Pulmonary Edema, Noncardiogenic

Background

Pulmonary edema is differentiated into 2 categories: cardiogenic and noncardiogenic. The latter, noncardiogenic pulmonary edema (NPE), is caused by changes in permeability of the pulmonary capillary membrane as a result of either a direct or an indirect pathologic insult. Many causes of NPE exist, including
, fluid overload, aspiration, inhalation injury, neurogenic pulmonary edema, allergic reaction, and (ARDS). The correct diagnosis relies on clinical and radiologic findings, despite some overlap in the clinical and imaging findings between the different causes.

An initial and rapid increase in pulmonary vascular pressure due to pulmonary vasoconstriction or pulmonary blood flow can lead to pulmonary microvascular injury. An increase in vascular permeability consequently results in edema formation, as suggested by the frequent observation of pulmonary hemorrhage in NPE (ie, the blast theory).

Two major components contribute to the pathogenesis of NPE: elevated intravascular pressure and pulmonary capillary leak. Therefore, hemodynamic cardiogenic and noncardiogenic components exist. These components often work in concert, as in pulmonary edema after epileptic convulsions or intracranial pressure elevation. The hemodynamic component is relatively brief and may unmask pure NPE, such as that seen in experimental seizures.

Whether the hemodynamic changes produce a pulmonary capillary leak through pressure-induced mechanical injury to the pulmonary capillaries or whether some direct nervous system control over pulmonary capillary permeability exists remains uncertain. The neuro-effector site for nervous system–induced pulmonary edema appears to be relatively well established in regions about the caudal medulla, where nuclei regulating systemic arterial pressure, as well as afferent and efferent pathways to and from the lungs, are located.

In order to avoid life-threatening complications, prompt recognition of NPE is important. The use of chest radiography and other tests is key to establishing the diagnosis and to distinguishing between the 2 types of pulmonary edema.

Pathophysiology

pulmonary edema is a major manifestation of left ventricular renal insufficiency, shock, and diffuse alveolar damage and lung hypersensitivity states.

Fluid is retained within the lungs. In early stages, the fluid retention is confined to the lower lobes; in advanced edema, however, all lung lobes may be involved, acquiring a rubbery, gelatinous consistency. On pathologic sectioning of the lungs, there is free escape of a mixture of air and fluid in the form of frothy, sanguineous fluid.

Histologic examination of lung tissue shows that the edema fluid first accumulates about the septal capillaries, with widening of the septa. With further progression of pulmonary edema, proteinaceous fluid, no longer retained in the histologic section, escapes into the alveolar sacs. The alveolar fluid appears as a granular pink coagulate. Edema fluid, when present for some time, is often complicated by hypostatic pneumonea.

Types of NPE or conditions that can result in NPE include the following :

• ARDS
• Neurogenic pulmonary edema
• Pulmonary edema in renal failure and/or fluid overload
• Negative-pressure pulmonary edema
• Pulmonary edema in marathon runners
• Decompression sickness
• Heroin and naloxone overdose
• NPE associated with cytotoxic chemotherapy
• Pulmonary complications of pregnancy
• Drowning
• NPE induced by a molecular adsorbent recirculating system
• Transfusion-related pulmonary edema between mother and child
• NPE after lung transplantation
• NPE in children with nonaccidental injury

Adult respiratory distress syndrome

ARDS is a syndrome of severe respiratory failure associated with pulmonary infiltrates that is similar to infant hyaline membrane disease. ARDS can occur in children as well as in adults. The condition originates from a number of insults involving damage to the alveolocapillary membrane with subsequent fluid accumulation in the airspaces of the lung.

Histologically, these changes have been termed diffuse alveolar damage. NPE results from the loss of integrity of the alveolar-capillary membrane, resulting in increased permeability to plasma. Fluid enters the alveolar space and disrupts the function of pulmonary surfactant, resulting in micro-atelectasis and impaired gas exchange. Ultimately, regional variations in pulmonary perfusion, ventilation/perfusion (V/Q) mismatch with shunting of blood through unventilated alveoli, and an increased alveolar-arterial oxygen gradient occurs.

ARDS is defined as the presence of bilateral pulmonary infiltrates on chest radiograph, impaired oxygenation resulting in a PaO₂ -to–fraction of inspired oxygen (FIO₂) ratio of less than 200, and absence of elevated pulmonary arterial occlusion pressure (PAOP) or left atrial pressure. Stated another way, ARDS is the presence of pulmonary edema in the absence of volume overload or depressed left ventricular function.

Neurogenic pulmonary edema

The pathogenesis of NPE is not completely understood. The most common neurologic event associated with NPE is increased intracranial pressure, which is considered a key etiologic factor.

