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Causes and treatment of oedemajhuuhu


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Causes and treatment of oedemajhuuhu

  1. 1. 156  |  MARCH 2013  |  VOLUME 10 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 Causes and treatment of oedema in patients with heart failure Andrew 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, 156–170; published online 15 January 2013; doi:10.1038/nrcardio.2012.191 Introduction A striking feature of most patients presenting with heart failure (HF) is the presence of pulmonary oedema, peri­ pheral 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 episodes of HF. Improved understanding of the patho­physiology of oedema might allow treatments to be used more e­ffectively, 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 fluid- loaded ‘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 2006–2007, there were more than 250,000 deaths and hospital discharges for HF.1–3 Data from the national audit of HF hospital admissions in the UK suggest that breathlessness at rest, presu­mably indi­ cating 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 breathless­ ness at rest (Table 1); thus, the evidence-based informa­ tion 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 develop­ ments have re-awakened 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 guide treatment. Pulmonary oedema Pathophysiology and presentation Acute pulmonary oedema usually presents as a drama­ tic 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 precipitant— acute 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.4–6 Other causes include a high dietary salt load and uncontrolled hypertension. Competing interests J. 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. REVIEWS © 2013 Macmillan Publishers Limited. All rights reserved
  2. 2. 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 Frank–Starling mechanism holds: As the load on the left ventricle increases prior to theonsetofsystole,sodoestheworkoftheheartduringthe subsequent contraction (Figure 1). The preload is equiva­ lent to the end-diastolic (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 protec­ tive mechanism is provided by lymphatic wash-out of any albumin that reaches the interstitium, result­ ing in an increase in the osmotic pressure gradient between the capillary and the interstitium, which seems to reduce transudation of fluid.8 In addition, some resistance to transudation of fluid is provided by the alveolar–c­apillary basement membrane. In the normal circulation, fluid is continuously transu­ded from the capillaries into the interstit­ ium, and fluid crossing into the interstitial space is removed by the lymphatic system. The pulmo­ nary capillary wall is relatively impervious to fluid, and the tight apposition of the pulmo­nary capil­ lary 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 end- diastolic 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 capilla­ries. 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 a­ccumulate in the airspaces of the lungs (alveolar oedema). Elegant experiments in dogs have demonstrated the presence of such a critical tipping point. Beyond the threshold, there is a near-linear relation between the increase in left atrial pressure and the rate of oedema formation (Figure 2).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 haemo­ dynamic changes results in fluid moving to the ‘wrong’ body compartment. Indeed, some evidence suggests that the fluid extravasation into the alveoli results in a reduc­ tion in blood volume during acute pulmonary oedema, which then increases back to normal levels during s­uccessful 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 are lacking ■■ 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 using vasodilators ■■ Peripheral oedema is characterized by an excess of total body water ■■ Peripheral oedema is best treated by removing fluid, either with diuretics or mechanically 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 (per min)* LVEF (%)* β-blocker use (%) Digoxin use (%) Time to study inclusion 30-day mortality (%) VERITAS63 Tezosentan Endothelin antagonist 70 40 131 81 26 [24] 29 [40] 48 21 24 h 4 SURVIVE87 Levosimendan Calcium sensitizer 67 28 116 84 NR 24 [30] 51 NR NR 13 EVEREST180 Tolvaptan Vasopressin antagonist 66 26 120 80 NR 28 [40] 70 46 48 h 5 ASCEND68 Nesiritide Natriuretic peptide 67 34 124 82 23 40 in 81 NR NR 48 h 4 PROTECT187 Rolofylline Adenosine antagonist 70 33 124 80 21 32 [any] 76 28 24 h 15 3CPO43‡ C-PAP NA 78 57 161 114 33 [20] NR NR NR NR 16 *Numbers in square brackets denote the upper limit permitted by the trial design. ‡ 3CPO trial included ‘puffers’; the other trials included ‘bloaters’. Abbreviations: C‑PAP, continuous positive airways pressure; LVEF, left ventricular ejection fraction; NA, not applicable; NR, not reported. REVIEWS © 2013 Macmillan Publishers Limited. All rights reserved
