapy and can be difficult to manage in patients with acute pulmo nary oedema, for whom lying flat is contra indicated. Keeping the feet elevated is advisable in this case, while the clinician considers what else can be done. In early studies, relaxin was associated with faster improvement in symptoms than placebo and a possible improvement in outcome.72 In a study of 1,161patients with acute HF, relaxin was shown to improve breathlessness to a greater extent than placebo.73 Relaxin use was associated with a lower mortality at 6months than placebo, but had no effect on the rate of readmission to hospital for HF or renal problems.73 The number of adverse events was small, and if the beneficial effects are confirmed by further studies, relaxin could be an e normous step forward in the management of acute HF.

Another novel arterial vasodilator is clevidipine, an extremely shortacting dihydropyridine calcium antagonist (with a halflife measured in several seconds). In the PRONTO study of 104 patients with acute pulmonary oedema and hypertension who were recruited within a few hours after presenting with symptoms, clevidipine was associated with a faster reduction in blood pressure and relief of breathlessness than standard treatment.74

New pharmacological approachesClearance of pulmonary oedema is, at least in part, an active process, involving an epithelial amiloridesensitive sodium channel, sodium potassium ATPase, and possibly aquaporins.75,76 Alveolar sodium uptake might be enhanced by 2adrenergic receptor stimulation,

77,78 but no convincing clinical data are yet available.79

The transient receptor potential channel TRPV4 is a calciumpermeable channel that has been implicated in disruption of the alveolar membrane during the development of pulmonary oedema. Research in a mouse model suggests that inhibiting TRPV4 with the investigational compound GSK2193874 might speed recovery from or prevent cardiogenic pulmonary oedema.80

Native soluble guanylate cyclase (sGC) requires a haem moiety to be activated. Cinaciguat is a nitric oxide (NO)independent direct activator of haemfree sGC that causes pulmonary and systemic vasodilatation.81 Excessive reductions in blood pressure have been a limiting factor for cinaciguat use to date, but adjustment of dose and target population might enable it to become a useful drug.81 Other agents have been developed, such as riociguat, to stimulate sGC in the presence of haem. Both riociguat and cinaciguat might have other effects on endothelial, renal,82 and myocardial83 function, which are independent of their haemodynamic effects.

Inotropic supportPositive inotropic drugs are commonly used for patients with pulmonary oedema when cardiac output, blood pressure, or both, are low and when the patient is resistant to immediate therapy. Dobutamine is most widely used, but little evidence exists to support this practice. In a randomized trial comparing the effects of dobutamine and nitroprusside in patients with severe HF, nitroprusside was safer.84 Furthermore, the results

Vasodilation Vasoconstriction

Exogenousnitrate

Relaxin Cinaciguat NP Endothelinantagonist

Endothelium

NO cGMP

cGMP cGMP

Smooth muscle cells

sGC

NOSGC

Endothelin

Figure 4 | Schematic representation of possible routes through which vasodilators exert their action. A schematic drawing of arteriolar wall is shown. Vasodilators cause smooth muscle relaxation, either via interaction with receptors in the endothelium (relaxin, NP) or via interaction with the smooth muscle itself (nitrate, cinaciguat). Endothelin antagonists mediate their effects by blocking the interaction of endothelin with its receptor on vascular smooth muscle. Abbreviations: cGMP, cyclic GMP; GC, guanylate cyclase; NO, nitric oxide; NOS, nitric oxide synthase; NP, natriuretic peptide; sGC, soluble guanylate synthase.

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of a metaanalysis of the available data suggest that positive inotropic support with agents working through adre nergic pathways (both adrenergic agonists and phopho diesterase inhibitors) is associated with a worse outcome than placebo.85 Levosimendan, an agent that is both a calciumconcentrationdependent calcium sensiti zer and arterial vasodilator, could be useful in patients with severe chronic HF,86 but its effects do not seem to t ranslate into a benefits in the acute setting.87,88

Myosin activators enhance actinmyosin binding, increasing the efficiency of ATP utilization and prolonging the duration of systole.89 These actions increase stroke volume and cardiac output without increasing the inotropic state of the myocardium (and, therefore, without increasing the amount of energy consumed).90 Myosin activators are thus very different from dobutamine, which increases the force of contraction and energy consumption, but shortens systole. A trial of myosin activators in patients with acute HF is ongoing.91

