Neurogenic Pulmonary Edema

Etiology

The underlying causes of NPE reported in the literature include the following common and rarer etiologies:

• Common etiologies
  • Acute subarachnoid hemorrhage (SAH)
  • Intracerebral haemorrhage
  • Traumatic brain injury (eg, subdural/epidural hematoma, brainstem or upper cervical spinal trauma)
  • Epilepsy
• Rare etiologies
  • Enterovirus 71-associated brainstem encephalitis
  • Ischemic stroke
  • Intracranial/spinal surgery
  • Multiple sclerosis
  • Electroconvulsive therapy
  • Meningitis
  • Poisoning
  • Drug-induced (pemetrexed) [4]
  • Hypoxia
  • Aqueductal glioma
  • Spinal cord infarction [5][6][7][8]

Any acute CNS injury may result in NPE. However, the 3 most common causes of this syndrome are open or closed cranial trauma, subarachnoid hemorrhage (SAH) following aneurysmal rupture, and epilepsy with generalized tonic-clonic seizures.[5][6][7] Pulmonary complications occur in up to 50% of aneurysmal SAH patients, with NPE being one of the more serious manifestations.[9] NPE is associated with high mortality, particularly in patients with severe brain injury or poor neurological status. Reported mortality rates vary, with some series citing figures as high as 60% to 100%.[2][3][10]

Epidemiology

The actual incidence of NPE remains unknown. However, through pathological data analysis, experts have proposed that the condition is often observed at autopsy in patients who die suddenly after a seizure, eg, in sudden, unexpected death epilepsy, and also in victims of severe head injury. Although NPE is rare in the general population, autopsy studies suggest it may be present in up to 20% of patients with severe traumatic brain injury.[11][12][13][14]

Pathophysiology

A comprehensive understanding of the pathophysiology of NPE remains uncertain (see Image. Pathophysiology of Neurogenic Pulmonary Edema). The CNS disturbance will cause a massive sympathetic discharge (or catecholamine surge), leading to systemic vasoconstriction, which increases venous return and 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:

• Increased pulmonary capillary hydrostatic pressure causing fluid movement into the alveoli as a result of Starling forces
• Increased permeability of the pulmonary capillary endothelium due to catecholamine-mediated injury

For a complete, comprehensive understanding of the pathophysiology of NPE, 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 NPE are located in specific areas of the CNS that elicit NPE. 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 NPE is unclear. Experimental studies suggest that NMDA receptor activation enhances sympathetic output, while GABAergic inhibition may counteract this response after CNS injury.

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

Excessive sympathetic discharge is considered the key driver of NPE pathogenesis, leading to a catecholamine surge and subsequent cardiovascular and pulmonary changes.[15] The sudden over-activation of the NPE 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.[16][15] 

Parasympathetic contribution

Although the vagus nerve influences heart rate and bronchomotor tone, its role in NPE remains unclear. Some speculate that vagally mediated bradycardia may contribute, but no definitive causal relationship has been established. Clinicians should also note that the correlation between vagus nerve activity and the pathogenesis of NPE 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 NPE 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 (Takotsubo-like Cardiomyopathy): Catecholamine surge can cause neurogenic myocardial stunning, leading to transient left ventricular dysfunction, which exacerbates pulmonary congestion and edema. 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.[17][18][19][20] 
  • Indirect (physical or "blast injury"): The rapid and severe elevation in pulmonary capillary hydrostatic pressure can cause direct mechanical stress and barotrauma to the delicate capillary endothelium and alveolar epithelium.[21][22][23]

History and Physical

Clinical Features

Rapid changes characterize the early stages of NPE. NPE has been reported across all age groups, but some studies suggest it may be more frequent in children and young adults following acute intracranial injury. In cases of blunt head injuries, NPE may develop within a matter of minutes. While no pathognomonic symptom defines NPE, its clinical presentation typically mirrors that of acute pulmonary edema. NPE is most often concomitant with the initial phase of the neurological pathology. Clinical signs mimic pulmonary edema but typically lack features of left ventricular failure, helping distinguish NPE from cardiogenic causes. Classic NPE typically manifests within 2 to 12 hours after neurological injury, though onset can be more rapid in severe cases.

