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Neurogenic Pulmonary Edema: Pathogenesis, Clinical Picture,and Clinical Management

Grigore Toma, Valery Amcheslavsky, Vladimir Zelman, Douglas S. DeWitt, and Donald S. Prough

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urrent clinical and experimental data leavelittle doubt that the injured brain is highly

ulnerable to secondary ischemic insults. Manynsults, such as hypoxemia and hypotension, occurfter patients have entered the medical care system.onsequently, prevention, early diagnosis, and ef-

ective treatment of hypoxemia and hypotension inatients with acute severe brain injury should helpo limit personal, social, and economic costs.

Severe brain injury disrupts multiple respiratoryunctions, depending on the site and extent of theeurological injury (Table 1). Importantly, each ofhese respiratory complications as well as otheredical sequelae can contribute significantly to

hort- and long-term morbidity, disability, andortality related to severe brain injury. Familiarityith important respiratory complications is an in-

egral part of the management of critically ill pa-ients with brain injury.1

The development of pulmonary edema in theetting of an acute neurologic event is termedeurogenic pulmonary edema (NPE) and was firstescribed in 1908 by Shanahan in patients withpilepsy who died of postictal respiratory distress.2

cute NPE is an uncommon, perhaps inconsis-ently recognized, clinical entity that can occurfter virtually any form of insult to the centralervous system (CNS). Most commonly, NPE fol-ows subarachnoid hemorrhage (SAH),3-5 but theyndrome is also associated with other acute neu-ologic insults such as traumatic brain injury,6

eizures,2,7 stroke,8 intracranial hemorrhage,9 in-ection, induction of anesthesia,10 and electrocon-ulsive therapy.11

CLINICAL SYNDROME

The clinical presentation of NPE is often abruptnd dramatic but resembles other forms of acuteulmonary edema. Often, the acuteness of onset ofespiratory failure is the primary aspect that sug-ests the diagnosis. Colice12 described 2 patternsf evolution of NPE. In the early or classic form,hich occurs most commonly, pulmonary edema

evelops within minutes to a few hours after an

eminars in Anesthesia, Perioperative Medicine and Pain, Vol 23, N

cute CNS insult. The delayed form of NPE de-elops more slowly, progressing over 12 hours toeveral days after the precipitating event.12-14

Most patients present with symptoms of respi-atory failure soon after the acute neurologic eventTable 2). The most common presenting signs ofPE are dyspnea, tachypnea, tachycardia, and cy-

nosis. One of the hallmark characteristics, thoughvident in only about one third of patients, is theevelopment of pink, frothy sputum, accompaniedy crackles, rales, and fever. Chest radiographyemonstrates diffuse bilateral alveolar and intersti-ial pulmonary infiltrates (“whiteout”). The diag-osis is supported by marked hypoxemic respira-ory failure and pulmonary edema with lowulmonary arterial occlusion pressure (PAOP).AOP may be increased shortly after onset,15 but

s usually normal after several hours,9,16 therebyeading many clinicians to consider NPE a form ofoncardiogenic pulmonary edema. Other causes ofcute respiratory failure that must be excludednclude congestive heart failure, fluid overload,oreign body aspiration, gastric aspiration, andarotrauma.17

In the delayed form of NPE, the clinical presen-ation typically includes gradual development overeveral days of hypoxemia, chest radiographic ab-ormalities, and dyspnea. Distinguishing the de-ayed form of NPE from other etiologies in patientsith acute neurologic insults can be challenging. In

From the Department of Anesthesiology, the University ofexas Medical Branch, Galveston, TX, USA; the Department ofeuroscience ICU, the Burdenko Neurosurgical Institute, Mos-ow, Russia; and the Department of Anesthesiology, Keckchool of Medicine, University of Southern California, Losngeles, CA, USA.Address requests for reprints to Dr. Grigore Toma, Depart-

ent of Anesthesiology, University of Texas Medical Branch,01 University Blvd, Galveston, TX 77555-0830. E-mail:rtoma@utmb.edu.© 2004 Elsevier Inc. All rights reserved.0277-0326/04/2303-0000$30.00/0

doi:10.1053/j.sane.2004.01.014

221o 3 (September), 2004: pp 221-229

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ntubated critically ill patients, atelectasis or pneu-onia can produce similar hypoxemia, chest radio-

