Neurogenic Pulmonary Edema

Etiology

Any acute CNS injury may result in neurogenic pulmonary edema. However, the 3 most common causes of this syndrome are open or closed cranial trauma, subarachnoid hemorrhage following aneurysmal rupture in more than 50% of cases, and epilepsy with generalized seizures.[4][5] Neurogenic pulmonary edema has also been reported in other pathological situations, eg, stroke, cervical medullary trauma, after intracranial surgery, and in meningitis.[6]

The occurrence of neurogenic pulmonary edema in a brain-injured patient is usually associated with a poor prognosis, where the mortality rate is as high as 60% to 100%. Mortality is attributed to both the pulmonary involvement and the primary brain injury.[2][3][7]

Epidemiology

The actual incidence of neurogenic pulmonary edema remains unknown. However, through pathological data analysis, experts have proposed that the condition is usually present at autopsy in patients who die immediately after a seizure and also in victims of severe head injury. Overall, the cases of neurogenic pulmonary edema are rare, with only 20% of serious head injury patients having the condition.[8][9][10][11]

Pathophysiology

A comprehensive understanding of the pathophysiology of neurogenic pulmonary edema remains uncertain.

The CNS disturbance will cause a sympathetic overflow, leading to a state of systemic vasoconstriction. This process directs blood from the systemic circulation into the pulmonary circulation, thereby increasing the pulmonary capillary hydrostatic pressure. That change in pressure will result in the leakage of intravascular fluid into both the alveoli and the pulmonary interstitial space through the following 2 mechanisms:

• A change in the pressure across the alveolar bed as a result of Starling forces
• A change in the permeability of the capillary walls

For a complete, comprehensive understanding of the pathophysiology of neurogenic pulmonary edema, clinicians should consider 3 different sectors: the central, autonomic, and cardiovascular and pulmonary systems. However, the fact that this clinical condition results from the overlapping of these sectors through cause and effect is worth noting.

Central Nervous System

Structural considerations

The injured CNS will initiate a state of sympathetic overactivity. Specific centers in the CNS, when stimulated, will result in activation of the autonomic sympathetic system. Centers responsible for autonomic contributions to the pathogenesis of neurogenic pulmonary edema are located in specific areas of the CNS that elicit neurogenic pulmonary edema. These areas are located in the rostral ventrolateral medulla, area postrema, nuclei of the solitary tract, nuclei of A1 and A5, the medial reticulated nucleus, and the dorsal motor vagus nucleus.

Chemical processes

The role of neurotransmitters in the pathogenesis of neurogenic pulmonary edema is unclear. Experimental studies have shown that the activity of NMDA receptors and GABA receptors in neurogenic pulmonary edema influences sympathetic flow following a CNS insult.

Physiological events

Increased intracranial pressure (ICP) is a common occurrence after CNS injury. The abrupt increase in ICP will result in the Cushing triad of hypertension, irregular breathing, and bradycardia. These physiological changes, along with sympathetic overflow, promote the development of pulmonary edema. Experimental studies in animals have demonstrated an increase in pulmonary artery pressure and an increase in extravascular pulmonary fluid volume in response to ICP.

Autonomic Nervous System

Sympathetic overflow

The sympathetic system is the primary driver in the pathogenesis of neurogenic pulmonary edema.[12] The sudden over-activation of the neurogenic pulmonary edema trigger zone, either due to direct injury or irritation, activation of ascending neural pathways, or as a response to the raised ICP will lead to sympathetic overflow and a catecholamine release that initiates 3 important pathophysiological responses; systemic vasoconstriction, hypertension, and an increase in venous return.[13][12] 

Parasympathetic contribution

The tenth cranial nerve, known as the vagus nerve, provides the parasympathetic supply to the lungs and heart. Although the effect of the vagus nerve on the heart during CNS injury is fairly well understood, the correlation between the vagus nerve response and the development of neurogenic pulmonary edema is vigorously debated and lacks clear supporting evidence. Clinicians should also note that the correlation between vagus nerve activity and the pathogenesis of neurogenic pulmonary edema raises the question of whether bradycardia is an essential or an accessory factor in the development of pulmonary edema.

Cardiovascular and Pulmonary Systems

Sympathetic overflow and a catecholamine surge result in an increase in systemic resistance, venous return, and blood pressure. The proposed theories of the development of neurogenic pulmonary edema include:

• Hemodynamic changes: Increased functional demand on the cardiac muscle due to the previously mentioned outcomes of the sympathetic overflow will cause the movement of blood from the systemic highly resistant circulation to the less resistant pulmonary circulation, increasing the pulmonary capillary positive hydrostatic pressure that results in the movement of fluid from the capillaries into the lung tissue and the interstitial space.
• Neurogenic myocardial injury: Neurogenic myocardial injury is primarily the result of the sudden catecholamine surge. The increase in systemic blood pressure and venous return will cause a volume overload on the heart. As the left ventricle fails to functionally meet the loading change, accumulation of blood in the ventricle occurs, leading to cardiac damage and diastolic dysfunction. This will lead to pulmonary vascular congestion and subsequent pulmonary edema.
• Pulmonary capillary permeability: The following 2 possible causes govern increased pulmonary capillary permeability:
  • Direct (humoral): Damage to the pulmonary capillary endothelium in direct response to the catecholamine release, regardless of hemodynamic changes.[14][15][16][17] 
  • Indirect (physical): Damage to the capillary bed as a mechanical response to the abrupt rise in the pulmonary capillary hydrostatic pressure.[18][19][20]

History and Physical

Rapid changes characterize the early stages of neurogenic pulmonary edema. The most common patients are usually children or young adults who have suffered from a recent intracranial injury. In cases of blunt head injuries, neurogenic pulmonary edema may develop within a matter of minutes. No specific symptomatology for neurogenic pulmonary edema has been established. Neurogenic pulmonary edema is most often concomitant with the initial phase of the neurological pathology. The clinical signs are typically indicative of pulmonary edema, with the absence of signs of left ventricular failure, which is generally characteristic of cardiogenic edema. For classic neurogenic pulmonary edema, the manifestation is immediate, and it can be detected clinically within 2 to 12 hours after injury.