Istaroxime stimulates the reuptake of calcium by the sarcoplasmic reticulum during diastole, while increasing the available intracellular calcium during systole by blocking the sodium pump (as does digoxin). In the phaseII HORIZONHF trial,92 conducted in 120 patients with acute HF, istaroxime was shown to improve diastolic function, reduce left ventricular filling pressure, increase blood pressure, and decrease heart rate.93

Mechanical support has a role in selected patients, particularly in those in whom the cause of the pulmonary oedema can be resolved. Anecdotally, intraaortic balloon counterpulsation can be effective in bridging patients to surgery for severe acute mitral regurgitation. However, the results of the SHOCKII trial94 suggested that intraaortic balloon pump had no survival benefit in patients with cardio genic shock receiving primary angioplasty for acute myocardial infarction.95 Other approaches include left ventricular assist devices and pumps inserted transcutaneously.96 At present, the role of these devices is restricted to carefully selected patients in specialist centres. Reducing venous return to the heart by occluding the inferior vena cava has also been tried in a small study.97

Peripheral oedemaPathophysiology and presentationAt the other end of the spectrum from pulmonary oedema is peripheral oedema, also known as anasarca, which occurs when fluid retention is severe and generalized. Two processes are involved in the development of peripheral oedema: an increase in total body fluid and transfer of fluid into the tissues. The latter is a straightforward process. As with pulmonary oedema, tissue oedema forms when the capillary hydrostatic pressure exceeds the plasma colloid osmotic pressure by an amount sufficient for the rate of transudation from capillary into tissue to exceed the rate at which the lymphatic system can drain away the fluid from the interstitium. Capillary permeability is again important. The upright posture causes an increase in the hydrostatic pressure in the lower extremities. Therefore, in ambulant patients, fluid first begins to accumulate in lower parts of the body. An unwary doctor might be caught out by a patient who has been confined to bed for several days in whom the fluid has migrated from the legs to the sacral region.

Traditional understanding is that sodium handling is the primary abnormality involved in oedema formation, whereby water movement passively follows salt movement. Total body sodium level is certainly increased in patients with HF, especially if they have peripheral oedema,98 but also in those without oedema.99 However, patients are oedematous because they have an excess of body fluid,100 not because they have an excess of sodium.

Why do patients with a failing heart have excess fluid? Two possible reasons are excessive fluid intake and inade quate fluid loss. Harris drew attention to the concept of HF as a byproduct of mammalian (and human) evolu tion.101 A high arterial blood pressure is required to sustain the high metabolic rate required for rapid movement of a mammal (and the upright posture of a human). As the heart fails, blood pressure starts to decrease and the body responds in the same way as it would to the volume contraction that might occur with dehydration or haemorrhage. The setpoint for blood pressure varies from one individual to another and, at least in industri alized societies, rises with age.102 The body might be more sensitive than a sphygmomanometer in detecting deviation from its desired blood pressure. The neuro hormonal response is determined by the need to m aintain blood pressure and, thus, tissue perfusion.

Since the 1940s, we have known that renal perfusion decreases and the kidneys retain sodium as HF develops.103 This process is mediated, in part, by the production of renin in the juxtaglomerular apparatus of the kidney. As mean arterial pressure decreases, more renin is produced,104 leading to increased production of angio tensin I and angiotensin II and, ultimately, aldosterone. The renin response is enhanced by the concomitant sympa thetic nervous system activation caused by HF,105 and by aldosterone, which causes sodium and water retention in the distal convoluted tubule (DCT) of the nephron. The fact that neuroendocrine activation is not the only cause for salt and water retention is indicated by the

Figure 5 | The right thigh of a patient presenting with fluid retention and pitting oedema. The patient subsequently lost 23 kg in weight (equivalent to 23 l of fluid).

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observation that intensive blockade of multiple neuroendocrine systems does not overcome the avidity with which the kidney retains salt and water, perhaps because the underlying cause for the decrease in blood pressure has not been corrected. Powerful diuretics are required to poison renal function. Restoration of blood pressure can reverse sodium retention, but exactly how blood pressure mediates salt and water retention isunclear.

