Neurogenic pulmonary edema

INTRODUCTION — Neurogenic pulmonary edema (NPE) is an increase in pulmonary interstitial and alveolar fluid that is due to an acute central nervous system injury and usually develops rapidly after the injury [1]. It is sometimes classified as a form of the acute respiratory distress syndrome (ARDS), but its pathophysiology and prognosis are different.

The clinical features, differential diagnosis, diagnosis, etiology, pathogenesis, and treatment of NPE are reviewed here. ARDS and noncardiogenic pulmonary edema due to other causes are discussed elsewhere. (See "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults" and "Noncardiogenic pulmonary edema".)

ETIOLOGY — The primary precipitants of NPE are epileptic seizures, traumatic brain injury, and various forms of intracranial hemorrhages [2,3]. NPE is also an increasingly recognized complication of pediatric encephalitis with Enterovirus-71 (Hand, foot, and mouth disease) [4]. Reported etiologies of NPE are listed in the table (table 1) [4-15].

Epileptic seizures — Among all patients with epilepsy the occurrence of NPE is rare. However, several case series reported that up to one-third of patients with fatal status epilepticus had clinical evidence of NPE, while an autopsy study found that 87 percent of patients with epilepsy and unexplained sudden death had NPE [3,16,17]. In a small retrospective study of patients presenting to an emergency department with seizures, who received thoracic computed tomographic (CT) imaging, signs of NPE were seen in 5 of 26 patients with generalized tonic-clonic seizures (19 percent) [18]. It is uncertain whether NPE was the proximate cause of death in these studies, but it is clear that the NPE is more likely with increasing seizure severity. NPE due to epileptic seizures generally occurs during the postictal period and it may occur repeatedly in a given individual [2,19-21]. (See "Convulsive status epilepticus in adults: Classification, clinical features, and diagnosis".)

NPE has also been reported following elective electroconvulsive therapy [22].

Traumatic brain injury — Blunt or penetrating head injury and neurosurgical procedures can cause NPE [2,23,24]. The NPE is usually associated with elevated intracranial pressure (ICP), but raised ICP is not a necessary condition [25]. The incidence of NPE in traumatic brain injury has been estimated at 20 percent, and appears to increase with increasing severity of injury [26]. (See "Evaluation and management of elevated intracranial pressure in adults".)

Intracranial hemorrhage — NPE can result from multiple forms of intracranial hemorrhage (table 1) [5-9].

●Subarachnoid hemorrhage (SAH) – NPE can complicate up to 43 percent of cases of SAH [27-32]. In a series of 78 cases of fatal subarachnoid hemorrhage, 31 percent had antemortem clinical evidence of NPE and 71 percent had pathological evidence of NPE at autopsy [29]. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".)

Onset is typically within minutes to hours of the hemorrhage although late onset days after hemorrhage or recurrence after apparent resolution have also been described [33]. NPE has also been reported during coil embolization of a ruptured cerebral aneurysm [34].

NPE following subarachnoid hemorrhage is associated with more severe clinical grade, younger age, and a vertebral artery source of the hemorrhage [32,35]. Electrocardiographic abnormalities, decreased heart rate variability, and laboratory abnormalities, including hyperglycemia, acidemia, hyperlactatemia, elevated troponin, and leukocytosis, are also associated with the development of NPE following nontraumatic subarachnoid hemorrhage [36-40].

●Intracerebral hemorrhage (ICH) – NPE can also be seen in up to 35 percent of patients with ICH, with the primary risk factors in such patients being higher Acute Physiology and Chronic Health Evaluation (APACHE) II scores and increased levels of serum inflammatory markers [41]. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" and "Management of acute moderate and severe traumatic brain injury".)

●Other forms of hemorrhage – NPE has also been reported following various other forms of intracranial hemorrhage including intraventricular, epidural, subdural hemorrhage [12-14].

PATHOGENESIS — The mechanism by which central nervous system injury leads to NPE is not completely understood. It is recognized that a central, transient sympathetic discharge is likely the primary instigator of the resulting pulmonary pathology.

Neurologic structures — The medulla oblongata is considered the critical anatomic structure involved in the pathogenesis of NPE. The importance of the medulla is supported by the observation that bilateral lesions in the nucleus of the solitary tract, area postrema and lesions in the A1 and A5 neuroadrenergic neurons (all of which are in the medulla) can cause systemic hypertension and NPE [42-45].