In the central nervous system (CNS), the sites responsible for the development of NPE are not fully established. Animal studies indicate a potential role played by the hypothalamus, the medulla, intracranial hypertension, and activation of the sympathetic system. Hypothalamic lesions and stimulation of the vasomotor centers of medulla can increase output along the sympathetic trunk.

The medulla is believed to activate the sympathetic nervous system. Experimental work shows that bilateral lesions of the nuclei in the medulla can produce profound pulmonary and systemic hypertension and pulmonary edema. Alpha-adrenergic blockade (ie, phentolamine) and spinal cord transection at the C7 level prevent the formation of NPE, suggesting an important role for sympathetic activation.

An acute neurologic insult, associated with a marked increase in intracranial pressure, may stimulate the hypothalamus and the vasomotor centers of the medulla. This, in turn, initiates a massive autonomic discharge mediated by preganglionic centers within the cervical spine.

A CNS lesion can produce a dramatic change in Starling forces, which govern the movement of fluid between capillaries and the interstitium. The hemodynamic (cardiogenic) and nonhemodynamic (noncardiogenic) components contribute toward edema formation.

Alterations in pulmonary vascular pressures appear to be the most likely Starling force to influence the formation of NPE, as evidenced by protein-rich edema fluid. Experimental observations suggest 2 mechanisms by which pulmonary capillary hydrostatic pressures can be acutely increased; one of these involves increased left atrial pressure, and the second involves pulmonary venoconstriction.

An increase in left atrial pressure may occur due to an increase in sympathetic tone and an increase in venous return. Left ventricular performance may deteriorate secondary to the direct effects of catecholamines and other mediators, as well as secondary to transient systemic hypertension.

Pulmonary venoconstriction occurs with sympathetic stimulation, which may increase the capillary hydrostatic pressure and produce pulmonary edema without affecting left atrial or pulmonary capillary wedge pressure. An increase in capillary permeability can result in NPE without the elevation of pulmonary capillary hydrostatic pressure, since causative hemodynamic alteration is inconsistent; however, evidence shows that alpha-adrenergic blockade can protect against NPE.

Epinephrine, norepinephrine, and even a release of secondary mediators may directly increase pulmonary vascular permeability. Whether the capillary leak is produced by pressure-induced mechanical injury because of the elevated capillary hydrostatic pressure or results from some direct nervous system control over the pulmonary capillary permeability remains uncertain.

Pulmonary edema in renal failure/fluid overload

Impaired salt and/or water excretion leads to plasma volume expansion. This, along with decreased plasma oncotic pressure and an increase in capillary permeability, results in pulmonary edema. Secondary left ventricular failure and cardiogenic pulmonary edema can also occur.

Negative-pressure pulmonary edema

Negative-pressure pulmonary edema is associated with upper airway obstruction. Most described cases are associated with croup or epiglottitis requiring airway intervention in the pediatric population and adults requiring emergent airway intervention for laryngospasm or upper airway tumors. Laryngospasm is life threatening, and rapid identification and resolution of the obstructed glottis is required. Although the incidence of laryngospasm is low, postextubation laryngospasm is possible in any patient.

The pathogenesis is multifactorial. Negative intrapleural pressure is the primary pathologic event. This induces pulmonary edema formation by increasing venous return to the right heart and by decreasing the output of the left ventricle, thereby increasing pulmonary blood volume and microvascular pressures. These effects are augmented by the hypoxia and hyperadrenergic state that develop secondary to the airway obstruction, promoting translocation of blood from the systemic to the pulmonary circulation and further increasing pulmonary microvascular pressures.²

Pulmonary edema in marathon runners

Hyponatremia, cerebral edema, and NPE can occur in healthy marathon runners. In these persons, NPE is often associated with hyponatremic encephalopathy. The condition may be fatal if undiagnosed. It can be successfully treated with hypertonic saline.

Decompression sickness

NPE is a recognized but uncommon manifestation of type 2 decompression sickness. It typically occurs within 6 hours of a dive. Because ARDS in this setting is believed to be due to microbubbles in the pulmonary vasculature, recompression in a hyperbaric chamber has been recommended as a form of therapy.

Heroin and naloxone overdose

NPE is a known complication of heroin or naloxone overdose. pathogenesis of the pulmonary edema in this setting is unknown. It is usually clinically apparent immediately after or within 2 hours following drug use. Signs include rales; significant hypoxia; pink, frothy sputum; and bilateral, fluffy infiltrates on chest radiography. Most patients require mechanical ventilation because of severe hypoxia and respond in 24-36 hours with supportive care. This syndrome has been characterized as noncardiogenic on the basis of hemodynamic and pulmonary fluid analyses.