In addition to activation of the reninangiotensinaldosterone system, production of antidiuretic hormone (ADH; or arginine vasopressin) by the anterior pituitary gland is increased. ADH has an important role as an osmostat, being released in response to a rise in osmolality and causing a decrease in renal free water clearance to restore osmotic balance. ADH mediates its effects through mobilizing aquaporin channels in the collecting duct of the nephron, which increases the movement of water from the lumen of the nephron to the medulla of the kidney.106 ADH is also a systemic vaso constrictor and increases platelet activation. Other nonosmotic stimuli leading to the release of ADH include a reduction in blood pressure and a rise in angiotensinII level.107,108 ADH level rises as HF becomes more severe,109 causing renal water retention. However, because the stimulus is nonosmotic, increased ADH production might lead tohyponatraemia.110

Thirst can be a prominent symptom in patients with HF,111,112 even in elderly patients,113 in whom the sensation of thirst is otherwise often impaired.114 This finding could reflect neuroendocrine activation, particularly of angiotensinII115,116 and ADH, which might have additive effects.117 Thirst is often exacerbated by the common practice of restricting fluid intake, although no evidence has shown that such a practice improves outcomes,118 particularly in stable patients.119

Peripheral oedema usually develops gradually. Around 5 l of excess fluid (and a consequent weight gain of ~5 kg) accumulates before peripheral, pitting oedema forms, but this volume may be less if the patient has a low albumin level, remains seated and immobile for a long time, or has varicose veins, or ulcers, or both. Because the fluid gain can be gradual, some patients do not attend hospital until they have accumulated 20 l of fluid (Figure5), by which time pitting oedema might form in the abdominal or even the thoracic wall, as well as pleural and peri cardial effusions. The distribution of fluid in some patients is rather even, and severe oedema might be missed in a casual physical examination because the patients legs might be thickened but maintain their normal form.

TreatmentIn contrast to patients with pulmonary oedema, patients with peripheral oedema have the problem of an absolute excess of fluid, and the mainstay of treatment is to try to remove the fluid. Careful monitoring of patients is important during fluid removal, with at least daily measure ments of urea, creatinine, and electrolyte levels, and body weight. Fluid balance should be recorded with care. Bed rest is appropriate120 and some studies

performed before modern diuretic therapy was available showed that bed rest alone could help patients to lose the fluid.121 Diuretics might be most effective when the patient is in supine position.122 Keeping the legs elevated could help fluid removal, allowing gravity to aid the reabsorption of oedema, but can acutely increase cardiac filling pressures and should be avoided in patients with incipient pulmonary oedema.123 Prophylactic lowmolecularweight heparin is usually given, as patients with HF are prone to venous thromboembolism. Using compression stockings might help to force fluid back into the circulation and might also reduce the risk of venous thrombi formation.124 The time course of weight loss in a typical patient is shown in Figure6.

A key factor in treating patients with cardiogenic oedema is renal function. Renal dysfunction is a common comorbidity in patients with HF,125 and as renal function deteriorates, so does the response to diuretics.126

The origin of renal dysfunction is multifactorial127 (Box1), with both the HF syndrome alone and intrinsic renal disease being implicated. Most successful medical therapies for HF (blockers, ACE inhibitors, and mineralo corticoid antagonists) and diuretics cause a decline in renal function. Treatment for oedema often exacerbates renal dysfunction,128 which could reflect adenosinemediated increases in sodium reabsorption in the proximal renal tubule.129 However, studies of adenosine antagonists, such as rolofylline, in patients with acute HF have been unsuccessful.130 Several treatment strategies are available for management of patients with renalimpairment.

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Figure 6 | Pattern of weight loss in a patient presenting with peripheral oedema. During the first 10days after admission, oral diuretics had no effect. An intravenous infusion of furosemide is followed by immediate diuresis, negative fluid balance, and weight loss.

