Neurogenic Pulmonary Edema

Background

Neurogenic pulmonary edema (NPE) is a relatively rare form of pulmonary edema caused by an increase in pulmonary interstitial and alveolar fluid. Any acute central nervous system (CNS) insult can result in pulmonary edema. The most common causes are subarachnoid hemorrhage,^{[1, 2, 3, 4]} cerebral hemorrhage,^[5] traumatic brain injury (TBI),^[6] and seizures.^[7]

Neurogenic pulmonary edema most commonly develops within a few hours after a neurologic insult, and is characterized by dyspnea, bilateral basal pulmonary crackles, and the absence of cardiac failure.^[8] However, a delayed form of NPE that develops 12 to 24 hours after the CNS insult has been reported.^[9] Symptoms often spontaneously resolve within 24 to 48 hours; however, in patients with ongoing brain injury and elevated intracranial pressure (ICP), the NPE often persists.

No specific laboratory study confirms the diagnosis of neurogenic pulmonary edema (NPE). NPE is a diagnosis of exclusion,^{[9, 10]} and diagnosis requires exclusion of other causes of pulmonary edema (eg, high-altitude pulmonary edema).

The management of NPE is focused on treating the underlying neurologic condition. Treatment efforts to reduce ICP, including decompression and clot evacuation, osmotic diuretics, anti-epileptics, tumor resection, and steroids have all been associated with improvements in oxygenation.

For patient education resources, see the Brain and Nervous System Center and Stroke.

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Pathophysiology

General

The pathogenesis of neurogenic pulmonary edema (NPE) is not completely understood.^[8] Because the most common neurological events are associated with increased intracranial pressure, intracranial hypertension is considered a key etiologic factor.

Within the central nervous system, the sites responsible for the development of neurogenic pulmonary edema are not fully elucidated. Animal studies suggest that hypothalamic lesions, stimulation of the vasomotor centers of the medulla, elevated intracranial pressure, and activation of the sympathetic system have potential roles.^{[11, 12]} Cervical spinal cord nuclei also may have a role. Both hypothalamic lesions (paraventricular and dorsomedial nuclei) and stimulation of the vasomotor centers of the medulla (A1 and A5, nuclei of solitary tract, and area postrema, medial reticulated nucleus, and the dorsal motor vagus nucleus in the medulla oblongata) can increase output along the sympathetic trunk. Neurogenic pulmonary edema trigger zones may exist in these structures, with specific neurologic foci or centers producing massive sympathetic discharges that lead to neurogenic pulmonary edema.^[13]

Neuroanatomic structures

The medulla is believed to activate sympathetic components of the autonomic nervous system. Experimentally, bilateral lesions of the nuclei in the medulla produce profound pulmonary and systemic hypertension and pulmonary edema. Alpha-adrenergic blockade (with phentolamine) and spinal cord transection at the C7 level prevent the formation of neurogenic pulmonary edema, suggesting an important role for sympathetic activation.

An acute neurological crisis, accompanied by 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.

Mechanism of edema formation

A central nervous system event produces a dramatic change in Starling forces, which govern the movement of fluid between capillaries and the interstitium. Both hemodynamic (cardiogenic) and nonhemodynamic (noncardiogenic) components contribute to edema formation. Factors leading to the development of edema in patients with subarachnoid hemorrhage are illustrated in the flowchart below; however, these can be extrapolated to other types of central nervous system insults.

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Factors leading to the development of neurogenic pulmonary edema in patients with subarachnoid hemorrhage.

Changes in capillary hydrostatic pressure

Alterations in pulmonary vascular pressures appear to be the most likely Starling force to influence the formation of neurogenic pulmonary edema. Experimental observations suggest the following mechanisms by which pulmonary capillary hydrostatic pressures can be increased acutely:

• An increase in left atrial pressure may occur because of increases in sympathetic tone and venous return. Left ventricular performance may deteriorate secondary to the direct effects of catecholamines and other mediators, as well as 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 pressures.

Changes in pulmonary capillary permeability

An increase in capillary permeability can result in neurogenic pulmonary edema without elevation of pulmonary capillary hydrostatic pressure, because causative hemodynamic alteration is inconsistent. However, evidence shows that alpha-adrenergic blockade can protect against neurogenic pulmonary edema. 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 because of some direct nervous system control over the pulmonary capillary permeability remains uncertain.

An initial and rapid rise in pulmonary vascular pressure due to pulmonary vasoconstriction or pulmonary blood flow can lead to pulmonary microvascular injury. Consequently, an increase in vascular permeability results in edema formation, as suggested by the frequent observation of pulmonary hemorrhage in neurogenic pulmonary edema (ie, blast theory).^{[14, 15, 16]}

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Etiology

Any acute central nervous system (CNS) insult can result in pulmonary edema. The most common causes of neurogenic pulmonary edema (NPE) are subarachnoid hemorrhage,^{[1, 2, 3, 4]} cerebral hemorrhage,^[5] traumatic brain injury (TBI),^{[6, 17]}  COVID-19,^[18] and seizures.^[7] Other conditions, including nonhemorrhagic stroke,^[19] medication overdose, arteriovenous malformation, meningitis/encephalitis,^{[20, 21]} and spinal cord infarction, have been reported and linked to the formation of NPE.