  3. 3. 158  |  MARCH 2013  |  VOLUME 10 A patient with acute pulmonary oedema classically pre­ sents 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 ven­ tricular 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 phaeo­ chromocytoma, 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 systo­lic function, highlighting the involvement of the neuro­hormonal system in the genesis of acute pulmonary oedema.13 Angiotensin II seems to have a particularly important role in flash pulmonary oedema. When infused into renal arteries at a low perfu­ sion pressure (mimicking renal artery stenosis), angio­ tensin II causes marked systemic hypertension, salt and water retention, and pulmonary oedema.14 The role of abnormalities in the pulmonary vascula­ ture, the alveolar–capillary membrane, and the alveo­ lar 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 phaeo­ chromocytoma, may cause an increase in pulmonary capillary permeability resulting in pulmonary oedema without a great increase in left ventricular filling pres­ sure.15 In high-altitude pulmonary oedema, capillary stress fracture can contribute to the development of oedema, although the major cause of pulmonary oedema is excessive hypoxia-induced pulmonary hypertension.16 In adult respiratory distress syndrome, damage to the alveolar–capillary 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 inflam­ matory 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 d­evelopment of acute cardiogenic pulmonary oedema. Another potential contributor to pulmonary oedema formation is sleep-disordered breathing, which is very common in patients with HF.19 Recurrent airway obstructions have been shown to precipitate pulmo­ nary 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 toler­ ate extremely high left atrial pressures that would provoke severe pulmonary oedema in an otherwise healthy person. This observation might indicate increased pulmo­nary lymphatic drainage,22 particularly in patients with mitral stenosis.23 Alternatively, the alveolar–­capillary membrane may become thickened, reducing pulmonary microvas­ cular 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 pulmo­nary 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 Leftventricularwork Figure 1 | The Frank–Starling 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). 0 10 20 30 Left atrial pressure (mmHg) Rateofoedemaformation 50 0 6 4 3 2 1 7 5 40 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, 649–657 (1959).9 REVIEWS © 2013 Macmillan Publishers Limited. All rights reserved
  4. 4. NATURE REVIEWS | CARDIOLOGY VOLUME 10  |  MARCH 2013  |  159 Treatment An X‑ray 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 (Figure 3).The prognosis is bleak following acute pulmonary oedema, with an in- hospital mortality of 10–20%, varying greatly with age and presence of comorbidity.6 The 1‑year mortality is at least 20% in patients with the lowest blood pressure (systolic 100 mmHg) at admission.27 These data conceal the outcome for more severely affected patients. In the EFICA study28 of patients admitted to high-dependency units with acute severe HF (82% of whom had pulmo­ nary oedema), mortality was 27.4% at 4 weeks and 46.5% at 1 year, but when preadmission deaths were included, mortality was 43.2% and 62.5% at the two time points, respectively. These data highlight the potential impor­ tance of delivering treatment to patients with severe HF as quickly as possible. The evidence-based information for the treatment of patients with acute pulmonary oedema is minimal, particularly compared with that for the management of chronic HF. Patients often present in the middle of the night with acute severe symptoms, which makes their recruitment into clinical trials difficult. Consequently, the following discussion is based on many small studies and is not definitive. Few randomized trials have been able to allocate patients to different interventions within 6 h of presentation, and yet surveys show that most patients have already responded symptomatically to conven­tional treatment within that time frame.29 Quicker relief of symptoms would be welcomed by all clinicians and patients, but designing studies with intervention within the first 2 or 3 h of presentation is difficult. Although large, randomized, controlled trials have been conducted in patients with acute HF, few of these individuals had severe pulmonary oedema. Many patients were comfortable at rest, and only developed symptoms during slight exertion. Most patients were ‘bloaters’, rather than ‘puffers’ (Table 1). In many studies, haemodynamic end points, such as left ventricular filling pressure, but not symptoms, morbidity, or mortal­ity, have been measured. Haemodynamic end points might be easier to achieve and could also be biased by the investi­ gators’ judgement about patients’ symptoms. Perhaps crucial to the success of new therapies, particularly for acute severe pulmonary oedema, is the timing of treat­ ment