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DiureticsIn the normal kidney, >99% of filtered sodium is usually reabsorbed; 6070% in the proximal tubule, 2025% in the loop of Henle, 510% in the DCT, and 3% in the collecting duct.131 Loop (or high ceiling) diuretics block the sodiumpotassiumchloride cotransporter in the thick ascending loop of Henle. They work from the luminal surface of the nephron and hence are dependent on the presence of some glomerular function. These agents work within minutes of intravenous administration, but are short acting after a singledose.132 As much of the filtered sodium is reabsorbed by the loop of Henle, loop diuretics are very potent. They increase sodium excretion, but the urine is hypotonic as free water clearance increases, contributing to hyponatraemia. Loop diuretics also increase excretion of potassium and calcium.132

Thiazide diuretics work in the DCT of the nephron. They are less potent than loop diuretics, as less sodium is reabsorbed at this site, but they have a longer duration of action. Thus, the overall effect of thiazide and loop diuretics on total daily sodium excretion was similar in some studies.133,134 Thiazides cause more electrolyte disturbances than loop diuretics,132 but cause calcium retention,135 which could be why patients with hypertension using thiazides have a low fracture rate.136 Metolazone, a thiazidelike diuretic, is widely used to relieve fluid retention caused by HF; this drug might have some effects in the proximal tubule, and remains effective in patients with renal impairment.137 As metolazone is only used in conjunction with loop diuretics for treating severe oedema and is rarely used for hypertension, use of this drug stops lesswellinformed clinicians being confused about the purpose of the thiazide, as other types of t hiazides are used for other indications.

Potassiumsparing diuretics work on the DCT where they block the sodiumpotassium exchanger. Loop and thiazide diuretics increase the sodium load in the DCT, leading to increased activity of the exchanger and loss of potassium. Potassiumsparing diure tics have little diuretic effect when used alone, but can prevent hypo kalaemia when used with other diure tics.138 Spironolactone and eplerenone are potassiumsparing diuretics that block the effects of aldosterone on the sodiumpotassium exchanger. They are principally used as disease modifying agents, rather than for their diuretic effects.139,140 However, in patients with gross oedema, liver congestion prevents the degradation of aldosterone, which might then have an increased role

in the genesis of fluid retention. The use of aldosterone antagonists in this setting, especially at high doses, could produce diuresis141 and might preventhypokalaemia.

As HF worsens, systolic arterial pressure decreases and central venous pressure rises, thus reducing the filtra tion pressure across the glomerulus. Loop diuretics increase the sodium load to the DCT, resulting in tubular hypertrophy and an increase in its capacity to reabsorb sodium.142,143 The DCT adaptation is particularly important with intermittent diuretic dosing, because in the absence of diuretic between doses, the hypertrophied DCT will enable rebound reabsorption of sodium.

Intravenous administration of diuretics is usually more effective than oral dosing. Furosemide, in particular, has a variable bioavailability, which may be marked in patients with bowel wall oedema.144,145 Continuous intravenous infusion of loop diuretic can avoid some of the problem of diuretic braking (that is, the general problem of a diminishing response to diuretics)146151 and seems to offer a greater dosefordose natriuresis than repeated bolus administration. The DOSE trial152 is the only substantial study in which various diuretic strategies have been compared. In a twobytwo factorial design, 308 patients were randomly assigned to receive intra venous furosemide at low or high dose, either as a conti nuous infusion or by repeated boluses. Greater diuresis and a slightly greater reduction in dyspnoea occurred in the highdose groups than in the lowdose groups at 72 h, although the high dose was associated with a slightly greater decline in renal function. No differ ence in di uresis was found for continuous and bolus admini stration.152 An alternative strategy would be to give thiazide diuretics orally in addition to either bolus or continuous intravenous therapy. The best loop diuretic dosing strategy for patients with gross fluid retention remains unclear.

Combination diuretic therapy, sometimes called sequential nephron blockade, involves a loop diuretic used with a thiazide. The subsequent diuresis can be profound,153,154 and patients should be closely monitored when combination treatment is used. Metolazone is the thiazide most often used in combination therapy. However, in the only comparative trial of this strategy, no difference was found between metolazone and another thiazide diuretic, bendroflumethiazide.154 No study has provided definitive evidence that sequential nephron blockade is better than simply increasing the dose of intravenous loop diuretic.

