Drowning in a Flash: A Review on Neurogenic Pulmonary Edema

You’re at the head of the bed when a trauma is brought in. A man in his early 30s is moved over to your stretcher. His head is wrapped in gauze that is saturated in blood.

You’re told that he has two apparent ballistic wounds, one to his right temple and one to his left. He has been intubated in the field and is oxygenating well with no overt secretions in his tube. Aside from his dismal neurologic exam, he is hemodynamically stable. You run through the trauma resuscitation, and the patient is ultimately moved to the CT scanner and then to an ED room while awaiting a surgical ICU bed.

Once in the room, the patient suddenly becomes hypertensive and tachycardic. You push a dose of Labetalol and call for a Nicardipine drip. A few seconds later, the patient’s oxygen saturation drops to the 60s, and the ventilator alarms due to high pressures. He is deep-suctioned with return of copious bloody, frothy secretions. His pulse ox continues to drop. You move him to the bag valve to no avail. He becomes increasingly difficult to bag. The next few minutes consist of frantically suctioning whatever you can and trying to bag. His blood pressure then drops, his pulse is lost, and CPR is begun. Despite the heroic efforts the team puts in coding him, he ultimately succumbs to his injuries, and the time of death is called. You look at the suction canister and see 800 cc’s of bloody, frothy sputum.

While this patient would have likely succumbed to his devastating neurologic insult, the immediate cause of his death was severe and sudden pulmonary edema. This patient experienced a phenomenon known as neurogenic pulmonary edema (NPE), which was first described by Shanahan in 1908 and can occur with any neurologic insult.¹ Presentation of NPE can be rapid or delayed and presents similarly to an acute respiratory distress syndrome (ARDS) picture.¹

Epidemiology
NPE can occur in any patient who has sustained a central nervous system (CNS) insult.¹ This phenomenon is likely under-reported and is most often described in case and autopsy reports.² NPE is also associated with a high mortality, with one large population study evaluating deaths among traumatic brain injury patients showing that 32% of this population had developed NPE, increasing to 50% if death occurred within 96 hours of the initial insult.³ Also notable, studies have found that more than 80% of those who die from status epilepticus are found to have developed NPE as well.⁴

While NPE can occur from any central nervous system insult, it can be most expected among those who have sustained a sudden CNS insult that led to an abrupt increase in intracranial pressure (ICP).^1,3 NPE is most seen in subarachnoid hemorrhages and head trauma.¹ Risk factors associated with the development of NPE include increasing extent of injury, increasing age, delay to treatment, vertebral artery origin or involvement, and status epilepticus.¹ NPE can also occur post-operatively in neurosurgical patients, particularly in those who have undergone a tumor resection or are experiencing a shunt malfunction.⁵ Any process that leads to an extreme elevation in ICP can precipitate NPE.^1,3

Pathophysiology
There are four main theories for the etiology and pathophysiology of NPE; however, its development is likely a combination of multiple inciting processes.¹ It is widely accepted that there is an interplay of the neurologic, cardiac, and pulmonary systems; however, there is potentially an inflammatory component as well. It is likely that there are still many aspects of this disease process that remain undescribed.

The first major mechanism proposed is based on the neurocardiac axis. This mechanism is proposed to occur after a CNS insult leads to a massive catecholamine release causing reversible damage to the myocardium, leading to decreased cardiac output, backup of blood into the pulmonary vasculature, and leakage of fluid into the alveoli, known as pulmonary edema.^1,3 This mechanism is likened to Takotsubo cardiomyopathy.³ Research has supported this mechanism by showing an increased occurrence of echocardiographic segmental wall abnormalities, including decreased left ventricular ejection fraction, elevated myocardial enzymes in the serum, electrocardiographic changes, and histologic signs of contraction band necrosis post-mortem in NPE patients.^{6, 7}

The second theory proposed is the neurohemodynamic mechanism. A sympathetic surge is also central to this theory. Following a CNS insult, there is a massive catecholamine release that affects both the heart and the vasculature. The increased sympathetic tone leads to an initial increase in left ventricle function; however, it quickly crosses its optimum functional threshold and begins to fail. In addition, systemic vascular resistance is increased, worsening the demand of the left ventricle. This causes a shift in blood into the pulmonary circuit, where there is a buildup of hydrostatic pressure, forcing fluid from the pulmonary vasculature into the alveoli.^1,3 This alone, however, would not explain the protein and red blood cells found in the translocated fluid.