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Epidemiology

Neurogenic pulmonary edema is an underdiagnosed condition.^[22] Patients with neurologic events often have multiple other comorbidities, which may obscure or mimic the diagnosis of neurogenic pulmonary edema. The lack of a standardized definition for neurogenic pulmonary edema also makes defining its epidemiology difficult.^[17]

As many as one third of patients with status epilepticus may have evidence of neurogenic pulmonary edema.^[7] More than half the patients with severe, blunt, or penetrating head injury have associated neurogenic pulmonary edema. Approximately 71% of fatal cases of subarachnoid hemorrhage are complicated by neurogenic pulmonary edema. Neurogenic pulmonary edema may complicate subarachnoid and intracerebral hemorrhage in 30-70% of patients and may recur after initial resolution.^{[23, 24]}

A series of 457 patients with subarachnoid hemorrhage reported a 6% prevalence of severe neurogenic pulmonary edema.^[25] Solenski et al reported in 1995 that increased age and a worse clinical grade of subarachnoid hemorrhage were associated with neurogenic pulmonary edema.

No data suggest differences in the international incidence of neurogenic pulmonary edema compared with the experience in the United States. However, note that epidemiologic data on this entity in general are very sparse because of the difficulties in recognition and diagnosis and lack of a standardized definition.

Age is not a specific risk factor for neurogenic pulmonary edema, other than the increased risk for neurologic events and cardiovascular abnormalities associated with increasing age.

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Prognosis

Data regarding morbidity and mortality following neurogenic pulmonary edema (NPE) have not been well documented, given the relatively low prevalence and likely underdiagnosis. Neurogenic pulmonary edema usually is generally well tolerated by the patient, although some patients require ventilatory support. Neurogenic pulmonary edema resolves within 48-72 hours in the majority of affected patients.

Morbidity related to neurogenic pulmonary edema is reported to be in the range of 40-50%, and reported mortality from neurogenic pulmonary edema is low, at approximately 7%. Overall, patient outcome is usually determined by the underlying neurological insult that led to neurogenic pulmonary edema unless significant respiratory complications develop.

Complications include but are not limited to the following:

• Prolonged hypoxic respiratory failure
• Hemodynamic instability
• Nosocomial infections (ie, related to prolonged mechanical ventilation and hospitalization)

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History and Physical Examination

History

Neurogenic pulmonary edema (NPE) characteristically presents within minutes to hours of a severe central nervous system insult. NPE is characterized by dyspnea, bilateral basal pulmonary crackles, and the absence of cardiac failure.^[8]

Physical examination

Physical findings may include the following:

• Tachypnea
• Tachycardia
• Bibasilar crackles
• Respiratory distress
• Pulmonary edema occurs but with normal jugular venous pressure and an absence of cardiac gallop, which should raise the possibility of a neurogenic cause
• Fever - May occur secondary to the neurological disturbance (eg, subarachnoid hemorrhage)

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Laboratory Studies

No specific laboratory study confirms the diagnosis of neurogenic pulmonary edema (NPE). Cardiac injury enzyme levels are elevated in patients with neurologic injury, especially subarachnoid hemorrhage. The magnitude of elevation often correlates with the severity of the neurologic event and its effect on cardiac function.

In one series, 20% of patients with subarachnoid hemorrhage were found to have serum troponin I levels greater than 1 mcg/L (range, 0.3-50 mcg/L).^[26]

Elevated natriuretic peptides, A-type and B-type, have also been reported in patients with subarachnoid hemorrhage, with B-type natriuretic peptide peak levels reported as 355 ± 80 pg/mL.^[27]

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Imaging Studies

Chest radiographs demonstrate a bilateral alveolar filling process and a normal-sized heart. This may mimic congestive heart failure with cephalization of blood flow, although other features of heart failure, such as septal Kerley B lines, are usually not evident. See the images below.

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Neurogenic pulmonary edema in a patient with a subdural hematoma.

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Progression of neurogenic pulmonary edema in the same patient in the image above, with subdural hematoma (day 2).

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Other Tests

No specific cardiac test confirms the diagnosis of neurogenic pulmonary edema. Initial studies of cardiac function are usually unremarkable. These include normal ECG findings, echocardiography findings, central venous pressure, and pulmonary artery occlusion (pulmonary artery capillary wedge) pressure.

Serial monitoring of cardiac function may demonstrate reduced left ventricular function attributed to a neurogenic stress cardiomyopathy. Findings include regional wall motion abnormalities that extend beyond a single vascular bed. Echocardiographic findings may demonstrate a reduced ejection fraction and large areas of akinesis in the setting of modestly elevated serum troponin levels. Normal pulmonary artery capillary wedge pressures may increase and approach high levels.