The medulla oblongata probably acts via the sympathetic component of the autonomic nervous system, as suggested by the following evidence from animal models [46-49]:

●Alpha adrenergic blockade (eg, with phentolamine or prazosin) can prevent the development of NPE

●NPE can be prevented by spinal cord transection at or above the C7 level, below which sympathetic fibers leave the lateral part of the cord to form the paraspinal sympathetic trunks

●NPE can be prevented by denervation via transection of the splanchnic sympathetic fibers to the lungs

●NPE may be produced by stimulation of the cord at the C7-C8 level, with the cord and sympathetic nerves intact

In addition to the role of the medulla oblongata, theories regarding the pathogenesis of NPE have centered on the potential contributions of the hypothalamus, elevated intracranial pressure, activation of the sympathoadrenal system, and vagus nerve axonal injury [42,43,46-48,50-60]. Among these, the role of the hypothalamus in NPE is most controversial. Experimental models have shown, for example, that inducing hypothalamic lesions precipitates NPE [61], while a case series of 22 patients with NPE found that half of them had radiographic evidence of hypothalamic injury, a finding associated with worse outcome [62]. However, in other animal models, mid-columnar decerebration does not prevent NPE, suggesting that higher CNS centers such as the hypothalamus are not involved in NPE development [63].

Mechanisms of edema formation — NPE requires a central nervous system injury or event (eg, seizure) that alters the Starling's forces in a way that increases the movement of fluid from the capillaries to the pulmonary interstitium, increases the permeability of the pulmonary capillaries, or both (figure 1).

●Capillary hydrostatic pressure – Increased capillary hydrostatic pressure likely contributes to most cases of NPE, since it is unlikely that a CNS injury or event could change capillary or interstitial oncotic pressure rapidly [2]. This is supported by the observation that alveolar fluid has a low fluid to serum protein ratio early during the course of NPE, consistent with hydrostatic pulmonary edema [64].

Experimental studies using animal models and uncontrolled observations in humans suggest several mechanisms by which pulmonary capillary hydrostatic pressure may increase acutely:

•Pulmonary venoconstriction may occur with intracranial hypertension or sympathetic stimulation. This increases the pulmonary capillary hydrostatic pressure, producing pulmonary edema [46,65-68]. Alpha adrenergic antagonists appear to attenuate this effect [69].

•Excessive systemic venoconstriction may occur leading to a significant increase in venous return to the right heart and pulmonary circulation. Support for this concept comes from animal studies in which prophylactic phlebotomy (15 percent of blood volume) prior to CNS insult prevented development NPE [70].

•Left ventricular performance may deteriorate for several reasons: direct myocardial damage or stunning secondary to brain injury, increased afterload due to systemic hypertension, and negative inotropic and chronotropic influences of excessive vagal tone [68,71,72]. This can cause passive elevation of the left atrial and pulmonary capillary pressures, leading to pulmonary edema [52,53,71,73-77].

Despite the evidence that increased pulmonary capillary hydrostatic pressure plays a role in NPE, there are likely additional contributors. This notion is based upon reports of NPE occurring with little or no elevation in the pulmonary capillary wedge pressure and in the absence of left atrial or systemic hypertension [65].

●Pulmonary capillary permeability – Increased pulmonary capillary permeability is likely also important to the pathogenesis of NPE. This idea is supported by the finding of protein-rich edema fluid in some animal models and patients with NPE, as well as the observation that NPE can occur in the absence of the hemodynamic alterations associated with pulmonary edema [27,64,78,79].

As an example, a study used thermal green dye techniques to measure extravascular lung water in 18 patients with either head trauma or subarachnoid hemorrhage and 13 control patients (trauma patients without head injury) [27]. Nine of the 18 patients with brain injuries had pulmonary edema, defined as extravascular lung water values greater than two standard deviations above the control group mean. The pulmonary edema was independent of intracranial or pulmonary vascular pressure, suggesting increased vascular permeability.

The mechanism by which neural influences produce changes in pulmonary vascular permeability remain unclear. Several hypotheses have been put forth:

•Neuropeptide Y, which is released by sympathetic nerves along with norepinephrine, increases pulmonary vascular permeability by acting directly on endothelial cells and has been found in alveolar macrophages and edema fluid in rats with NPE [63].

•Alpha adrenergic agonists released in response to brain injury may cause the release of a second mediator, which increases vascular permeability (eg, endorphins, histamine, bradykinin) [2].