The blast theory is the third major mechanism. This proposes that some combination of the mechanisms described above leads to increased capillary pressure which, in addition to barotrauma, leads to irreversible damage to the endothelial lining of pulmonary capillaries and the alveolar membrane.^1,3,8 This leads to leakage of fluid as well as protein and red blood cells. This mechanism is supported by case studies showing persistence of pulmonary vasculature damage even after reversal of all other components of NPE.⁹

The fourth mechanism proposed is the pulmonary venule adrenergic hypersensitivity theory.^1,9 This theory posits that the massive catecholamine and chemical signal release following a CNS insult causes direct damage to the pulmonary vasculature. With this mechanism, pulmonary edema would develop regardless of systemic vasculature changes.^1,9This is supported by the fact that pulmonary vascular beds have adrenergic receptors. Following a catecholamine surge, the pulmonary vascular beds can be stimulated to vasoconstrict, which can ultimately lead to endothelial damage.¹⁰ Other molecules of note are endothelin-1, which is released as an acute phase reactant following CNS insult, and neuropeptide-Y, which is released into the CSF and blood following CNS injury.^11,12 Both are also potent vasoconstrictors.^11,12 Vasoconstriction and endothelial damage can then precipitate NPE.¹

There is also evidence of an inflammatory component to NPE. Following injury to the brain, there is a substantial release of cytokines.¹³ These cytokines can cross the blood brain barrier due to its loss of integrity following the injury. They can then travel to the lungs where they both act directly on pulmonary vasculature as well as stimulate release of other cytokines. This response will lead to an inflammatory lung injury, including endothelial leakage allowing for translocation of fluid from capillaries into the alveoli. Hyperventilation may also contribute to this mechanism.¹³

There is no single mechanism proposed that is widely accepted as being the sole cause of NPE. Rather, it is likely that NPE occurs as a result of a combination of the mechanisms described above and additional processes yet to be described.

Clinical Characteristics
NPE is characterized as occurring in either early or late phases.³ NPE in the early phase occurs most often, with an onset of 30 to 60 minutes following neurologic insult. NPE is a clinical diagnosis in both stages. It is important to rule out ventilator-associated pneumonia, aspiration pneumonitis, sepsis-related ARDS, transfusion-related acute lung injury, heart failure, and post airway obstruction pulmonary edema.³

Clinically, the patient will have a sudden onset respiratory distress and hypoxia, and start producing pink and frothy sputum.³ Patients who are intubated may require frequent suctioning. A chest X-ray will show bilateral opacifications. An important aspect of NPE is that if the patient survives initial decompensation, there should be a rapid resolution after 48-72 hours.³ If the pulmonary edema does not begin to improve, evaluation for other causes should be investigated.³

Management
NPE is ultimately treated by addressing the neurologic process causing the increased ICP.¹⁴ Patients are typically mechanically ventilated if they have suffered an insult significant enough to cause NPE, and if they are not, then intubation should be considered to optimize pulmonary supportive care, providing adequate PEEP and frequent suctioning.¹⁴

Controlling the ICP is essential in managing patients with NPE. Patients should be maintained with normotension, normocapnia, and normothermia. Hypertonic infusions may be necessary to promote osmotic diuresis. Seizure prophylaxis is also often warranted following a severe neurologic insult, as seizures can increase ICP.¹⁴ If possible, placement of an external ventricular drain or a cranial decompression may be necessary. If the ICP is continually unmanageable despite aggressive resuscitative measures, the patient may require a barbiturate coma which decreases ICP by decreasing cerebral metabolism and oxygen demand, leading to a lower blood volume.^14,15