administration. The information about the timing of intervention is often not available from trials. Early intervention, when symptoms are most severe, might lead to rapid resolution of symptoms, but would require a study to be conducted during a time window of 6 h from presentation or an even shorter duration. Alternatively, delaying intervention until patients have failed conven­ tional treatment would identify those with recalcitrant symptoms requiring novel therapies. The immediate aims of management include the relief of anxiety and improvement in oxygenation whilst instituting medical therapy in an attempt to reverse the haemodynamic cause of pulmonary oedema. As the problem is not so much one of excess fluid, but of fluid in the wrong body compartment, the key strategy is to drive fluid from the lung tissues back into the circula­ tion. This aim can be achieved either by reducing pulmo­ nary capillary hydrostatic pressure, increasing lymphatic drainage by reducing systemic venous pressure (both achieved with vasodilators), pushing fluid out of the alveoli (achieved in part by ventilator support), or alter­ ing pulmonary capillary permeability (with experimental agents). An important part of the management strategy is to try to reverse any potential precipitant of pulmo­ nary oedema, such as myocardial ischaemia, arrhythmia, mitral regurgitation, or infection; however, this topic is not discussed further here. Opiates Opiates are often used to relieve distress, anxiety, pain, and the sensation of breathlessness. The 2008 ESC guide­ lines for the management of acute HF from the state that “[morphine] should be considered in the early stage of the treatment of patients admitted with severe [acute HF]”.30 The recommendation is made on the basis of opinion rather than clinical trial data, although small studies suggest that opiates (diamorphine is often used in the UK31 ) might be effective vasodilators. The updated guidelines published in 2012 still suggest that opiates might be helpful.32 Opiates undoubtedly ease the pain of myocardial infarction and relieve distress, but no good evidence exists to suggest that their use improves outcomes. Although morphine might induce some relaxation of vascular smooth muscle,33 the effect seems to be medi­ ated by histamine release rather than by a direct effect of opiate receptor stimulation.34 Some case reports suggest that morphine can directly cause worsening of left ventri­cular function and even induce shock.35 In a review of the small number of published trials of opiates in acute pulmonary oedema, investigators found that although opiates did relieve anxiety, their use was associated with Figure 3 | X‑ray of the chest of a patient presenting with acute pulmonary oedema. The air spaces are bilaterally filled with oedema fluid. REVIEWS © 2013 Macmillan Publishers Limited. All rights reserved
  5. 5. 160  |  MARCH 2013  |  VOLUME 10 an increase in mortality and the need for intubation.36 In a retrospective study of nearly 150,000 patients admit­ ted 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 support Patients 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 venti­lation temporarily reverses the situation,39 immedi­ ately 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. Continuous positive 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 non­ invasive 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 resist­ ance to pulmonary blood flow, but meta-analyses 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 short-term mortality or the need for intuba­ tion among the three groups, although a small improve­ ment 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’. Diuretics Standard practice in the management of acute pul­ monary oedema has been the use of intravenous loop diure­tics, as the ensuing diuresis is understood to remove the fluid in the lungs. Certainly, loop diuret­ ics reduce circulating fluid volume and, consequently, filling pressure, but they may also have bradykinin- mediated vaso­dilator effects. The notion that loop diu­ retics reduce preload through venodilatation, and that the veno­dilatation 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 follow­ing intravenous furosemide,44 others report slow changes45 and empha­ size that changes in haemodynamic variables are seen only in patients with a subsequent diure­sis.46 One small study suggested that furosemide does not relieve symp­ toms in acute pulmonary oedema.47 In anuric patients undergoing haemo­dialysis, neither low-dose nor high- dose furosemide had an effect on central haemodynamic variables.48 Others have found that furosemide causes an increase in peri­pheral vascular resistance and a decrease in stroke volume when adminis­tered acutely.45,49 Part of the difficulty in sifting through the data on haemody­ namics with furosemide is that most patients included in studies had had an acute myocardial infarct and thus their condition was i­nherently