Cardiogenic Pulmonary Edema

Background

Cardiogenic pulmonary edema (CPE) is defined as pulmonary edema due to increased capillary hydrostatic pressure secondary to elevated pulmonary venous pressure. CPE reflects the accumulation of fluid with a low-protein content in the lung interstitium and alveoli as a result of cardiac dysfunction (see the image below). (See Etiology.)

Radiograph shows acute pulmonary edema in a patient who was admitted with acute anterior myocardial infarction. Findings are vascular redistribution, indistinct hila, and alveolar infiltrates.

Pulmonary edema can be caused by the following major pathophysiologic mechanisms:

Imbalance of Starling forces - Ie, increased pulmonary capillary pressure, decreased plasma oncotic pressure, increased negative interstitial pressure Damage to the alveolar-capillary barrierLymphatic obstructionIdiopathic (unknown) mechanism

Increased hydrostatic pressure leading to pulmonary edema may result from many causes, including excessive intravascular volume administration, pulmonary venous outflow obstruction (eg, mitral stenosis or left atrial [LA] myxoma), and LV failure secondary to systolic or diastolic dysfunction of the left ventricle. CPE leads to progressive deterioration of alveolar gas exchange and respiratory failure. Without prompt recognition and treatment, a patient's condition can deteriorate rapidly. (See Etiology, Prognosis, Presentation, Workup, Treatment, and Medication.)

Complications

The major complications associated with CPE are respiratory fatigue and failure. Prompt diagnosis and treatment usually prevent these complications, but the physician must be prepared to provide assisted ventilation if the patient begins to show signs of respiratory fatigue (eg, lethargy, fatigue, diaphoresis, worsening anxiety). (See Prognosis and Treatment.)

Sudden cardiac death secondary to cardiac arrhythmia is another concern, and continuous monitoring of heart rhythm is helpful in prompt diagnosis of dangerous arrhythmias.

Patient education

To help prevent recurrence of CPE, counsel and educate patients in whom pulmonary edema is due to dietary causes or medication noncompliance.

NextEtiology

CPE is caused by elevated pulmonary capillary hydrostatic pressure leading to transudation of fluid into the pulmonary interstitium and alveoli. Increased LA pressure increases pulmonary venous pressure and pressure in the lung microvasculature, resulting in pulmonary edema.

Mechanism of CPE

Pulmonary capillary blood and alveolar gas are separated by the alveolar-capillary membrane, which consists of 3 anatomically different layers: (1) the capillary endothelium; (2) the interstitial space, which may contain connective tissue, fibroblasts, and macrophages; and (3) the alveolar epithelium.

Exchange of fluid normally occurs between the vascular bed and the interstitium. Pulmonary edema occurs when the net flux of fluid from the vasculature into the interstitial space is increased. The Starling relationship determines the fluid balance between the alveoli and the vascular bed. Net flow of fluid across a membrane is determined by applying the following equation:

Q = K(Pcap - Pis) - l(Pcap - Pis),

where Q is net fluid filtration; K is a constant called the filtration coefficient; Pcap is capillary hydrostatic pressure, which tends to force fluid out of the capillary; Pis is hydrostatic pressure in the interstitial fluid, which tends to force fluid into the capillary; l is the reflection coefficient, which indicates the effectiveness of the capillary wall in preventing protein filtration; the second Pcap is the colloid osmotic pressure of plasma, which tends to pull fluid into the capillary; and the second Pis is the colloid osmotic pressure in the interstitial fluid, which pulls fluid out of the capillary.

The net filtration of fluid may increase with changes in different parameters of the Starling equation. CPE predominantly occurs secondary to LA outflow impairment or LV dysfunction. For pulmonary edema to develop secondary to increased pulmonary capillary pressure, the pulmonary capillary pressure must rise to a level higher than the plasma colloid osmotic pressure. Pulmonary capillary pressure is normally 8-12 mm Hg, and colloid osmotic pressure is 28 mm Hg. High pulmonary capillary wedge pressure (PCWP) may not always be evident in established CPE, because the capillary pressure may have returned to normal when the measurement is performed.

Lymphatics

The lymphatics play an important role in maintaining an adequate fluid balance in the lungs by removing solutes, colloid, and liquid from the interstitial space at a rate of approximately 10-20 mL/h. An acute rise in pulmonary arterial capillary pressure (ie, to >18 mm Hg) may increase filtration of fluid into the lung interstitium, but the lymphatic removal does not increase correspondingly. In contrast, in the presence of chronically elevated LA pressure, the rate of lymphatic removal can be as high as 200 mL/h, which protects the lungs from pulmonary edema.