raphic abnormalities, and dyspnea. In addition,he characteristic pattern of pulmonary edema maye less evident in portable chest radiographs.Although NPE should be suspected in any pa-

ient in whom symptoms of respiratory failure fol-ow an acute neurologic event, the diagnosis ofPE remains one of exclusion. Therefore, the in-

idence of NPE is difficult to establish; given itsonspecific presentation, it is likely that the diag-osis is missed, especially in the later onset form,ut also that it is applied incorrectly to patientsith other reasons for respiratory compromise. Thehysician faced with the difficult task of caring forpatient with a combination of acute neurologic

isease and respiratory complications must balanceeveral competing priorities. As an example of theifficulties of diagnosing and treating this life-hreatening condition, we report a fatal case ofPE that was triggered by an episode of increased

ntracranial pressure (ICP).

CASE REPORT

A 9-year-old female, 48 hours after a motor-ehicle accident, was admitted to the Neurosciencentensive Care Unit (ICU) of the Burdenko Neu-osurgical Institute of the Russian Academy of

edical Sciences in Moscow, Russia. Head com-uted tomography (CT) showed right frontal andeft temporal contusions and signs of intracranialypertension (compression of lateral ventricles,asal cisterns, and subarachnoidal spaces). On neu-ological examination, the patient was found to ben a coma (Glasgow Coma Scale score 5) withigns of brainstem dysfunction, ie, increased mus-le tonus with decerebrate posture, absence of pu-ilary and corneal reflexes, paralysis of upward

Table 1. Respiratory Complications of Severe Brain Injury

Impaired chest wall mechanics and diaphragm functionAbnormal breathing patterns

Cheyne–Stokes respirationCentral neurogenic hyperventilationApneustic breathingAtaxic breathingHypoventilation or apnea

Pulmonary embolismDysphagia, aspiration, and pneumoniaNeurogenic pulmonary edema

aze reflex, hyperthermia to 40°C, and severe he-

odynamic instability. The patient was intubatednd ventilated with controlled mechanical ventila-ion. The ventilator was set at a tidal volume of 400L, FiO2 of 0.30 and positive end-expiratory pres-

ure (PEEP) of 5 cm H2O. Arterial blood gas levelsere the following: pH 7.55; PaCO2 42.5 mm Hg;aO2 97.7 mm Hg; base excess (BE) �20.4Eq/L; and oxygen saturation (SaO2) 98%. ICPas less than 20 mm Hg. Jugular venous bulb

ampling (right jugular vein) yielded the followingndings: pH 7.44; jugular venous bulb PCO2

PjvCO2) 51.8 mm Hg; PjvO2 32.4 mm Hg; SjvO2

6.4%. The cerebral arterio-venous difference oflucose was 0.1 mmol/L. The electrolytes wereithin normal limits. Pharmacologic therapy in-

luded intravenous fluid support, mannitol, antibi-tics, and sedation with diazepam and morphine.By the third post-trauma day, hyperthermia had

mproved (core temperature, 37.5°C). Arteriallood pressure (ABP) remained near 110/70 mmg and heart rate was 100 to 140 beats per minute.oward the end of day 3 (�70 hours after trauma),

here was a spontaneous increase of ICP from 12 to0 mm Hg, with subsequent severe cardiovascularnstability (ABP decreased to 60/30 mm Hg) andypoxemia (Fig 1). One hour 15 minutes later, aecond episode of intracerebral hypertension oc-urred. Oxygen saturation measured by pulseximetry gradually decreased from 98% to 80% to0%. On physical examination, the patient wasypoxemic and pink frothy sputum was suctionedhrough the endotracheal tube. Pulmonary auscul-ation revealed bilateral diffuse crackles. The clin-cal diagnosis of acute NPE was made and sup-orted by chest radiography, which demonstratediffuse bilateral infiltrates.Intensive therapy of acute pulmonary edema in-

luded loop diuretics (furosemide 40 mg), inotro-

Table 2. Common Symptoms and Signs of NeurogenicPulmonary Edema

ypoxemiayspnea

Lung findings—bilateral, diffuseinterstitial/alveolar

achypnea Infiltrates (“whiteout”)ink frothy sputumulmonary crackles,rales

Normal to high pulmonary arterywedge pressure

ECG—signs of cardiac ischemianginaachycardia

Cardiovascular instabilityNormal to high CK-MB, troponinLeukocytosis

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ic support (dopamine 10 �g/kg/min), and 4 mg oforphine. FiO2 was increased from 0.3 to 1.0 andEEP from 5 to 10 cm H2O. Despite aggressive

herapy, the patient died 4 hours after onset ofPE. On autopsy, there were bilateral frontal skull

ractures, traumatic SAH, hemorrhagic contusionf the right frontal and left temporal lobes, andiffuse cerebral edema with axial dislocation. The

