Neurogenic Pulmonary Edema

Etiology

Any sort of acute CNS injury may trigger neurogenic pulmonary edema; however, the 3 most common triggers of this syndrome are cranial trauma (open or closed), subarachnoid hemorrhage (counting rupture of an aneurysm where it is found in more than 50% of cases), and epilepsy (generalized seizure). Neurogenic pulmonary edema has also been reported in some other pathological situations such as cervical medullary trauma, a postoperative period of intracranial surgery, and meningitis.

The occurrence of neurogenic pulmonary edema in a brain-injured patient is associated with a poor prognosis as the mortality rate is very high (60% to 100%). It is not only attributed to pulmonary involvement but also to primary brain injury.[2][3][4]

Epidemiology

There has been no confirmed incidence of neurogenic pulmonary edema. However, through pathological data, experts have projected that the condition is usually found in the autopsy of patients who die immediately after a seizure episode and also from those who are victims of severe head injuries. The cases of neurogenic pulmonary edema are generally rare. Only 20% of victims with serious head injury suffers from the condition.[5][6][7][8]

Pathophysiology

The full understanding of the pathophysiology of neurogenic pulmonary edema is still, to an extent, a baffling puzzle. It is important to understand the essence of the theory of an association between a CNS disturbance and developing pulmonary edema.

The CNS disturbance will cause a sympathetic overflow leading to a state of systemic vasoconstriction. This will cause pooling of the blood from the systemic circulation to the pulmonary circulation, hence eliciting an increase in the pulmonary capillary hydrostatic pressure. That change of pressure will mediate the leakage of intravascular fluid to both the alveoli and the pulmonary interstitial space through 2 mechanisms: (1) change of pressure across the alveolar bed dictated by Starling forces, (2) the changes in permeability on the capillary walls.

For a more comprehensive understanding of the pathophysiology of the neurogenic pulmonary edema, it is important to understand 3 different sectors. However, it is worthy to note that this clinical condition results from the overlapping of these sectors through cause and effect. See Table 1.

Central Nervous System

1. Structural: The injured CNS will initiate a state of sympathetic overflow. Specific centers in the CNS (if stimulated) manage autonomic sympathetic system activation. Centers responsible for autonomic contribution to the pathogenesis of neurogenic pulmonary edema are located in specific areas of the CNS, called trigger zones for neurogenic pulmonary edema. These include rostral ventrolateral medulla, area postrema, nuclei of the solitary tract, nuclei of A1 and A5, and the medial reticulated nucleus, and the dorsal motor vagus nucleus.
2. Chemical: The role of neurotransmitters is not clear in the pathogenesis of neurogenic pulmonary edema. Experimental studies relate NMDA receptors and GABA receptors activity in neurogenic pulmonary edema trigger zones to affect the sympathetic flow following CNS insult.
3. Physiological: Raised intracranial pressure (ICP) is a common encounter in CNS injuries. The abrupt increase in ICP will lead to the Cushing triad (increased blood pressure [BP], irregular breathing, and bradycardia). These physiological changes along with sympathetic overflow facilitate the development of pulmonary edema. Experimental studies on animals showed an increase in pulmonary artery pressure and extravascular pulmonary fluid in response to increased ICP.

Autonomic Nervous System

1. Sympathetic overflow: The sympathetic system is the key player in the pathogenesis of neurogenic pulmonary edema. The sudden over-activation of the neurogenic pulmonary edema trigger zones (either due to direct injury/irritation, activation of ascending neural pathways or as a response to the raised ICP) prompts sympathetic overflow and an outburst of catecholamines initiating 3 important pathophysiological responses; systemic vasoconstriction, increased blood pressure, and increased venous return.  
2. Parasympathetic contribution: The 10th cranial nerve (CN X) vagus provides the parasympathetic supply to the lungs and heart. Although the effect of vagus nerve rule on the heart during CNS injury is fairly elicited, yet the correlation of vagus nerve with the development of neurogenic pulmonary edema is strongly debatable and lacks clear supporting evidence. It is worth to mention that the hypothetical rationalization of the correlation of the vagus nerve activity to neurogenic pulmonary edema pathogenesis is the question of whether bradycardia is an essential or accessory factor in the development of pulmonary edema.