•An initial rapid increase in pulmonary vascular pressure (eg, due to pulmonary vasospasm and/or increased systemic venous return) may cause pulmonary microvascular injury with a subsequent increase in permeability [80]. This theory, sometimes called the "blast theory" is supported by studies in rabbits showing that pulmonary capillaries are damaged when pressures exceed 40 mmHg [81]. It is also supported by the observation that patients with NPE frequently have mild hemoptysis or pulmonary hemorrhage [23]. The hypothesis is imperfect because the rapid development of acute pulmonary hypertension is not a necessary condition for NPE [82,83] and in animal models elevated pulmonary vascular pressures do not invariably lead to NPE [84].

Inflammatory mechanisms may also contribute to increased capillary permeability [59]. Evidence for inflammatory responses to severe brain injury include:

•Excess catecholamines can themselves lead to the release of inflammatory mediators [85,86].

•S100B, a serum biomarker of brain injury, has been shown to induce the release of pro-inflammatory cytokines in alveolar type 1-like cells in vitro [87].

•Brain injury has been associated with increased intracranial production of pro-inflammatory mediators and subsequent release of these mediators into the systemic circulation [88,89]. In a case series of patients with intracerebral hemorrhage, patients who developed NPE were more likely to have elevated interleukin (IL)-6 levels [41].

•A rat model of SAH documented increased expression of endothelial activation markers on pulmonary endothelial cells, and increased pulmonary TNF-alpha expression, which was attenuated by administration of the immune modulator IFN-beta [90].

•Modulation of inflammation through a number of pathways has been associated with attenuation of NPE in several experimental rat models [90-93].

Two cellular level mechanisms, presumably induced by neural and inflammatory mediators, have been described that would result in increased pulmonary capillary permeability. In one study, an experimental animal model of epilepsy-induced NPE, suggested cell apoptosis contributes to the development of NPE by increasing Bax, decreasing Bcl-2, and activating caspase 3 [94]. In an autopsy series of pediatric patients with NPE in the setting of enterovirus 71 infection down-regulation of alveolar fluid clearance proteins, including aquaporin 4, was reported [95].

CLINICAL PRESENTATION — NPE characteristically presents within minutes to hours of a severe central nervous system insult such as subarachnoid hemorrhage or traumatic brain injury. However, more rapid onset (immediate) and delayed onset (hours to days) have been described [2,23,27]. Resolution usually occurs within several days [96].

Dyspnea is the most common symptom, although mild hemoptysis or pink frothy sputum is present in many patients. The physical examination generally reveals tachypnea, tachycardia, and basilar crackles. Chest radiographs typically show a normal size heart with bilateral alveolar opacities, often with air bronchograms; unilateral opacities have also been described [28,97,98]. Hemodynamic measurements are usually normal by the time NPE is diagnosed, including the blood pressure, cardiac output, and pulmonary capillary wedge pressure.

There is a broad range of severities of NPE and mild cases may never be detected. While NPE can be fulminant and contribute to death, mortality is more commonly due to the neurologic insult that precipitated the onset of NPE.

EVALUATION — Evaluation of patients with suspected NPE is similar to that of patients with acute respiratory distress syndrome (ARDS) and should be focused on ruling out potential mimicking etiologies. (See "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults", section on 'Initial diagnostic evaluation'.)

DIFFERENTIAL DIAGNOSIS — Several conditions may mimic NPE.

Aspiration pneumonitis — The clinical findings of NPE may be confused with aspiration pneumonitis. Reliable differentiation between these syndromes is difficult because they are both common in settings of altered consciousness, such as postictal states or traumatic brain injury. NPE tends to develop more rapidly than aspiration pneumonia, while fever and focal opacities, particularly in the lower lung zones, favor aspiration. In addition, NPE tends to resolve more rapidly than lung injury related to aspiration, particularly if aspiration pneumonia develops. (See "Aspiration pneumonia in adults".)

Pulmonary edema — Other causes of pulmonary edema should also be considered, such as acute respiratory distress syndrome or heart failure (table 2). The latter can sometimes be seen following severe neurologic injury as a result of neurogenic stunned myocardium [99] or, more generally, stress-induced cardiomyopathy, often referred to as Takotsubo cardiomyopathy. (See "Heart failure: Clinical manifestations and diagnosis in adults" and "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults", section on 'Differential diagnosis'.)

DIAGNOSIS — Definitive diagnosis of NPE is difficult because the clinical signs and routine diagnostic tests are nonspecific. Thus, NPE is a clinical diagnosis based upon the occurrence of pulmonary edema in the appropriate setting and in the absence of a more likely alternative cause. The following criteria for the diagnosis and classification of NPE have been proposed [100]:

●Bilateral opacities

●PaO₂/FiO₂ ratio <200 mmHg

●No evidence of left atrial hypertension

●Presence of central nervous system (CNS) injury

●Absence of other common causes of acute respiratory failure or acute respiratory distress syndrome (ARDS; eg, aspiration, massive blood transfusion, sepsis)

TREATMENT

Treat the underlying disorder — The outcome of patients with NPE is usually determined by the course of the neurologic insult and not the NPE. Thus, treatment should focus on the neurological disorder while NPE is managed in a supportive fashion. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis" and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis" and "Management of acute moderate and severe traumatic brain injury" and "Convulsive status epilepticus in adults: Management".)