Fig 1. Intracerebral hypertension (arrows 1 and 2) trigecrease in SpO2 from 98% to 70%. Note cardiovascular i

ungs were grossly edematous. a

This case report illustrates the rapid onset ofardiopulmonary insufficiency in close temporalelationship to acute intracranial hypertension.

PATHOGENESIS OF NPE

NPE is characterized by an increase in extravas-ular lung water in patients who have sustained audden change in neurologic condition. The mech-

18

e development of neurogenic pulmonary edema with aty during these episodes.

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athophysiological mechanisms of NPE includelterations in capillary permeability, elevations inulmonary venous hydrostatic pressure, or leftentricular dysfunction (Fig 2).

ermeability Abnormalities

In both animal and human studies of NPE, theemonstration of elevated interstitial or alveolaruid protein concentrations suggests that increasedapillary permeability contributes to pulmonarydema.19,20 Increased permeability may be causedither by hydrostatic overdistension of the pulmo-ary capillaries or by direct neural influences onapillary permeability. Theodore and Robin21 ad-anced the “blast theory,” which proposes that aeurally induced, transient rise in pulmonary intra-ascular pressure, caused by a massive sympa-hetic surge, may damage the endothelium, causingrotein-rich plasma to escape into the interstitialnd alveolar spaces. The high protein content in thedema fluid supports the “blast theory.”21 Investi-

Fig 2. Potential pathophysiological mechanisms of neuronjury can result in sympathetic activation that causes pulmoentricular).

ators have speculated that this “stress failure” of p

he pulmonary capillaries resembles alveolar hem-rrhage seen in galloping racehorses.22

In support of this theory, high intravascular pres-ures have been shown to damage pulmonary cap-llaries, and such high pressures can develop innimals during experimental NPE.23,24 In humans,levated PAOP has been observed in a few cases.9,25

owever, pulmonary edema can develop with nor-al PAOP, suggesting the possibility of a neural-ediated, pressure-independent influence on capil-

ary permeability.3,26 It is important to note that theypical sequence of NPE would be one in which acuteulmonary edema unexpectedly occurs, after whichoth treatment and invasive monitoring are initiated.onsequently, the acute increase in PAOP or pulmo-ary arterial pressure could be resolved before hemo-ynamic data are obtained. Neurally and humorallyediated increases in sympathetic tone after CNS

njury that lead to pulmonary venoconstriction withulmonary capillary hypertension may cause endo-helial damage and increased pulmonary capillary

27

pulmonary edema initiated by increased ICP. Acute brainema and cardiac failure (ICP, intracranial pressure; LV, left

genicnary ed

ermeability. Consistent with this theory, NPE in-

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uced experimentally by infusion of epinephrine cane attenuated by �-adrenergic blocking agents.28

ydrostatic Pulmonary Edema

Hydrostatically induced pulmonary edema canccur without endothelial damage. One possibleequence leading to NPE is acutely increased sym-athetic tone that abruptly increases left ventricularfterload and causes intense venoconstriction,hereby elevating left ventricular filling pressuresnd inducing pulmonary capillary hypertension.his is consistent with the finding that cardiaclling pressures are normal in some patients withPE and elevated in others.Active pulmonary venoconstriction can increase

ulmonary capillary pressure and produce hydro-tatic edema. In canine studies, induced intracra-ial hypertension resulted in pulmonary venocon-triction and hydrostatic pulmonary edema.29 Insolated lung models, induced intracranial hyper-ension resulted in venoconstriction and elevatedesistance to pulmonary blood flow, perhaps due toncreased circulating catecholamines, predomi-antly epinephrine.29,30 Pulmonary venoconstric-ion could result in increased capillary hydrostaticressure that is reflected in increased pulmonaryystolic and diastolic pressure but not in increasedAOP. During balloon occlusion, no flow wouldnter the occluded vascular segment and normaleft atrial pressure would be measured. Such aechanism could explain both the observed vari-

nce in pulmonary edema protein concentration inhe presence of normal PAOP in patients withPE. In a series of 12 patients with NPE, Smith27

bserved that 7 of 12 patients apparently had aydrostatic mechanism for NPE with edema fluido plasma protein ratios �0.65. Once again, it ismportant to note that pulmonary arterial catheter-zation after an acute episode of NPE could be tooate to document increased PAOP.