Stages

The progression of fluid accumulation in CPE can be identified as 3 distinct physiologic stages.

Stage 1

In stage 1, elevated LA pressure causes distention and opening of small pulmonary vessels. At this stage, blood gas exchange does not deteriorate, or it may even be slightly improved.

Stage 2

In stage 2, fluid and colloid shift into the lung interstitium from the pulmonary capillaries, but an initial increase in lymphatic outflow efficiently removes the fluid. The continuing filtration of liquid and solutes may overpower the drainage capacity of the lymphatics. In this case, the fluid initially collects in the relatively compliant interstitial compartment, which is generally the perivascular tissue of the large vessels, especially in the dependent zones.

The accumulation of liquid in the interstitium may compromise the small airways, leading to mild hypoxemia. Hypoxemia at this stage is rarely of sufficient magnitude to stimulate tachypnea. Tachypnea at this stage is mainly the result of the stimulation of juxtapulmonary capillary (J-type) receptors, which are nonmyelinated nerve endings located near the alveoli. J-type receptors are involved in reflexes modulating respiration and heart rates.

Stage 3

In stage 3, as fluid filtration continues to increase and the filling of loose interstitial space occurs, fluid accumulates in the relatively noncompliant interstitial space. The interstitial space can contain up to 500mL of fluid. With further accumulations, the fluid crosses the alveolar epithelium in to the alveoli, leading to alveolar flooding. At this stage, abnormalities in gas exchange are noticeable, vital capacity and other respiratory volumes are substantially reduced, and hypoxemia becomes more severe.

Cardiac disorders manifesting as CPE

Atrial outflow obstruction

This can be due to mitral stenosis or, in rare cases, atrial myxoma, thrombosis of a prosthetic valve, or a congenital membrane in the left atrium (eg, cor triatriatum). Mitral stenosis is usually a result of rheumatic fever, after which it may gradually cause pulmonary edema. Other causes of CPE often accompany mitral stenosis in acute CPE; an example is decreased LV filling because of tachycardia in arrhythmia (eg, atrial fibrillation) or fever.

LV systolic dysfunction

Systolic dysfunction, a common cause of CPE, is defined as decreased myocardial contractility that reduces cardiac output. The fall in cardiac output stimulates sympathetic activity and blood volume expansion by activating the renin-angiotensin-aldosterone system, which causes deterioration by decreasing LV filling time and increasing capillary hydrostatic pressure.

Chronic LV failure is usually the result of congestive heart failure (CHF) or cardiomyopathy. Causes of acute exacerbations include the following:

Acute myocardial infarction (MI) or ischemiaPatient noncompliance with dietary restrictions (eg, dietary salt restrictions)Patient noncompliance with medications (eg, diuretics)Severe anemiaSepsisThyrotoxicosisMyocarditisMyocardial toxins (eg, alcohol, cocaine, chemotherapeutic agents such as doxorubicin [Adriamycin], trastuzumab [Herceptin])Chronic valvular disease, aortic stenosis, aortic regurgitation, and mitral regurgitation

LV diastolic dysfunction

Ischemia and infarction may cause LV diastolic dysfunction in addition to systolic dysfunction. With a similar mechanism, myocardial contusion induces systolic or diastolic dysfunction.

Diastolic dysfunction signals a decrease in LV diastolic distensibility (compliance). Because of this decreased compliance, a heightened diastolic pressure is required to achieve a similar stroke volume. Despite normal LV contractility, the reduced cardiac output, in conjunction with excessive end-diastolic pressure, generates hydrostatic pulmonary edema. Diastolic abnormalities can also be caused by constrictive pericarditis and tamponade.

Dysrhythmias

New-onset rapid atrial fibrillation and ventricular tachycardia can be responsible for CPE.

LV hypertrophy and cardiomyopathies

These can increase LV stiffness and end-diastolic pressure, with pulmonary edema resulting from increased capillary hydrostatic pressure.

LV volume overload

LV volume overload occurs in a variety of cardiac or noncardiac conditions. Cardiac conditions are ventricular septal rupture, acute or chronic aortic insufficiency, and acute or chronic mitral regurgitation. Endocarditis, aortic dissection, traumatic rupture, rupture of a congenital valve fenestration, and iatrogenic causes are the most important etiologies of acute aortic regurgitation that may lead to pulmonary edema.

Ventricular septal rupture, aortic insufficiency, and mitral regurgitation cause elevation of LV end-diastolic pressure and LA pressure, leading to pulmonary edema. LV outflow obstruction, such as that caused by aortic stenosis, produces increased end-diastolic filling pressure, increased LA pressure, and increased pulmonary capillary pressures.