Many episodes of NPE are well tolerated and resolve within 48 to 72 hours.

Supportive care, oxygenation, mechanical ventilation — Most patients with NPE are hypoxemic and require supplemental oxygen. Some patients may require mechanical ventilation.

While most patients with NPE are hypoxemic and require supplemental oxygen, there is insufficient evidence to support specific oxygenation goals. Maintenance of an oxyhemoglobin saturation ≥88 percent or PaO₂ ≥55 mmHg is generally acceptable in undifferentiated lung injury, but specific targets in NPE should also take into consideration the effect that relative hypoxemia may have on the underlying neurological injury and the risk of secondary injury.

Oxygenation goals may be achieved in some patients with noninvasive measures such as oxygen by nasal cannula, simple facemask, non-rebreather mask, or high-flow delivery systems, but mechanical ventilation may be necessary in other circumstances. Mechanical ventilation and the decision to intubate a patient are discussed separately. (See "Overview of initiating invasive mechanical ventilation in adults in the intensive care unit" and "Noninvasive ventilation in adults with acute respiratory failure: Benefits and contraindications" and "The decision to intubate".)

Mechanical ventilation in patients with NPE is similar to that in patients with other causes of respiratory failure, although there are some important differences:

●High levels of positive end expiratory pressure (PEEP) can reduce cerebral venous return and worsen intracranial hypertension [101,102]. (See "Positive end-expiratory pressure (PEEP)", section on 'Intracranial disease'.)

●Hypercapnia, which is often tolerated in patients with ARDS, can cause cerebral vasodilation, thereby increasing cerebral blood flow and potentially increasing ICP [1]. (See "Permissive hypercapnia during mechanical ventilation in adults", section on 'Contraindications'.)

●Noninvasive positive pressure ventilation or continuous positive airway pressure can be challenging to apply in patients with altered mental status.

If ICP elevation is a clinical concern, ICP monitoring may be considered to guide mechanical ventilation. If ICP monitoring is available, PEEP can safely be increased to higher levels, provided PEEP is maintained at a level less than ICP, and MAP and cerebral perfusion pressure are preserved [103].

Single case reports document the use of prone ventilation, inhaled nitric oxide, and extra corporeal membranous oxygenation (ECMO) in patients with NPE and severe hypoxemia, but there is no systematic evidence supporting a benefit from these practices in such circumstances [104-106]. Because ECMO carries the risk of intracranial hemorrhage, extreme care must be taken with its application in patients with central nervous system (CNS) injury, particularly in patients following large cerebrovascular accidents who are at risk for hemorrhagic conversion. (See "Prone ventilation for adult patients with acute respiratory distress syndrome" and "Extracorporeal life support in adults in the intensive care unit: Overview".)

Maintenance of low cardiac filling pressures with diuretics and limitation of intravenous fluids may decrease pulmonary edema. However, care must be taken to avoid compromising cardiac output and cerebral perfusion, which can worsen the original neurologic injury. Pulmonary artery catheterization was historically thought to be helpful in guiding therapy, but has since fallen out of favor as part of routine fluid management [96]. (See "Pulmonary artery catheterization: Indications, contraindications, and complications in adults".)

The utility of less invasive methods of assessing cardiac function and pulmonary edema to guide treatment in NPE has been suggested in case reports and uncontrolled case series, but high quality, well-controlled studies are lacking [107,108]. Simultaneous assessment of cardiac output, extravascular lung water, global end diastolic volume, and pulmonary vascular permeability using less invasive hemodynamic monitors has been proposed as a method to guide management decisions, but the data are insufficient to support specific recommendations [107]. Small, limited studies have also evaluated the utility of lung ultrasound exams in NPE [109].

Investigational medications — A variety of medications have been used to treat patients with NPE, but their effectiveness is not definitively proven. These include:

●Beta adrenergic antagonists are thought to increase lymph flow, decrease edema, and reduce histamine-induced augmentation of pulmonary vascular permeability [2]. They are generally well-tolerated, but may precipitate bradyarrhythmias.