Discontinuation of potentially nephrotoxic drugs while trying to initiate diuresis is essential. Nonsteroidal antiinflammatory drugs, including aspirin, can blunt the effects of diuretics.155 Whether other HF medication should also be stopped is not clear. The standard advice is to reduce or stop blocker therapy when the patient is admitted to hospital, but some provisional evidence suggests that those who continue to receive blockers once they are admitted have a better outcome than those who stop taking blockers.156,157

The interest in digoxin has declined, perhaps owing to the large DIG study,158 which showed no survival benefit for digoxin in patients with chronic HF. However,

Box 1 | Causes of renal impairment in heart failure127

Predominantly cardiacDecreased systemic arterial blood pressureIncreased central venous pressureIncreased renal venous pressure by renal oedemaAfferent glomerular arteriolar vasoconstriction

Intrinsic renalDiabetesHypertensionAtherosclerosisIatrogenic

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digoxin has a diuretic effect,159 as well as a positive inotropic effect, and some evidence from the DIG trial indicates that digoxin might reduce the risk of hospitalization and mortality in patients with low serum digoxin concentration.160 The effect of digoxin in patients with acute HF is not well studied, and digoxin will largely remain an adjunct to conventional therapy until more data becomeavailable.

Anecdotal evidence exists that, once a patient has achieved dry weight (the weight that they were at before developing oedema), their diuretic requirement might be reduced and they could be discharged from hospital to receive loop diuretics at similar doses to those they were taking before admission. Presumably, this observation represents resolution of renal venous hypertension and reduced ventricular volume.

UltrafiltrationFor many years, ultrafiltration has been known to be an extremely effective method for rapid removal of fluid from patients with oedema.161 In venovenous ultrafiltration, venous blood is pumped out from the patient, usually using a rotary pump. As the blood passes through an extracorporeal filter, hydrostatic pressure forces fluid out of the blood, taking with it some solutes, particularly sodium and potassium. The concentrated blood is then returned to the patient. With ultrafiltration, 5 l of fluid can be safely removed from a patient in 24 h.162 In the RAPIDCHF trial, however, even faster removal of >3 l of fluid in 8 h was shown to be safe and effective.163 Ultrafiltration might be useful for patients who are refractory to diuretics, and could also trigger renal diuresis, presumably owing to a reduction in venous pressure and relief of renal parenchymal oedema.164

The investigators of the UNLOAD trial165 compared standard diuretic treatment with ultrafiltration in 200 patients with fluid retention caused by HF. Ultrafiltration was safe and well tolerated, and resulted in slightly increased fluid removal with no adverse effects on renal function. Surprisingly, rehospitalization for HF was reduced at 90days, although this measure was not the primary end point of the study.

The role of ultrafiltration in HF is not yet clear. This treatment is effective in patients with otherwise intractable oedema, and has some interesting effects on neurohormonal activation with more profound reductions in noradrenaline, plasma renin activity, and natriuretic peptides than those seen with furosemide.164,166 In addition, the ultrafiltrate contains more sodium and less potassium than the urine of patients receiving standard diuretic treatment,167 and ultrafiltration can be used to correct hyponatraemia.168 However, in patients with refractory fluid retention, ultrafiltration might worsen renal function.169 The researchers in the CARESS study170,171 specifi cally investigated whether ultrafiltration is beneficial in patients with deteriorating renal function and fluid retention, and found that creatinine levels increased signifi cantly with ultrafiltration compared with standard therapy. Whether this result represents worsening renal function or the effects of haemoconcentration is not clear.

The adverse effects of ultrafiltration on renal function could simply suggest that the patients had endstage disease; more than onethird of the patients in the study died or were readmitted at 60days. Ultrafiltration might be effective in less severely ill patients, might reduce the length of hospital stay, and could have beneficial effects on longterm outcomes. Further trials are needed to define the role of ultrafiltration better in patients with HF.

Treatment of hyponatraemiaA decrease in serum sodium levels with diuretic treatment is common, and is associated with poor quality of life and a poor prognosis.172 Hyponatraemia develops when a nonosmotic stimulus to ADH production causes water retention and dilutional hyponatraemia, despite an overall excess of sodium in the body.173 Hyponatraemia might, therefore, simply reflect increased n eurohormonal activation.

Traditional management of hyponatraemia has been to restrict salt and water intake, an approach that has met with minimal success and can cause distressing thirst. Some data are in support of the opposite approachinfusing hypertonic saline whilst continuing diuretic treatment (Figure7),174 which results in a more rapid reduction in Btype natriuretic peptide than orthodox management.175 Perhaps surprisingly, in light of traditional understanding, a normal salt diet is associated with a lower rate of admission for HF and of mortality, as well as less hyponatraemia than a diet in which salt intake is restricted.176,177 In the absence of any definitive trial data, the lowsalt diet traditionally prescribed for patients with HF should be abandoned.