unstable. Anecdotal reports exist on the use of nebulised furo­ semide in patients with end-stage 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 end-stage disease at home. Vasodilators Although diuretics are the most-widely 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 (Figure 4). These drugs reduce preload and afterload, increase cardiac output, and help to reduce any myocardial ischaemia. Very little data exist for the direct compari­ son between vasodilators and loop diuretics, but vaso­ dilators seem to result in more-pronounced reductions in filling pressures and an increase in cardiac output, compared with no change or a modest decline in cardiac output with furosemide.54–56 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 high-dose nitrate therapy (with low-dose furo­ semide) was probably more effective than high-dose furo­semide and low-dose nitrate.57 High-dose nitrate therapy was associated with a reduced need for intubation and a lower risk of myocardial infarction. Some studies suggest that a high-dose nitrate strategy is of greater benefit and is possibly safer than routine use of NIPPV and low-dose nitrate.58 Some evidence indicates that acute administration of an angiotensin-converting-enzyme (ACE) inhibitor might relieve pulmonary oedema more rapidly than standard therapy alone.59 Tezosentan, an endothelin antagonist, acutely reduces pulmonary vascular resist­ ance,60 but had no effect on outcomes in a study of 84 patients with pulmonary oedema.61 In large studies of acute HF, such as the RITZ62 and VERITAS63 trials, REVIEWS © 2013 Macmillan Publishers Limited. All rights reserved
  6. 6. NATURE REVIEWS | CARDIOLOGY VOLUME 10  |  MARCH 2013  |  161 tezosentan given at a variety of doses had no positive effect on outcome. Tezosentan did reduce left ventri­ cular filling pressure and increase cardiac output, but these apparently beneficial effects were accompa­ nied 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 pulmonary hypertension. Natriuretic peptides have attracted a great deal of interest as possible agents for the treatment of acute pulmo­nary oedema. The recombinant human B‑type natriuretic peptide, nesiritide, causes vasodilatation, reducing both afterload and preload and causing natri­ uresis.66 Nesiritide was approved for use in the USA follow­ing publication of a study showing haemo­dynamic 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 rehospitaliza­ tion or death. Some evidence indicates that natri­uretic peptides might increase capillary permeability,69,70 which might c­ounteract the other beneficial effects of these agents. Other vasodilators that are in development include relaxin, a potent hormone responsible for vaso­ dilatation 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 vasodila­ tors. Syncope caused by peri­pheral pooling of venous blood is resistant to therapy and can be difficult to manage in patients with acute pulmo­nary oedema, for whom lying flat is contra­indicated. Keeping the feet elevated is advisable in this case, while the clini­ cian 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 1,161 patients 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 6 months 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 e­normous step forward in the management of acute HF. Another novel arterial vasodilator is clevidipine, an extremely short-acting dihydropyridine calcium antag­ onist (with a half-life measured in several seconds). In the PRONTO study of 104 patients with acute pulmo­ nary 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 approaches Clearance of pulmonary oedema is, at least in part, an active process, involving an epithelial amiloride-sensitive sodium channel, sodium potassium ATPase, and possi­ bly aquaporins.75,76 Alveolar sodium uptake might be enhanced by β2 -adrenergic receptor stimulation,77,78 but no convincing clinical data are yet available.79 The transient receptor potential channel TRPV4 is a calcium-permeable channel that has been implicated in disruption of the alveolar membrane during the develop­ ment 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 haem-free sGC that causes pulmonary and systemic vasodilatation.81 Excessive reductions in blood pressure have been a limit­ ing 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 support Positive 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 Exogenous nitrate Relaxin Cinaciguat NP Endothelin antagonist Endothelium NO cGMP cGMP cGMP Smooth muscle cells sGC NOS GC 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. REVIEWS © 2013 Macmillan Publishers Limited. All rights reserved