Drug-Related NPE

NPE and acute paraplegia in a 35-year-old woman has been reported following the accidental intra-arterial injection of benzathine penicillin in the gluteal region. A magnetic resonance imaging (MRI) scan indicated that syringomyelia and spinal cord ischemia at T9 through T10 were present. Vascular injury from microemboli of the injected crystals of the penicillin salts was implicated.

Essential hypertension is commonly treated with diuretics, especially the thiazide type. Hypotension, photosensitivity, hypokalemia, anorexia, and epigastric distress constitute the most frequent adverse reactions. However, the adverse reactions are rarely life threatening. Goetschalckx and colleagues reported on a patient in whom pulmonary edema was associated with low left ventricular filling pressures and hypotension, which developed soon after the person ingested 12.5 mg of hydrochlorothiazide.

Forty-nine cases of NPE have been reported in the literature following administration of thiazide-type diuretics. The Goetschalckx study postulated an allergic type III reaction as the mechanism behind this reaction.

A severe, life-threatening NPE has been reported following an idiosyncratic reaction after clopidogrel use.

NPE associated with cytotoxic chemotherapy

Pulmonary complications are said to occur in 20% of patients receiving cytotoxic chemotherapy. The following types of drug-induced injury may occur:

• NPE
• Hypersensitivity lung disease
• Chronic pneumonitis/fibrosis

The clinical and imaging findings are similar to those of NPE due to other causes.

Pulmonary complications of pregnancy

NPE can occur in pregnancy. Physiologic changes during pregnancy affect nearly every organ system. In the thoracic cavity, the diaphragm is elevated by as much as 4 cm because of displacement of the abdominal organs by the gravid uterus, decreasing lung volumes. Maternal blood volume and cardiac output increase approximately 45% by midpregnancy. Cardiac output can increase as much as 80% during vaginal delivery and up to 50% with cesarean delivery. These changes result in pulmonary vascular engorgement, progressive left ventricular dilatation, and mild hypertrophy.

Drowning

In drowning, the extent and severity of the edema depends on the amount of water aspirated and the degree of hypoxia. Pulmonary edema in drowning is due to injury of the alveolar septa, increased permeability of the pulmonary vascular endothelium, pulmonary microvascular platelet aggregation, and intra-alveolar edema. Whether the water is fresh or salt makes no difference on the pulmonary findings.

NPE induced by a molecular adsorbent recirculating system

NPE is a well-recognized manifestation of acute lung injury that has been related, among others, to blood or blood-product transfusion, intravenous contrast injection, air embolism, and drug ingestion.

Doria and colleagues described 2 cases of NPE after use of a molecular adsorbent recirculating system, a cell-free dialysis technique. in that series were undergoing evaluation for liver transplantation. Two (6.6%) of 30 patients thus treated for acute-on-chronic liver failure and intractable pruritus had normal chest radiographs before treatment. After treatment, both developed severe pulmonary edema in the absence of cardiogenic causes.

For each patient, the investigators reviewed the history of blood or blood-product transfusion, daily chest radiographs, and, as available, echocardiograms, pretreatment and posttreatment blood pressures, central venous pressures, pulmonary arterial pressures, cardiac output, cardiac index, systemic vascular resistance index, and arterial blood gases. Their data suggested that NPE may result from the molecular adsorbent recirculating system, possibly by means of an immune-mediated mechanism.

Transfusion-related pulmonary edema between mother and child

Transfusion-related acute lung injury (TRALI) is an underdiagnosed and serious complication of blood transfusion characterized by the rapid onset of respiratory distress, hypoxia, and NPE during or soon after blood transfusion. presence of anti–human leukocyte antigen (anti-HLA) and/or antigranulocyte antibodies in the plasma of donors is implicated in the pathogenesis of TRALI.

Yang and colleagues reported 2 cases of TRALI that were caused by designated blood transfusion between mothers and daughters. of these occurred in a 4-month-old girl who received designated packed red blood cells (RBCs) donated by her mother; the second occurred in a 78-year-old mother who received blood from her daughter. In both cases, examination of mother's serum revealed panel-reactive, cytotoxic HLA antibodies. The mothers were likely sensitized from earlier pregnancy and produced HLA antibodies against the daughters' paternally derived HLA antigens.

Designated blood transfusion between multiparous mothers and their children might add an additional transfusion-related risk owing to the increased likelihood of the HLA antibody-antigen specificity between mother and child.

NPE after lung transplantation

Lung transplantation has become a well-established treatment for end-stage pulmonary parenchymal and vascular disease. Complications of lung transplantation include the reimplantation response, acute rejection, pleural effusion, lymphoproliferative disorders, bronchiolitis obliterans, infection, and airway stenosis or dehiscence.