ACE inhibition might correct or provoke hyponatraemia.178 A more logical pharmacological approach is to use an ADH antagonist, or vaptan. Vaptans block the effect of ADH on the renal collecting duct, which reduces water reabsorption and increases free water clearance,

0 5 10 15Admission days

Ser

um N

a+ (m

mol

/l)

20 25 50

0

135

130

125

120

115

140

30 35 40 45

Extreme uidrestrictionNo salt diet

Frusemideinfusion

(10 mg/h)

Fluidrestriction

2N* saline 1 lFrusemide infusion (20 mg/h)

Figure 7 | Time course of serum sodium level changes in a patient presenting with oedematous heart failure. Salt and fluid restriction, the traditional management, resulted in further declines in serum sodium levels, which were only restored when additional sodium was given. Abbreviation: 2N saline, 1.8% sodium chloridesolution.

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thereby correcting hyponatraemia.179 However, in EVEREST, which was conducted in more than 4,000 patients admitted to hospital with HF, no survival advantage was found with tolvaptan.180 Interestingly, patients who had hyponatraemia at admission had a strikin g increase in serum sodium levels with tolvaptan.180 Therefore, the vaptans might have a particular role in the treatment of patients with hyponatraemia rather than of those with HF in general. Cardiac resynch ronisation devices can also help to correct hypo natraemia by improvement of pump function,181 highlighting that HF syndrome is the ultimate cause of hyponatraemia and that hyponatraemia will resolve after HF is corrected.

Long-term management strategiesLongterm treatment of patients with HF is important. Most patients will benefit from education about the importance of compliance with longterm medical therapy and of avoiding an excessively high salt load. Various strategies, ranging from nurse specialist support to home telemonitoring systems with noninvasive or implanted technologies, can be used to educate and monitor patients.182

For most patients with cardiogenic oedema, recovery means living with a diagnosis of chronic HF. Medical management of chronic HF can be extremely success ful, especially if HF is a result of left ventri cular systo lic dysfunction.183 The opportunity to prescribe life prolonging (and enhancing) medication to patients (such as blockers, ACE inhibitors, and mineralocorticoid antagonists) should not be missed.

Most patients have one or more precipitating factors that caused or exacerbated their illness. Those with ischaemia or with an arrhythmia should be investigated and treated with appropriate therapy. Common comorbid ities and opportunities for further treatment should be sought. Atrial fibrillation is present in around 25% of patients with HF184 and requires ventricular rate control and antic oagulation. Cardioversion might be appropriate in selected patients with atrial fibrillation once HF iscontrolled.

QRS prolongation is common in patients with left ventri cular systolic dysfunction185 and its presence should prompt consideration of cardiac resynchronisation therapy. Patients should be assessed for their suitability for treatment with an implantable defibrillator. Anaemia is common, and often caused by iron deficiency or renal dysfunction. Serum iron and transferrin saturation should be checked routinely if anaemia is present. Serum ferritin levels are often falsely elevated in this setting. However, anaemia might be dilutional, indicating plasma volume expansion. Treatment of oedema could resolve anaemia. Ultimately, guidelines and other published guidance, such as the quality standards for HF issued by the UK National Institute for Health and Clinical Excellence,186 will help drive up standards ofcare.

ConclusionsCardiogenic oedema is a fundamental feature of HF syndrome. High venous pressure causes fluid to transude out of capillaries into tissue spaces faster than lymphatics can drain the fluid away. In the pulmonary circulation, the consequence is pulmonary oedema formation. Reducing venous pressure is the mainstay of treatment, and new vasodilators may have a role. New approaches using pharmaceuticals to accelerate the rate of fluid removal from the airspaces are on the horizon. In the systemic circulation, the rise in venous pressure is due to fluid retention, and treatment relies on removal of that fluid. Studies are only now starting to explore the best strategy for diuretic use, and the possible role of ultrafiltration.

Review criteria

A search for original articles published between 1960 and 2012 was performed in MEDLINE and PubMed databases. The search terms used were heart failure, pulmonary oedema, pulmonary edema, oedema and edema, alone and in combination. All articles identified were English-language, full-text papers. We also searched the reference lists of identified articles for further relevant papers.

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