  7. 7. 162  |  MARCH 2013  |  VOLUME 10 of a meta-analysis of the available data suggest that positive inotropic support with agents working through adre­nergic pathways (both β‑adrenergic agonists and phopho­diesterase inhibitors) is associated with a worse outcome than placebo.85 Levosimendan, an agent that is both a calcium-concentration-dependent calcium sensiti­zer and arterial vasodilator, could be useful in patients with severe chronic HF,86 but its effects do not seem to t­ranslate into a benefits in the acute setting.87,88 Myosin activators enhance actin–myosin binding, increasing the efficiency of ATP utilization and pro­ longing 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 dobuta­ mine, 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 increas­ ing the available intracellular calcium during systole by blocking the sodium pump (as does digoxin). In the phase II HORIZON-HF 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, par­ ticularly in those in whom the cause of the pulmonary oedema can be resolved. Anecdotally, intra-aortic balloon counterpulsation can be effective in bridging patients to surgery for severe acute mitral regurgitation. However, the results of the SHOCK-II trial94 suggested that intra-aortic balloon pump had no survival benefit in patients with cardio­genic shock receiving primary angioplasty for acute myocardial infarction.95 Other approaches include left ventricular assist devices and pumps inserted transcutane­ ously.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 oedema Pathophysiology and presentation At the other end of the spectrum from pulmonary oedema is peripheral oedema, also known as anasarca, which occurs when fluid retention is severe and general­ ized. 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 straight­ forward process. As with pulmonary oedema, tissue oedema forms when the capillary hydrostatic pres­ sure exceeds the plasma colloid osmotic pressure by an amount sufficient for the rate of transudation from capil­ lary 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 move­ ment. 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 inade­quate fluid loss. Harris drew attention to the concept of HF as a by-product of mammalian (and human) evolu­tion.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 ‘set-point’ for blood pressure varies from one individual to another and, at least in industri­alized societies, rises with age.102 The body might be more sensitive than a sphygmomanometer in detecting deviation from its ‘desired’ blood pressure. The neuro­hormonal response is determined by the need to m­aintain blood pressure and, thus, tissue perfusion. Since the 1940s, we have known that renal perfu­ sion decreases and the kidneys retain sodium as HF develops.103 This process is mediated, in part, by the production of renin in the juxtaglomerular appara­ tus of the kidney. As mean arterial pressure decreases, more renin is produced,104 leading to increased production of angio­tensin  I and angiotensin  II and, ultimately, aldosterone. The renin response is enhanced by the concomitant sympa­thetic nervous system activation caused by HF,105 and by aldoster­ one, 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). REVIEWS © 2013 Macmillan Publishers Limited. All rights reserved
  8. 8. NATURE REVIEWS | CARDIOLOGY VOLUME 10  |  MARCH 2013  |  163 observation that intensive blockade of multiple neuro­ endocrine 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 is unclear. In addition to activation of the renin–angiotensin– aldosterone 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 osmo­ lality and causing a decrease in renal free water clear­ ance to restore osmotic balance. ADH mediates its effects through mobilizing aquaporin channels in the collect­ ing 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 vaso­constrictor and increases platelet activation. Other nonosmotic stimuli leading to the release of ADH include a reduction in blood pressure and a rise in angiotensin II 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 to hyponatraemia.110 Thirst can be a prominent symptom in patients with HF,111,112 even in elderly patients,113 in whom the sensa­ tion of thirst is otherwise often impaired.114 This finding could reflect neuroendocrine activation, particularly of angiotensin II115,116 and ADH, which might have addi­ tive 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 (Figure 5), by which time pitting oedema might form in the abdominal or even the thoracic wall, as well as pleural and peri­cardial effusions. The distribu­ tion of fluid in some patients is rather even, and severe oedema might be missed in a casual physical examina­ tion because the patient’s legs might be thickened but maintain their normal form. Treatment In contrast to patients with pulmonary oedema, patients with peripheral oedema have the problem of an abso­ lute 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 measure­ments 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 low- molecular-weight 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 Figure 6. 