It is likely that a combination of factors in dif-ering proportions produces NPE and that explainshe differing clinical presentations. The role thatdrenergic tone might play in the cardiac responsef NPE is also potentially important. In experimen-al animal models, extreme sympathetic nervousystem overactivity can generate acute hemody-amic derangements, acute left ventricular failure,nd pulmonary edema. �-Adrenergic antagonists

31

ave been shown to prevent NPE. p

ther Possible MechanismsVarious forms of noncardiac pulmonary edema

ave been explained on the basis of hypoxic pul-onary vasoconstriction leading to pulmonary hy-

ertension, arterial wall rupture, and leakage ofrotein-rich fluid into the interstitium and alveoli.32

n alternative theory is that damaged arterial wallsttract fibrin and platelets, which form thrombi andicroemboli, producing pulmonary capillary hy-

ertension, capillary rupture, and edema formation.ctivated intravascular clotting or fibrinolysis mayave an important role in NPE, as well as in otherorms of noncardiac pulmonary edema.33

The clinical and pathologic features of NPE areuite similar to those of other forms of acuteespiratory distress syndrome. Moss et al34,35 pos-ulate that acute respiratory distress syndrome inany clinical situations has a common cerebral

ause—the initiating trauma interferes with hypo-halamic cellular metabolism, which leads to auto-omically mediated increased pulmonary venularesistance. This condition results in increased cap-llary pressures and vascular congestion, interstitialnd intraalveolar edema and hemorrhage, andight-to-left shunting. The transudate of plasmand resulting hyaline membrane formation inacti-ate surfactant and predispose to atelectasis. Thiss an attractive unifying theory to explain posttrau-atic pulmonary insufficiency and acute respira-

ory distress syndrome, as well as the varied formsf noncardiac pulmonary edema such as NPE.

MEDIATORS OF NPEAlthough brain injury results in NPE in scattered

linical cases and in a variety of experimentalodels, the mechanisms through which CNS in-

ury produces NPE are unclear. Experimental stud-es provide evidence for direct sympathetic mech-nisms as well as circulating mediators.

The high-pressure component of NPE is prob-bly mediated both by circulating vasoactivegents and by direct stimulation of sympatheticerves leading to pulmonary vessels. The pulmo-ary vasculature is richly innervated by sym-athetic nerves, and stimulation of the stellateanglion causes pulmonary venous and arterialpasm.34-39

Studies with isolated lung lobes have shown thatvasoactive agent, released into the venous circu-

ation after CNS injury, is an important mediator of40

ulmonary hypertension. This agent is probably

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catecholamine, because �-adrenergic blockersnhibited its effect. Catecholamines increase dra-atically within seconds of a variety of brain in-

uries.37,38,41 After SAH, the concentrations of epi-ephrine, norepinephrine, and dopamine increaselmost immediately to 1,200, 145, and 35 times theormal limits, respectively.42 Furthermore, epi-ephrine can remain increased in the circulationor at least 10 days.43 This could explain why NPEan occur as much as 14 days after a CNS insult.

After CNS insults, �-adrenergic blockers alsorevent systemic hypertension, suggesting that in-reased circulating catecholamines are responsibleor systemic as well as pulmonary and vascularonstriction.44 A pulmonary vascular membraneermeability defect in NPE might be mediated byhe increase in circulating catecholamines, releasef noncatecholamine mediators after the massive-adrenergic discharge, direct �-adrenergic effectsn endothelial cells, or some alteration in �-adren-rgic tone. �-Adrenergic blockers prevent changesn lymph protein clearance after intracranial hyper-ension and stellate ganglion stimulation, suggest-ng a catecholamine-mediated change in pulmo-ary endothelial permeability.45

The role of �-adrenergic tone in altering pulmo-ary endothelial permeability is unclear. �-Adren-rgic agonists prevented experimental histamine-nduced permeability abnormalities, but �-adrenergicntagonists seem to influence pulmonary transen-othelial protein flux by changing vascular surfacerea.46,47