Cardiovascular and Pulmonary Systems

Sympathetic overflow and catecholamines-surge result in an increase of systemic resistance, venous return, and BP. Knowing this, the proposed theory of the development of neurogenic pulmonary edema falls into one of three supposed explanation:

1. Hemodynamic changes: Increased functional demand on the cardiac muscle due to the aforementioned outcomes of the sympathetic overflow will cause the movement of blood from the systemic highly resistant circulation to the less resistant pulmonary circulation, resulting in an increase in pulmonary capillary positive hydrostatic pressure leading the movement of fluid from the capillaries to the lung tissue and interstitial space.  
2. Neurogenic myocardial injury: Mainly dictated by the sudden catecholamine surge. The increase in systemic BP and venous return will cause an overload on the heart. As the left ventricle fails to meet that loading change functionally, accumulation of blood in the ventricle occurs, causing cardiac damage, hence diastolic dysfunction. This will lead to pulmonary vascular congestion, hereafter pulmonary edema.
3. Increased pulmonary capillary permeability is governed by 2 possible causes:

• Direct (humoral): Damage to the pulmonary capillaries endothelium in direct response to the catecholamines regardless of hemodynamic changes. [9][10][11][12] 
• Indirect (physical): Damage to the capillary bed as a mechanical response to the abrupt rise in the pulmonary capillary hydrostatic pressure. [13][14][15]

History and Physical

Rapid developments characterize the early stages of neurogenic pulmonary edema. The common patients are usually children or young adults, who must have suffered an intracranial injury recently. In cases of blunt head injuries, neurogenic pulmonary edema may develop in a matter of minutes. There is no specific symptomatology of neurogenic pulmonary edema. It is most often concomitant of the trigger phase of the neurological pathology. The clinical signs boil down to classic signs of pulmonary edema with the absence of signs of left ventricular failure usually found in cardiogenic edema. For classic neurogenic pulmonary edema, the manifestation is immediate, and it could be detected clinically within 2 to 12 hours post-injury.

The symptomatology is that of any pulmonary edema with initially ventilation disorders often accompanied by systolic hypertension probably also testifying to intracranial hypertension. In patients with spontaneous ventilation, dyspnea, tachypnea, cough and rales with auscultation and tachycardia would be early signs, sometimes accompanied by pink foamy sputum or hemoptysis. More discrete symptoms of sympathetic stimulation, such as insomnia, sweating, paralytic ileus, and transient hypertension are also described. Ventilation/perfusion disorders, hypoxemia, and carbon dioxide retention will occur shortly after that.

The natural evolution leads to respiratory failure followed by cardiovascular collapse and has a high mortality, estimated at more than 60%. It is impossible to assess whether the direct cause of this mortality is pulmonary or neurological or even cardiovascular. In contrast to older descriptions, more recent publications seem to attribute mortality rather to brain causes. However, in pediatric encephalomyelitis cases, the cause of death would be mainly pulmonary and cardiovascular.[2][16][17]

Evaluation

Neurogenic pulmonary edema diagnosis is clinical, based on the presence of pulmonary manifestations in the fact of CNS injury. The diagnostics aim toward exclusion of differentials:

Chest X-Ray

A chest x-ray is important to differentiate between this condition and aspiration pneumonitis. With aspiration pneumonitis, the radiographic features take up to a few hours to evolve, and up to 3 weeks to resolve.  This is in contrast to the alveolar infiltrates in neurogenic pulmonary edema, which occurs instantly after the injury. Rule out other pulmonary causes (e.g., lung contusion, hemothorax, pneumothorax, among others).

Electrocardiography and Echocardiography

These point out the functional and structural abnormalities of the heart if any.

Biomarkers

There is no specific biomarker for neurogenic pulmonary edema, yet consideration toward cardiac enzymes should be taken into account.[18][19]

Treatment / Management

The evolution of this syndrome is often favorable after 48 to 72 hours under treatment, and the prognosis is then more related to the underlying neurological pathology. However, these cases where the functional or vital prognoses are committed to justifying systematic vigilance to ensure early diagnosis and appropriate treatment.

In all cases, these are very serious situations with high mortality requiring intensive care. The suspicion of neurogenic pulmonary edema initially requires symptomatic treatment, often artificial ventilation and intensive care monitoring. It is wise to consider the benefits of continuous measurement of ICP and possibly capillary pulmonary pressure.

Management should aim for a causal treatment, often difficult in severe head trauma. The main effort during diffuse injury to the CNS will, therefore, be to reduce ICP. Then, based on the current physiopathological hypotheses, the therapy will be mainly cardiovascular and will aim at the increase of the inotropic especially by beta-adrenergic stimulation, the reduction of the pulmonary vascular resistance is essential. Nitric oxide (NO) for this purpose is only experimental but may be useful.

In the later stages of neurogenic pulmonary edema, the cardiovascular and ventilation strategies used in acute respiratory distress syndrome (ARDS) will be required. The administration of steroids remains controversial.[20][21][22](B3)

Differential Diagnosis

• Adult respiratory distress syndrome

• Aspiration pneumonitis and pneumonia

• Bacterial pneumonia

• Cardiogenic pulmonary edema

• Subarachnoid haemorrhage