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 (Box 1), with both the HF syndrome alone and intrin­ sic renal disease being implicated. Most successful medical therapies for HF (β-blockers, ACE inhibitors, and mineralo­corticoid antagonists) and diuretics cause a decline in renal function. Treatment for oedema often exacerbates renal dysfunction,128 which could reflect adenosine-mediated increases in sodium reabsorption in the proximal renal tubule.129 However, studies of adeno­ sine antagonists, such as rolofylline, in patients with acute HF have been unsuccessful.130 Several treatment strategies are available for management of patients with renal impairment. 5 Sep 10 Sep 15 Sep 20 Sep Admission dates in 2006 Volume(l/24h) 25 Sep 30 Sep 5 Oct –8,000 8,000 4,000 0 –4,000 –6,000 10,000 6,000 2,000 –2,000 Weight(kg) 40 60 50 70 Furosemide infusion Input Output Balance Weight Figure 6 | Pattern of weight loss in a patient presenting with peripheral oedema. During the first 10 days after admission, oral diuretics had no effect. An intravenous infusion of furosemide is followed by immediate diuresis, negative fluid balance, and weight loss. REVIEWS © 2013 Macmillan Publishers Limited. All rights reserved
  9. 9. 164  |  MARCH 2013  |  VOLUME 10 Diuretics In the normal kidney, 99% of filtered sodium is usually reabsorbed; 60–70% in the proximal tubule, 20–25% in the loop of Henle, 5–10% in the DCT, and 3% in the col­ lecting duct.131 Loop (or ‘high ceiling’) diuretics block the sodium–potassium–chloride 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 single-dose.132 As much of the filtered sodium is reabsorbed by the loop of Henle, loop diuretics are very potent. They increase sodium excre­ tion, 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 diure­ tics on total daily sodium excretion was similar in some studies.133,134 Thiazides cause more electrolyte distur­ bances than loop diuretics,132 but cause calcium reten­ tion,135 which could be why patients with hypertension using thiazides have a low fracture rate.136 Metolazone, a thiazide-like diuretic, is widely used to relieve fluid reten­ tion 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 less-well-informed clinicians being confu­ sed about the purpose of the thiazide, as other types of t­hiazides are used for other indications. Potassium-sparing diuretics work on the DCT where they block the sodium–potassium exchanger. Loop and thiazide diuretics increase the sodium load in the DCT, leading to increased activity of the exchanger and loss of potassium. Potassium-sparing diure­tics have little diuretic effect when used alone, but can prevent hypo­kalaemia when used with other diure­tics.138 Spironolactone and eplerenone are potassium-sparing diuretics that block the effects of aldosterone on the sodium–potassium 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 prevent hypokalaemia. As HF worsens, systolic arterial pressure decreases and central venous pressure rises, thus reducing the filtra­tion 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 impor­ tant 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 intra­ venous infusion of loop diuretic can avoid some of the problem of diuretic ‘braking’ (that is, the general problem of a diminishing response to diuretics)146–151 and seems to offer a greater dose-for-dose natriuresis than repeated bolus administration. The DOSE trial152 is the only sub­ stantial study in which various diuretic strategies have been compared. In a two-by-two factorial design, 308 patients were randomly assigned to receive intra­venous furosemide at low or high dose, either as a conti­nuous infusion or by repeated boluses. Greater diuresis and a slightly greater reduction in dyspnoea occurred in the high-dose groups than in the low-dose groups at 72 h, although the high dose was associated with a slightly greater decline in renal function. No differ­ence in di­uresis was found for continuous and bolus admini­stration.152 An alternative strategy would be to give thiazide diure­ tics orally in addition to either bolus or continuous intra­ venous 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 moni­ tored 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 anti-inflammatory 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 β‑blocker therapy when the patient is admitted to hospital, but some provisional evidence sug­ gests that those who continue to receive β‑blockers once they are admitted have a better outcome than those who stop taking β‑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 cardiac Decreased systemic arterial blood pressure Increased central venous pressure Increased renal venous pressure by renal oedema Afferent glomerular arteriolar vasoconstriction Intrinsic renal Diabetes Hypertension Atherosclerosis Iatrogenic REVIEWS © 2013 Macmillan Publishers Limited. All rights reserved