The symptomatology is that of any pulmonary edema with initial ventilation disorders, often accompanied by systolic hypertension, probably also testifying to intracranial hypertension. In patients with spontaneous ventilation, early signs include dyspnea, tachypnea, cough, and rales on auscultation, as well as tachycardia, which may be accompanied by pink, foamy sputum or hemoptysis. More discrete symptoms of sympathetic stimulation, including insomnia, sweating, paralytic ileus, and transient hypertension, have also been described. Ventilation and perfusion disorders, hypoxemia, and carbon dioxide retention frequently occur shortly after that.

The natural evolution of neurogenic pulmonary edema leads to respiratory failure, followed by cardiovascular collapse, and has a high mortality that has been estimated at more than 60%. Determining whether the direct cause of this mortality is pulmonary, neurological, or cardiovascular is impossible. In contrast to older descriptions, more recent publications seem to attribute mortality to the brain injury. However, in cases of pediatric encephalomyelitis, the cause of death would be primarily pulmonary or cardiovascular.[2][21][22]

Evaluation

The diagnosis of neurogenic pulmonary edema is clinical and is based on the presence of pulmonary manifestations in patients with a CNS injury. The primary aim of diagnostic studies is to exclude other differential diagnoses.

Radiographic Studies

A chest x-ray is essential for differentiating this condition from aspiration pneumonitis. With aspiration pneumonitis, the radiographic features will evolve over a few hours and can take up to 3 weeks to resolve. This pattern contrasts with the alveolar infiltrates seen in neurogenic pulmonary edema, which typically occur immediately after the injury. Excluding other pulmonary causes, such as lung contusion, hemothorax, and pneumothorax, is necessary to confirm the diagnosis of neurogenic pulmonary edema.

Electrocardiography and Echocardiography

Cardiac assessments, including electrocardiography and echocardiography, help determine whether functional and structural heart abnormalities are present.

Biomarkers

No specific biomarker for neurogenic pulmonary edema has been established. However, clinicians should consider obtaining cardiac enzymes to evaluate cardiac function.[23][24]

Treatment / Management

The evolution of this syndrome is often favorable after 48 to 72 hours of proper treatment, at which point the prognosis will primarily depend on the underlying neurological pathology. All cases of neurogenic pulmonary edema have a high mortality, requiring intensive care. The suspicion of neurogenic pulmonary edema initially requires symptomatic treatment consisting of artificial ventilation and intensive care monitoring. Consideration should be given to continually measuring ICP and possibly capillary pulmonary pressure.

Management should provide causal treatment, which can often be difficult in severe head trauma. The primary goal in managing diffuse injury to the CNS is to reduce ICP. Based on current pathophysiological hypotheses, cardiovascular therapy aims to increase the inotropic response through beta-adrenergic stimulation, and reducing pulmonary vascular resistance is essential. Nitric oxide, used for this purpose, is experimental but may have beneficial effects.

In the later stages of neurogenic pulmonary edema, the cardiovascular and ventilation strategies used in acute respiratory distress syndrome (ARDS) will be required.[25] The administration of steroids remains controversial.[26][27][28](A1)

Differential Diagnosis

Differential diagnoses that should also be considered when evaluating a patient with suspected neurogenic pulmonary edema include:

• Adult respiratory distress syndrome
• Aspiration pneumonitis and pneumonia
• Bacterial pneumonia
• Cardiogenic pulmonary edema
• Subarachnoid hemorrhage

Prognosis

The prognosis of neurogenic pulmonary edema is closely tied to the severity of the underlying central nervous system injury rather than the pulmonary condition itself. Although the respiratory manifestations of neurogenic pulmonary edema can be severe, with rapid progression to respiratory failure and cardiovascular collapse, appropriate intensive care and supportive management often lead to significant improvement within 48 to 72 hours.

Despite this potential for recovery, the overall mortality rate remains high, estimated at over 60%, particularly in cases involving extensive brain injury. Outcomes are generally poorer in severe traumatic brain injuries and pediatric encephalomyelitis, where pulmonary and cardiovascular complications contribute significantly to mortality.

Complications

Neurogenic pulmonary edema can lead to several serious complications, primarily stemming from rapid respiratory and cardiovascular deterioration. Acute respiratory failure is a common consequence, often requiring mechanical ventilation and intensive care. Cardiovascular complications, eg, systemic hypertension, neurogenic myocardial injury, and eventual cardiovascular collapse, further worsen the clinical picture.

Hypoxemia and ventilation-perfusion mismatch can develop quickly, exacerbating neurological injury through secondary brain hypoxia. Additionally, the high pulmonary capillary pressures and increased permeability may cause long-term lung injury if not promptly managed. The overlapping impact of pulmonary, cardiac, and neurological dysfunction makes neurogenic pulmonary edema a condition with a high risk of multiorgan failure and death.