Some sodium retention may occur in association with LV systolic dysfunction. However, in certain conditions, such as primary renal disorders, sodium retention and volume overload may play a primary role. CPE can occur in patients with hemodialysis-dependent renal failure, often as a result of noncompliance with dietary restrictions or noncompliance with hemodialysis sessions.

Myocardial infarction

One of the mechanical complications of MI can be the rupture of ventricular septum or papillary muscle. These mechanical complications substantially increase volume load in the acute setting and therefore may cause pulmonary edema.

LV outflow obstruction

Acute stenosis of the aortic valve can cause pulmonary edema. However, aortic stenosis due to a congenital disorder, calcification, prosthetic valve dysfunction, or rheumatic disease usually has a chronic course and is associated with hemodynamic adaptation of the heart. This adaptation may include concentric LV hypertrophy, which itself can cause pulmonary edema by way of LV diastolic dysfunction. Hypertrophic cardiomyopathy is a cause of dynamic LV outflow obstruction.

Elevated systemic blood pressure can be considered an etiology of LV outflow obstruction because it increases systemic resistance against the pump function of the left ventricle.

PreviousNextPrognosis

In-hospital mortality rates for patients with CPE are difficult to assign because the causes and severity of the disease vary considerably. In a high-acuity setting, in-hospital death rates are as high as 15-20%.

Myocardial infarction, associated hypotension, and a history of frequent hospitalizations for CPE generally increase the mortality risk.

Severe hypoxia may result in myocardial ischemia or infarction. Mechanical ventilation may be required if medical therapy is delayed or unsuccessful. Endotracheal intubation and mechanical ventilation are associated with their own risks, including aspiration (during intubation), mucosal trauma (more common with nasotracheal intubation than with orotracheal intubation), and barotrauma.

PreviousProceed to Clinical Presentation , Cardiogenic Pulmonary Edema

Read More

Primary Pulmonary Hypertension

Practice Essentials

Primary pulmonary hypertension (PPH) is a rare disease characterized by elevated pulmonary artery pressure with no apparent cause. PPH is also termed precapillary pulmonary hypertension or, as is currently preferred, idiopathic pulmonary arterial hypertension (IPAH). Untreated IPAH leads to right-sided heart failure and death.

Essential update: FDA approves riociguat for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension

In October 2013, the FDA approved riociguat (Adempas) for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (CTEPH). Approval was based on 2 randomized, double-blind, placebo-controlled studies. A vasodilator that restores the nitric-oxide–soluble guanylate cyclase-cyclic guanosine monophosphate pathway, riociguat is approved for adults only; its safety in pediatric patients has not been determined.[1, 2]

Signs and symptoms

Common symptoms of IPAH include the following:

DyspneaWeaknessRecurrent syncope

Cardiovascular examination in patients with pulmonary arterial hypertension (PAH) often reveals the following findings:

The pulmonic component of the second heart sound is usually increased, which may demonstrate fixed or paradoxic splitting in the presence of severe right ventricular dysfunction; occasionally, the second heart sound may be palpable Pulmonic regurgitation (Graham Steell murmur) may be apparentA murmur of tricuspid regurgitation can be present, and a right ventricular lift (heave) may be notedJugular venous pulsations may be elevated in the presence of volume overload, right ventricular failure, or both; large V waves are often present because of the commonly present severe tricuspid regurgitation

Other findings may include the following:

Hepatomegaly with palpable pulsations of the liverAbnormal abdominal-jugular reflexAscites - Not uncommon in untreated patients and in patients with worsening decompensated right heart failurePitting edema - In the extremitiesPresacral edema - In patients who are bedridden

See Clinical Presentation for more detail.

Diagnosis

Cardiac catheterization

Cardiac catheterization is the criterion standard test to definitively confirm any form of PAH. Excluding left-sided heart disease, including diastolic dysfunction, is especially important in these patients because of major treatment implications. Catheterization is also performed to determine pulmonary vasoreactivity, which may have implications in the initiation and titration of high-dose calcium channel blocker (CCB) therapy.

Laboratory studies

Antinuclear antibodyThyrotropinB-type natriuretic peptide

Imaging studies

RadiographyEchocardiographyComputed tomography (CT) and lung scanningPulmonary angiography

Electrocardiography

Electrocardiographic results are often abnormal in patients with PAH, revealing right atrial enlargement, right axis deviation, right ventricular hypertrophy, and characteristic ST depression and T-wave inversions in the anterior leads. However, some patients with IPAH have few or no abnormal electrocardiographic findings.