Symptoms resemble other forms of pulmonary edema, including dyspnea, tachypnea, and impaired gas exchange, often accompanied by systolic hypertension, which may reflect 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. Additional sympathetic signs, such as diaphoresis, transient hypertension, paralytic ileus, and insomnia, may also be observed. Ventilation and perfusion disorders, hypoxemia, and carbon dioxide retention frequently occur shortly after that.

If untreated, the natural evolution of NPE leads to respiratory failure, followed by cardiovascular collapse, and has a high mortality rate that has been estimated at more than 60%. In many cases, determining whether mortality is primarily due to the pulmonary, neurological, or cardiovascular components of the illness is difficult. 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 predominantly pulmonary or cardiovascular failure.[2][24][25]

Evaluation

NPE is a clinical diagnosis made in the context of acute CNS injury when pulmonary symptoms are present and other causes of pulmonary edema have been excluded. The primary aim of diagnostic studies is to rule out alternative causes of pulmonary edema, eg, cardiogenic, infectious, or traumatic etiologies.

Radiographic Studies

A chest x-ray (CXR) 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 NPE, which typically occur immediately after the injury. Excluding other pulmonary causes, including lung contusion, hemothorax, and pneumothorax, is necessary to confirm the diagnosis of NPE.

Electrocardiography and Echocardiography

Electrocardiography and echocardiography are essential to assess for myocardial ischemia, valvular abnormalities, or left ventricular dysfunction that may indicate cardiogenic edema.

Biomarkers

Brain natriuretic peptide (BNP) and troponin levels may be measured to assess for concurrent cardiogenic causes, but are not specific to NPE. Cardiac enzymes (eg, troponins) can help identify myocardial injury and assist in distinguishing NPE from acute coronary syndromes.[26][27]

Treatment / Management

With appropriate treatment, NPE typically resolves within 48 to 72 hours, after which the severity of the underlying neurological injury largely determines the overall prognosis. Severe cases of NPE have a high mortality, requiring intensive care. If NPE is clinically suspected, the initial management involves oxygen supplementation, artificial ventilation, and intensive care monitoring if needed. Consideration should be given to continually measuring ICP, and pulmonary artery catheterization may be considered in selected cases to assess pulmonary capillary wedge pressure (PCWP).

Definitive treatment should target the underlying CNS insult, though this may be challenging in cases of severe traumatic brain injury (TBI). 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 efforts to reduce pulmonary vascular resistance are essential. Nitric oxide, used for this purpose, is experimental but may have beneficial effects. In the later stages of NPE, the cardiovascular and ventilation strategies used in acute respiratory distress syndrome (ARDS) will be required.[28] The administration of steroids remains controversial.[29][30][31](A1)

Differential Diagnosis

Differential diagnoses that should also be considered when evaluating a patient with suspected NPE include:

• Adult respiratory distress syndrome
• Aspiration pneumonitis and pneumonia
• Bacterial pneumonia
• Cardiogenic pulmonary edema (see Table. Differentiating Neurogenic Pulmonary Edema and Cardiogenic Pulmonary Edema)
• SAH

 Table. Differentiating Neurogenic Pulmonary Edema and Cardiogenic Pulmonary Edema

Prognosis

The prognosis of NPE is closely tied to the severity of the underlying central nervous system injury rather than the pulmonary condition itself. While the respiratory manifestations of NPE can be severe and may rapidly progress to respiratory failure and cardiovascular compromise in some cases, 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% in some studies, 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

NPE can lead to several life-threatening 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, including 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 NPE a condition with a high risk of multiorgan failure and death.