The reimplantation response is a form of NPE that begins soon after surgery and resolves in days to weeks. Acute rejection occurs in most recipients; a dramatic response to steroid therapy is the most diagnostic clinical feature. Imaging is important in differentiating the various complications. Infections remain the major cause of morbidity and mortality post transplant.

NPE in children with nonaccidental injury

NPE in children may occur after head injury, prolonged seizure, acute airway obstruction, or ingestion or inhalation of toxic drugs or chemicals. Rarely, NPE may be associated with child abuse or maltreatment.

Frequency

United States

The precise incidence of NPE is hard to quantify, as this is a clinical syndrome associated with a wide range of associated conditions. Furthermore, most cases occur after hospitalization. A worldwide rate of approximately 70 cases per 100,000 population has been suggested.

The incidence of pulmonary edema associated with airway obstruction has been estimated to be 12% and 11% in children and adults (respectively) requiring active airway intervention — that is, intubation or tracheostomy — for acute upper airway obstruction of varying etiology. Drowning is the third highest cause of accidental death in children; this is often associated with NPE.

Acute pulmonary edema occurs frequently (57%) after lung transplantation.

International

No data suggest that the incidence of NPE internationally varies from that in the US.

Mortality/Morbidity

Pulmonary edema is a serious complication of heart failure and renal insufficiency. Pulmonary edema due to noncardiogenic causes also carries serious risk, although the mortality and morbidity depend on the etiology. The patient's prognosis is determined by the course of underlying neurologic problems, as well as by other factors, such as patient age and any comorbid pathology.

Despite years of research, mortality rates related to ARDS remain as high as 40-60%.

Age

No specific epidemiologic data related to NPE are currently available. The distribution depends on that of the underlying pathology resulting in pulmonary edema.

Presentation

Clinical features of NPE

The characteristic features of NPE are dyspnea, hypoxemia, and radiographic pulmonary infiltrates developing within a few hours of a neurologic event.

Whatever the etiology, pulmonary edema impedes normal ventilatory lung function. Patients are breathless, have difficulty in lying flat, and have tachypnea and varying degrees of tachycardia. Characteristically, major auscultatory findings are coarse rales, particularly at the lung bases. In severe pulmonary edema, the collection of fluid in the bronchial tree gives rise to loud rales, which can be heard at the patient's bedside. Pulmonary edema is often complicated by hypostatic pneumonia.

Features of high-altitude pulmonary edema

Kobayashi and colleagues examined 27 consecutive patients with high-altitude pulmonary edema. The altitude at onset was 2680-3190 m above sea level. Symptoms included marked dyspnea, cough, and stridor. Physical findings included cyanosis, tachycardia, and rales. Neurologic disturbances, seen in 17 patients, included headache, vomiting, memory disturbance, clouding of consciousness, or coma.

Chest radiographs revealed patchy infiltrates throughout the pulmonary fields, often in an asymmetrical pattern, and enlargement of the right ventricle. Hemodynamic studies via right cardiac catheterization showed that the high-altitude pulmonary edema was noncardiogenic.

In 2 patients, pulmonary edema fluid collected through the endotracheal tube was rich in protein. Computed tomography (CT) scans of the brain showed small ventricles and cisterns, disappearance of sulci, and diffuse hypoattenuation of the cerebrum, indicating cerebral edema in 8 of 9 cases. Retinal hemorrhage and papilledema were observed in 5 patients.

Differential diagnosis

The differential diagnosis of NPE includes ARDS, cardiogenic pulmonary edema, bacterial pneumonia, and aspiration pneumonia. This last condition is one of the main differential diagnoses of NPE, because it also occurs in the setting of altered consciousness. NPE usually develops more rapidly than does aspiration pneumonia. Fever associated with NPE is unusual, but it may accompany the underlying neurologic insult that causes the NPE. Generally, aspiration pneumonia takes 1-2 weeks to resolve, whereas NPE resolves more quickly (from within hours to after several days).

Preferred Examination

Most patients with NPE are seriously ill and immobile. Conventional chest radiography is readily and universally available, and it has the added advantage of portability; chest radiography is the examination of choice.

In conjunction with the clinical presentation, radiographic findings are generally sufficient to arrive at a diagnosis of NPE.

Limitations of Techniques

The specificity of chest radiographs, particularly portable, anteroposterior (AP) images, is low, and it may not be possible to differentiate the various causes of lung parenchymal shadowing on radiographs alone. Most patients with NPE are generally ill, and there may be transportation problems to CT scanning and MRI units. Moreover, because these patients may be restless, sedation may be required to obtain images that are not degraded by motion artifacts.