Histology

Several histologic subtypes are associated with pulmonary arteriopathy in IPAH, one of which involves in situ thrombosis.

Exercise testing

In patients with IPAH, values for peak exercise oxygen consumption, oxygen pulse, and ventilator equivalents (ratio of expired volume to carbon dioxide output [ie, wasted ventilation fraction] at the anaerobic threshold) during exercise are abnormal to varying degrees.

See Workup for more detail.

Management

Calcium channel blocker therapy

Long-term treatment improves the quality of life and survival rate in patients who are proven responders to calcium channel blockers (CCBs). In general, CCBs are used at high doses in patients with IPAH.

Vasodilator therapy

For patients with IPAH in whom CCBs are contraindicated, ineffective, or poorly tolerated, guidelines from the American College of Chest Physicians (ACCP) recommend using the patient’s New York Heart Association (NYHA) functional class to guide the choice of vasodilator therapy.[3, 4] Grade A recommendations for vasodilator therapy by functional class from the ACCP are as follows:

Functional class II - SildenafilFunctional class III - Endothelin-receptor antagonists (bosentan), sildenafil, intravenous (IV) epoprostenol, or inhaled iloprostFunctional class IV - IV epoprostenol (treatment of choice)

Transplantation and septostomy

Lung transplantation - A single- or double-lung transplant is indicated for patients who do not respond to medical therapySeptostomy - Atrial septostomy is a palliative procedure that may afford some benefit to patients whose condition is deteriorating

See Treatment and Medication for more detail.

Image libraryCADD Legacy ambulatory infusion pump. Courtesy SIMS Deltec, St. Paul, Minn. NextBackground

Primary pulmonary hypertension (PPH) is a rare disease characterized by elevated pulmonary artery pressure with no apparent cause. PPH is also termed precapillary pulmonary hypertension or, more recently, idiopathic pulmonary arterial hypertension (IPAH). The term IPAH is now the preferred term for pulmonary arterial hypertension of unknown etiology; thus, IPAH represents pulmonary vascular disease with a spectrum of clinical presentations.

Dresdale and colleagues first reported a hemodynamic account of IPAH in 1951.[5] However, the pathophysiology of IPAH remains poorly understood. At least 15-20% of patients previously thought to have IPAH actually have a familial form of PAH involving at least one genetic defect, which has only recently been characterized (see Pathophysiology).

Cardiac catheterization is the criterion standard test to definitively confirm any form of PAH, including IPAH. However, a thorough workup includes a range of tests to exclude all reasonable causes of secondary pulmonary hypertension (see Workup).

Until recently, calcium channel blockers (CCBs) had been the most widely used class of drugs for IPAH. Patients with IPAH in whom CCBs are contraindicated, ineffective, or poorly tolerated may respond to long-term vasodilator therapy (see Treatment and Management).

Treating IPAH requires significant knowledge of and exposure to the available therapies for IPAH and their potential complications. Because IPAH is relatively rare, management is best left to expert personnel at centers with regular exposure to these patients (see Treatment and Management).

Patient education

Patient education about this rare fatal disease is paramount. If applicable, instruct patients on how to administer their daily parenteral medication. For patient education information, see the Lung and Airway Center and Heart and Blood Vessels Center.

For more information, see the Medscape Reference article Pediatric Primary Pulmonary Hypertension.

PreviousNextPathophysiology

The pathophysiology of IPAH is poorly understood. An insult (eg, hormonal, mechanical, other) to the endothelium may occur, possibly in the setting of increased susceptibility to pulmonary vascular injury (ie, multiple hit theory), resulting in a cascade of events characterized by vascular scarring, endothelial dysfunction, and intimal and medial (smooth muscle) proliferation.

At least 15-20% of patients previously thought to have IPAH actually have a familial form of PAH involving at least one genetic defect, which has only recently been characterized. The most common genetic defect in these cases involves the BMPR-II gene. However, only about a third of affected patients with a family history of PAH have an identifiable BMPR-II mutation. This suggests that additional genetic abnormalities and/or additional external factors may exist that predispose individuals to developing PAH.

In 2013, 6 mutations that appear to be associated with pulmonary arterial hypertension (PAH) and that may be treatable were discovered in a gene, KCNK3, that had not previously been linked to the disease. Each of the 6 mutations was linked to a loss of function of potassium ion channels.[6, 7] In vitro examination of the investigational agent ONO-RS-082 (2-[p-amylcinnamoyl]amino-4-chlorobenzoic acid), a phospholipase A2 inhibitor, found that for 2 of the 3 mutations tested, the drug restored function to nonworking potassium ion channels.