  10. 10. NATURE REVIEWS | CARDIOLOGY VOLUME 10  |  MARCH 2013  |  165 digoxin has a diuretic effect,159 as well as a positive ino­ tropic effect, and some evidence from the DIG trial indicates that digoxin might reduce the risk of hospitali­ zation 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 become available. 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. Ultrafiltration For many years, ultrafiltration has been known to be an extremely effective method for rapid removal of fluid from patients with oedema.161 In veno-venous ultra­ filtration, 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, particu­ larly 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 RAPID-CHF trial, however, even faster removal of 3 l of fluid in 8 h was shown to be safe and effec­ tive.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 90 days, 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 intract­ able oedema, and has some interesting effects on neuro­ hormonal activation with more profound reductions in noradrenaline, plasma renin activity, and natriuretic pep­ tides 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 refrac­ tory fluid retention, ultrafiltration might worsen renal function.169 The researchers in the CARESS study170,171 specifi­cally investigated whether ultrafiltration is benefi­ cial in patients with deteriorating renal function and fluid retention, and found that creatinine levels increased signifi­cantly 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 end-stage disease; more than one-third of the patients in the study died or were readmitted at 60 days. Ultrafiltration might be effective in less severely ill patients, might reduce the length of hospital stay, and could have beneficial effects on long-term outcomes. Further trials are needed to define the role of ultrafiltration better in patients with HF. Treatment of hyponatraemia A decrease in serum sodium levels with diuretic treat­ ment is common, and is associated with poor quality of life and a poor prognosis.172 Hyponatraemia devel­ ops 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 n­eurohormonal 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 approach— infusing hypertonic saline whilst continuing diuretic treatment (Figure 7),174 which results in a more rapid reduction in B‑type natriuretic peptide than orthodox management.175 Perhaps surprisingly, in light of tradi­ tional 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 low-salt diet traditionally prescribed for patients with HF should be abandoned. ACE inhibition might correct or provoke hypo­ natraemia.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 15 Admission days SerumNa+(mmol/l) 20 25 50 0 135 130 125 120 115 140 30 35 40 45 Extreme fluid restriction No salt diet Frusemide infusion (10 mg/h) Fluid restriction 2N* saline×1 l Frusemide 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 chloride solution. REVIEWS © 2013 Macmillan Publishers Limited. All rights reserved
  11. 11. 166  |  MARCH 2013  |  VOLUME 10 thereby correcting hyponatraemia.179 However, in EVEREST, which was conducted in more than 4,000 patients admitted to hospital with HF, no survival advan­ tage was found with tolvaptan.180 Interestingly, patients who had hyponatraemia at admission had a strikin­g 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 resynch­ronisation devices can also help to correct hypo­natraemia 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 strategies Long-term treatment of patients with HF is impor­ tant. Most patients will benefit from education about the importance of compliance with long-term 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, recov­ ery means living with a diagnosis of chronic HF. Medical management of chronic HF can be extremely success­ful, especially if HF is a result of left ventri­cular systo­lic dysfunction.183 The opportunity to prescribe life-­ prolonging (and enhancing) medication to patients (such as β‑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 investi­ gated and treated with appropriate therapy. Common comorbid­ities 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 antic­oagulation. Cardioversion might be appropriate in selected patients with atrial fibrillation once HF is controlled. QRS prolongation is common in patients with left ventri­cular systolic dysfunction185 and its presence should prompt consideration of cardiac resynchronisa­ tion therapy. Patients should be assessed for their suit­ ability for treatment with an implantable defibrillator. Anaemia is common, and often caused by iron deficiency or renal dysfunction. Serum iron and transferrin satura­ tion should be checked routinely if anaemia is present. Serum ferritin levels are often falsely elevated in this setting. However, anaemia might be dilutional, indica­ ting 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 of care. Conclusions Cardiogenic 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 phar­ maceuticals to accelerate the rate of fluid removal from the airspaces are on the horizon. In the systemic circula­ tion, 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. 1. Hospital Episode Statistics. HES online [online], (2012). 