Recent studies have identified abnormal Q or QS wave and nonspecific ST- or T-wave changes (NSSTTCs) as possible predictors of NPE following subarachnoid hemorrhage.^{[15, 28]}

Coronary angiography, if performed, shows no obstructing lesions.

Separating the cardiac effects of the neurologic event from the effect of therapy used in these critically ill patients may be difficult.

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Procedures

Hemodynamic measurements with right-sided heart catheterization (ie, Swan-Ganz catheter) may be necessary to differentiate neurogenic pulmonary edema from hydrostatic or cardiogenic pulmonary edema. Systemic blood pressure, cardiac output, and pulmonary capillary wedge pressure are usually normal by the time neurogenic pulmonary edema is diagnosed clinically.

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Approach Considerations

The initial focus of neurogenic pulmonary edema (NPE) treatment is control of the underlying neurologic insult and associated complications, which may include surgical options. Surgical management is directed at the neurologic insult (eg, intracerebral hemorrhage, subdural hematoma) because NPE has no direct surgical treatment.

Neurological insults severe enough to cause NPE always warrant admission to hospital. Most patients require close cardiac monitoring, requiring initial admission to a monitored bed. A telemetry unit or step-down unit bed may suffice for less severe cases. Intensive care admission may be required if patients develop increasingly severe hypoxemia or respiratory distress, or if invasive monitoring is required.

Patients with NPE generally have multiple comorbidities that dictate the setting in which they are receiving care. Transfer between levels of acute care (ie, ICU to transitional care units, and subsequently to general medical/surgical ward) is influenced by a variety of factors. The most important of these is likely the underlying neurological insult that led to the development of pulmonary edema. Once this is managed and stabilized, further transitions between level of care are dictated by clinical circumstances. These include an ongoing need for mechanical ventilation, hemodynamic parameters, and the need for regular neurologic monitoring.

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Medical Care

General supportive care for neurogenic pulmonary edema (NPE) includes supplemental oxygen to correct hypoxemia. Mechanical ventilation may be necessary, either noninvasive with a face mask or via an endotracheal tube.^[29] The goals of mechanical ventilation are to assure adequate oxygenation and ventilation and to prevent iatrogenic lung injury. To avoid excessively high inflation pressures, tidal volumes between 5 and 6 mL/kg or predicted body weight are used.

With the use of low inflation volumes, positive end-expiratory pressure (PEEP) is added to prevent compression atelectasis. The peak inspiratory (plateau) pressure should be kept below 30-35 cm water, and eucapnia should be maintained to avoid further increases in intracranial pressure. High levels of PEEP may be required to treat severe hypoxemia. Caution is advised, however, because PEEP can inhibit cerebral venous return and increase intracranial hypertension.

Diuretic therapy may reduce lung water by decreasing capillary hydrostatic pressure and increasing colloid osmotic pressure, but the strategies to reduce lung water are not uniformly successful. The use of diuretics to minimize or reduce fluid overload seems a more reasonable approach, but adequate cardiac output and cerebral perfusion pressure must be maintained.

The goal of management in respiratory failure is to achieve an adequate level of oxygenation in the vital organs. Swan-Ganz catheterization may be helpful in guiding fluid and hemodynamic management, particularly if diuretics are used.

To maintain adequate tissue oxygenation, sufficient cardiac output (cardiac index >2.2 L/min/m²) and hemoglobin (>10 g/L) are required to ensure optimal oxygen delivery. Because cardiac output depends on cardiac filling pressures (central venous pressure and wedge pressure), meticulous monitoring of intravascular volume is mandatory. See the Cardiac Output calculator.

Pharmacology

Pharmacological agents are not used routinely in the treatment of neurogenic pulmonary edema (NPE). Several agents, such as alpha-adrenergic antagonists, beta-adrenergic blockers, dobutamine, and chlorpromazine, have been advocated, but assessment of their effectiveness is difficult because NPE is usually a self-limited condition that resolves spontaneously.

Alpha-adrenergic antagonists (eg, phentolamine) can prevent NPE or hasten its resolution in experimental models. However, no human trials have established the safety and efficacy of these agents. These agents may be used to treat concomitant systemic hypertension, if present, but care must be taken to avoid significant hypotension that can diminish cerebral perfusion.^{[30, 31]}

Beta-adrenergic agonists, in theory, are used to counteract the alpha-adrenergic–induced increase in systemic vascular resistance by increased inotropic effect with reflex-mediated decrease in afterload. Some studies have used dobutamine and shown a distinct improvement in myocardial function in patients with NPE.^{[32, 33]} A more recent study looked at patients with NPE who were taking lower doses of dopamine (< 6 mcg/min/kg) and showed this to be a reasonable alternative to dobutamine. Recommendations against using higher doses of dopamine have also been published, given the possible effects on increased afterload.

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Consultations

Consultations may include the following:

• Critical care medicine specialist or intensivist for ongoing intensive care
• Neurosurgeon and/or neurologist for evaluation and management of any underlying precipitating event
• Interventional radiologist for some specific neurologic vascular issues

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