●Dobutamine increases cardiac output, decreases pulmonary capillary wedge pressure, and promotes diuresis [110,111]. Concerns for systemic hypotension and tachyarrhythmias preclude routine use. Our practice is to reserve it for cases of severe hypoxemia due to NPE where there is severe concomitantly reduced cardiac ejection fraction or bradycardia.

●Milrinone has both inotropic and lusitropic effects as well as anti-inflammatory properties that may target both the hydrostatic and capillary permeability related mechanisms of NPE. Small, open-label studies, primarily in the pediatric population have found improved short-term outcomes in those treated with both milrinone and dobutamine or milrinone and dopamine compared to either dobutamine or dopamine alone [112]. Our practice is to reserve this for cases of severe hypoxemia due to NPE where there is both severely reduced cardiac ejection fraction and pulmonary hypertension. As with dobutamine, systemic hypotension limits routine use.

●Chlorpromazine may block alpha adrenergic receptors to reduce edema [113]. Care must be taken as it can cause somnolence and interfere with monitoring of the underlying neurological insult.

●Levosimendin, an inotropic and vasodilating agent has been suggested as a useful adjunct for reducing pulmonary arterial pressure and augmenting cardiac output. However, controlled studies of this intervention are lacking and we cannot recommend it [108].

●Phentolamine, an alpha adrenergic antagonist has been shown to prevent NPE or hasten its resolution in animal models, while one report demonstrated rapid improvements in oxygenation following administration of phentolamine in a single patient with NPE due to a ruptured arteriovenous malformation [69]. However, unopposed alpha adrenergic antagonists may precipitate systemic hypotension and cerebral hypoperfusion, and in the absence of data from controlled trials, routine use of these agents cannot be recommended at this time. (See "Antihypertensive therapy for secondary stroke prevention" and "Evaluation and management of elevated intracranial pressure in adults".)

●Naloxone, an opioid receptor antagonist, has been shown to block increases in lung permeability and NPE formation in an ovine model of herniation. However, in a placebo-controlled, randomized blinded trial of 199 lung-eligible brain-dead organ donors with hypoxemia, administration of naloxone did not improve time to reversal of hypoxemia compared to placebo [114,115]. As a result, naloxone should not be used for treatment of NPE at this time.

PROGNOSIS — Although many episodes of NPE are well tolerated and most cases resolve within 48 to 72 hours, the development of NPE is associated with worse long-term outcomes. As an example, an observational study of 108 patients with non-traumatic intracranial hemorrhage, found that compared to those without NPE, those who developed NPE had a higher one-year mortality (37 versus 14 percent) [41].

SUMMARY AND RECOMMENDATIONS

●Neurogenic pulmonary edema (NPE) is an increase in pulmonary interstitial and alveolar fluid that is due to an acute central nervous system (CNS) injury. It usually develops rapidly following the injury. (See 'Introduction' above.)

●The primary precipitants of NPE are epileptic seizures, traumatic brain injury, and intracranial hemorrhages (table 1). (See 'Etiology' above.)

●NPE is thought to occur when a neurologic insult affects the medulla oblongata, leading to a massive sympathetic discharge. This sympathetic discharge causes abrupt alterations in cardio-pulmonary hemodynamics and subsequent increased capillary hydrostatic pressure and pulmonary vascular permeability. (See 'Pathogenesis' above.)

●NPE characteristically presents within minutes to hours of a severe CNS insult. Dyspnea is the most common symptom, although mild hemoptysis is present in many patients. The physical examination generally reveals tachypnea, tachycardia, and basilar rales. Chest radiographs typically show a normal size heart with bilateral alveolar filling, while hemodynamic measurements are usually normal. (See 'Clinical presentation' above.)

●NPE is a clinical diagnosis based upon the occurrence of pulmonary edema in the appropriate setting and in the absence of a more likely alternative cause. (See 'Differential diagnosis' above and 'Diagnosis' above.)

●The treatment of NPE should focus on treating the neurological disorder while NPE is managed in a supportive fashion. Most patients with NPE are hypoxemic and require supplemental oxygen. Some patients may require mechanical ventilation, which differs from that for other causes of respiratory failure such that permissive hypercapnia and high levels of positive end-expiratory pressure (PEEP) should be used cautiously, and use of noninvasive ventilation may be limited by altered mental status. A variety of medications have been used to treat patients with NPE, but their efficacy in this setting has not been established (See 'Treatment' above.)

●Many episodes of NPE are well tolerated and most resolve within 48 to 72 hours. However, the development of NPE is associated with worse long term outcomes. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Frank Drislane, MD, and Jess Mandel, MD, who contributed to earlier versions of this topic review.