2. Cleland, J. G. et al. The national heart failure audit for England and Wales 2008–2009 Heart 97, 876–86 (2011). 3. National Heart Failure Audit 2010. The NHS Information Centre [online], http:// 002_Audits/NHS_IC_National_Heart_Failure_ Audit_2010_04-01-11.pdf (2012). 4. Michalsen, A., König, G. Thimme, W. Preventable causative factors leading to hospital admission with decompensated heart failure. Heart 80, 437–441 (1998). 5. Fonarow, G. C. et al. Factors identified as precipitating hospital admissions for heart failure and clinical outcomes: findings from OPTIMIZE-HF. Arch. Intern. Med. 168, 847–854 (2008). 6. Roguin, A. et al. Long-term prognosis of acute pulmonary oedema--an ominous outcome. Eur. J. Heart Fail. 2, 137–144 (2000). 7. Starling, E. H. On the absorption of fluids from the connective tissue spaces. J. Physiol. 19, 312–326 (1896). 8. Erdmann, A. J. 3rd , Vaughan, T. R. Jr, Brigham, K. L., Woolverton, W. C. Staub, N. C. Effect of increased vascular pressure on lung fluid balance in unanesthetized sheep. Circ. Res. 37, 271–284 (1975). 9. Guyton, A. C. Lindsey, A. W. Effect of elevated left atrial pressure and decreased plasma protein concentration on the development of pulmonary edema. Circ. Res. 7, 649–657 (1959). 10. Figueras, J. Weil, M. H. Blood volume prior to and following treatment of acute cardiogenic pulmonary edema. Circulation 57, 349–355 (1978). 11. Cotter, G. et al. The role of cardiac power and systemic vascular resistance in the pathophysiology and diagnosis of patients with acute congestive heart failure. Eur. J. Heart Fail. 5, 443–451 (2003). 12. Pickering, T. G. et al. Recurrent pulmonary oedema in hypertension due to bilateral renal artery stenosis: treatment by angioplasty or surgical revascularisation. Lancet 2, 551–552 (1988). 13. Lohmeier, T. E., Mizelle, H. L., Reinhart, G. A.  Montani, J. P. Influence of angiotensin on the early progression of heart failure. Am. J. Physiol. Regul.Integr.Comp.Physiol. 278, R74–R86 (2000). 14. Hall, J. E. et al. Mechanisms of escape from sodium retention during angiotensin II hypertension. Am. J. Physiol. 246, F627–F634 (1984). 15. van Iperen, C. E., Giezen, J., Kramer, W. L. M., Lips, C. J. M. Bartelink, A. K. Acute dyspnea resulting from pulmonary oedema as the first sign of a pheochromocytoma. Respiration 68, 323–326 (2001). 16. Sartori, C., Allemann, Y. Scherrer, U. Pathogenesis of pulmonary edema: learning from high-altitude pulmonary edema. Respir. Physiol. Neurobiol. 159, 338–349 (2007). REVIEWS © 2013 Macmillan Publishers Limited. All rights reserved
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The role of pulmonary lymphatics in the clearance of hydrostatic pulmonary edema. J. Surg. Res. 43, 495–504 (1987). 23. Tandon, H. D. Kasturi, J. Pulmonary vascular changes associated with isolated mitral stenosis in India. Br. Heart J. 37, 26–36 (1975). 24. Davies, S. W. et al. Reduced pulmonary microvascular permeability in severe chronic left heart failure. Am. Heart J. 124, 137–142 (1992). 25. Huang, W. et al. Capillary filtration is reduced in lungs adapted to chronic heart failure: morphological and haemodynamic correlates. Cardiovasc. Res. 49, 207–217 (2001). 26. Puri, S. et al. Reduced alveolar-capillary membrane diffusing capacity in chronic heart failure. Its pathophysiological relevance and relationship to exercise performance. Circulation 91, 2769–2774 (1995). 27. Parissis, J. T. et al. Acute pulmonary oedema: clinical characteristics, prognostic factors, and in-hospital management. Eur. J. Heart Fail. 12, 1193–1202 (2010). 28. Zannad, F. et al. Clinical profile, contemporary management and one-year mortality in patients with severe acute heart failure syndromes: The EFICA study. Eur. J. Heart Fail. 8, 697–705 (2006). 29. Mebazaa, A. et al. The impact of early standard therapy on dyspnoea in patients with acute heart failure: the URGENT-dyspnoea study. Eur. Heart J. 31, 832–841 (2010). 30. Dickstein, K. et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Eur. Heart J. 29, 2388–2442 (2008). 31. Gossop, M., Keaney, F., Sharma, P. Jackson, M. The unique role of diamorphine in British medical practice: a survey of general practitioners and hospital doctors. Eur. Addict. Res. 11, 76–82 (2005). 32. McMurray, J. J. et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur. Heart J. 33, 1787–1847 (2012). 33. Vismara, L. A., Leaman, D. M. Zelis, R. The effects of morphine on venous tone in patients with acute pulmonary oedema. Circulation 54, 335–337 (1976). 34. Grossmann, M., Abiose, A., Tangphao, O., Blaschke, T. F. Hoffman, B. B. Morphine-induced venodilation in humans. Clin. Pharmacol. Ther. 60, 554–560 (1996). 35. Feeney, C., Ani, C., Sharma, N. Frohlich, T. Morphine-induced cardiogenic shock. Ann. Pharmacother. 45, e30 (2011). 36. Sosnowski, M. A. Review article: lack of effect of opiates in the treatment of acute cardiogenic pulmonary oedema. Emerg. Med. Australas. 20, 384–390 (2008). 37. Peacock, W. F. et al. 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