Early in PAH, as the pulmonary artery pressure increases because of increasing right ventricle work, thrombotic pulmonary arteriopathy occurs. Thrombotic pulmonary arteriopathy is characterized by in situ thrombosis of small muscular arteries. In later stages, as the pulmonary pressure continues to rise, plexogenic pulmonary arteriopathy develops. This is characterized by a remodeling of the pulmonary vasculature with intimal fibrosis and replacement of normal endothelial structure.

For more information, see the Medscape Reference article Persistent Newborn Pulmonary Hypertension.

Associated conditions

Pulmonary vascular disease can be associated with portal hypertension (sometimes called portopulmonary hypertension), suggesting that patients with shunting of splanchnic blood, with or without liver disease, have a higher risk of developing PAH.

Additionally, exposure of the pulmonary circulation to substances from the splanchnic circulation that are normally detoxified via the liver may contribute to the development of pulmonary hypertension. More research is necessary to better understand this relationship.

Patients with connective-tissue diseases, namely the CREST (calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia) variant of scleroderma, systemic lupus erythematosus, and mixed connective-tissue disease, are also predisposed to developing IPAH-like disease. This is now termed associated PAH, or APAH.

The pathophysiologic nature of this predisposition is unclear. In the past, most experts used the term "secondary" pulmonary arterial hypertension for these diseases, indicating that, similar to IPAH, the process involves the precapillary circulation but is somehow caused by or at least associated with the underlying (predisposing) disease.

A study by Soon et al determined that unexplained iron deficiency is more prevalent in patients with idiopathic pulmonary artery hypertension than in those with chronic thromboembolic pulmonary hypertension (CTEPH).[8] Interleukin-6 (IL-6) may play a role in this difference in prevalence.

PreviousNextEtiology

The strict definition of IPAH is pulmonary hypertension with no known cause. However, associations have been recognized (eg, connective-tissue diseases, liver cirrhosis, exposure to anorexigens and likely other alpha-adrenergic stimulants [eg, cocaine, amphetamines],[9] HIV infection). How these associated conditions predispose to or cause PAH remains unknown.

PreviousNextEpidemiology

IPAH is responsible for approximately 125-150 deaths per year in the United States and has an incidence rate of approximately 2-6 cases per million population per year. The incidence and prevalence of APAH are considerably higher than those of IPAH. The worldwide incidence of IPAH approximates that observed in the United States, but variations in prevalence exist worldwide. A registry of patients with IPAH in France found a prevalence of IPAH of about 6 cases per million population.[10] IPAH occurs at a female-to-male ratio ranging from 2-9:1, depending on the treatment center sampled. In the United States, the average female-to-male ratio reported in clinical trials and registries is close to 4:1. The reasons for this female predilection remain unknown.Typically, younger women of childbearing age develop IPAH. However, IPAH can also affect individuals in their fifth and sixth decades of life or older.[11]

PreviousNextPrognosis

IPAH has no cure. Untreated IPAH leads to right-sided heart failure and death. Prior to the 1990s, therapeutic options were limited. The emergence of prostacyclin analogues, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and other novel drug therapies has greatly improved the outlook for patients with IPAH and IPAH-like diseases.

For untreated IPAH, the estimated 3-year survival rate is approximately 41%. In one study of long-term continuous intravenous prostacyclin therapy, 3-year survival increased to approximately 63%.[12] With newer therapies, perhaps in combination, these figures are expected to improve further.

Data on long-term survival in patients treated with other pulmonary vascular therapies are emerging. Patients whose disease progresses and is unresponsive to medical treatments either undergo transplantation or die of progressive right-sided heart failure.

Using the largest registry of patients with PAH to date, the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry), Benza et al analyzed factors determining survival in 2716 patients.[13] Using this data, they derived a multivariable, weighted risk formula incorporating 19 independent factors identified as having an impact on PAH patient survival, thus allowing clinicians to incorporate factors encountered in real-world management of PAH in their overall risk/severity assessment.

In another analysis of data from the REVEAL Registry, Frost et al found that PAH patients with mean pulmonary capillary wedge pressure (PCWP) of 16-18 mmHg at diagnostic right heart catheterization were heavier, older, and were more likely to have comorbidities associated with left ventricular diastolic dysfunction at diagnosis than patients with PCWP ≤15 mmHg. Five-year survival was poor in both PCWP subgroups.[14]

PreviousProceed to Clinical Presentation , Primary Pulmonary Hypertension

Read More