It should be noted that there are several methods that are contraindicated in traumatic brain injuries.¹⁴ Hypercapnia should only be used as a temporizing measure, if used at all, and continued hyperventilation has been associated with increased ICP.¹⁴ Fluid restriction is not effective in treating NPE and may lead to hypotension which can increase ICP.¹⁴Proning of a patient may also lead to an increase in ICP.¹⁴

Prognosis
The prognosis associated with patients who develop NPE is generally poor. Mortality rates in patients developing NPE have been recorded to be between 60 and 100%.³ Early recognition and initiation of supportive measures in patients developing NPE is crucial.

Take-Home Points

• NPE is a clinical diagnosis. It is essential that other pathologies that may require different treatments be excluded.
• Support your patient through NPE while addressing the neurological insult.
• Understand and become comfortable with non-surgical methods in decreasing ICP, such as the use of hypertonics, hemodynamic optimization, and pharmacologic interventions.
• NPE is associated with a very high mortality.

References

1. Davison DL, Terek M, Chawla LS. Neurogenic Pulmonary Edema. Critical Care. 2012;16(2):212.
2. Finsterer J. Neurological Perspectives of Neurogenic Pulmonary Edema. Eur Neurol. 2019;81(1-2):94-102.
3. Rogers FB, Shackford SR, Trevisani GT, Davis JW, Mackersie RC, Hoyt DB. Neurogenic Pulmonary Edema in Fatal and Nonfatal Head Injuries. The Journal of Trauma: Injury, Infection, and Critical Care. 1995;39(5):860-868.
4. Simon RP. Neurogenic Pulmonary Edema. Neurologic Clinics. 1993;11(2):309-323.
5. Cruz AS, Menezes S, Silva M. Neurogenic Pulmonary Edema Due to Ventriculo-Atrial Shunt Dysfunction: A Case Report. Brazilian Journal of Anesthesiology (English Edition). 2016;66(2):200-203.
6. Gregory T, Smith M. Cardiovascular Complications of Brain Injury. Continuing Education in Anaesthesia Critical Care & Pain. 2012;12(2):67-71.
7. Mayer SA, Fink ME, Homma S, et al. Cardiac Injury Associated with Neurogenic Pulmonary Edema Following Subarachnoid Hemorrhage. Neurology. 1994;44(5):815-815.
8. Theodore J, Robin DE. Speculations on Neurogenic Pulmonary Edema (NPE). American Review of Respiratory Disease. 1976;113(4):405–411.
9. Mayer SA, Fink ME, Homma S, et al. Cardiac Injury Associated with Neurogenic Pulmonary Edema Following Subarachnoid Hemorrhage. Neurology. 1994;44(5):815–815.
10. O’Leary R, McKinlay J. Neurogenic Pulmonary Oedema. Continuing Education in Anaesthesia Critical Care & Pain. 2011;11(3):87–92.
11. Papa L, Goldberg SA. Head Trauma. Rosen's Emergency Medicine: Concepts and Clinical Practice. ELSEVIER - HEALTH SCIENCE, SI. 2022;317–323.
12. Rogers FB, Shackford SR, Trevisani GT, Davis JW, Mackersie RC, Hoyt DB. Neurogenic Pulmonary Edema in Fatal and Nonfatal Head Injuries. J Trauma. 1995;39(5):860-6; discussion 866-8.
13. Schebesch KM, Brawanski A, Bele S, et al. Neuropeptide Y – an Early Biomarker for Cerebral Vasospasm after Aneurysmal Subarachnoid Hemorrhage. Neurological Research. 2013;35(10):1038–1043.
14. Simon RP. Neurogenic Pulmonary Edema. Neurologic Clinics. 1993;11(2):309–323.
15. Theodore J, Robin DE. Speculations on Neurogenic Pulmonary Edema (NPE). American Review of Respiratory Disease. 1976;113(4):405–411.