NS Involvement

The specific neurologic loci or pathways thatenerate NPE remain conjectural and controver-ial, with somewhat contradictory animal data andimited human data. Based primarily on animalata, multiple “edemagenic” sites that have beenostulated as the origin of the pathophysiologicrocess include the hypothalamus and several locin the medulla oblongata.12 The posterior medulla,hich forms the inferior aspect of the floor of the

ourth ventricle, includes adrenergic areas 1 and 5nd the nucleus of the solitary tract. Nerve fibersass from area 5 to the intermediolateral cell col-mn of the thoracolumbar spinal cord (the site ofympathetic outflow) and from area 1 to the hypo-halamus. In experimental animals, stimulation of

48

hese areas generated NPE. (

Clinical evidence suggesting specific anatomicites has necessarily been anecdotal. Because NPEs extremely rare in patients with cervical spinalord lesions, the CNS regions responsible for NPEre assumed to be supraspinal. Brain-imaging tech-iques provide evidence that derangements of theedulla (which contains the vasomotor center)

ontribute to NPE. Simon et al49 described aoman with multiple sclerosis who had recurrentulmonary edema associated with a lesion in theosterior aspect of the rostral medulla involvinghe floor of fourth ventricle. Keegan and Lanier50

escribed a 21-year-old man who developed NPEn association with surgical resection of a perimed-llary brain tumor. These anecdotal reports supporthe concept that medullary disease can generatePE in humans, and that NPE can occur in these

ases in the absence of systemic hypertension.50

By causing sympathetic activation, posterior hy-othalamic lesions also can precipitate NPE inumans.51,52 In a series of 106 patients dying fromAH, 65 had hypothalamic lesions that had histo-

ogical evidence of ischemia, microhemorrhages,assive hemorrhage, or a combination of ischemia

nd hemorrhage.53 The hypothalamus probably isart of an integrated response, also involving por-ions of the medulla, that initiates NPE. Severaltudies have shown that the hypothalamus, alongith the nucleus tractus solitarius and ventrolateraledulla, plays an important role in regulating car-

iovascular responses by the autonomic nervousystem.54,55

CLINICAL MANAGEMENT OF NPE

There are no specific treatments for NPE, otherhan immediate management of such precipitatingauses as intracranial hypertension or evacuationf intracranial space-occupying lesions. Mainte-ance of intentional hypocarbia, diuretics, andannitol may also be helpful in controlling ICP, at

east temporarily. Management of respiratory com-romise is largely supportive and does not differubstantially from supportive care of acute respi-atory failure caused by other factors. Respiratoryupport consists of various combinations of sup-lemental oxygen therapy, mechanical ventilation,udicious fluid management and, possibly, sodiumitroprusside, which may be useful for its ability toirectly dilate peripheral and pulmonary vessels

1,56,57

Table 3). Care should be taken with the

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dministration of sodium nitroprusside because ofts potential for increasing ICP.

Mechanical ventilation with PEEP rapidly im-roves both oxygenation and radiographic evi-ence of NPE. PEEP is titrated to attain an accept-ble balance between systemic hemodynamics,rterial oxygenation, and FiO2. An assisted modef ventilation, such as intermittent mandatory ven-ilation or pressure control ventilation, with PEEPs often sufficient to resolve NPE, and weaning cane achieved fairly rapidly in many patients.1 These of PEEP to improve oxygenation may increaseCP in some patients with brain injury by increas-ng cerebral venous pressure. PEEP may furtherecrease cerebral perfusion pressure by decreasingardiac output and ABP. Excessive reduction oferebral perfusion pressure could aggravate neuro-ogic injury. If PEEP is required for managementf hypoxemia, ICP should be monitored concom-tantly. PEEP therapy may need to be reduced orombined with head elevation if PEEP is associ-ted with increasing ICP or neurological deterio-ation.

In patients with considerable hemodynamic in-tability, assessment of cardiac function with pul-onary arterial catheterization, transesophageal

chocardiography, or esophageal Doppler mayelp to guide therapy. Inotropic support may be

Table 3. Management of Patients with NeurogenicPulmonary Edema

ethods to control intracranial hypertensionPosition to improve cerebral venous return (neutral,

head-up position)Avoiding drugs that increase ICPDiuretics: osmotic (mannitol, hypertonic saline); tubular

(furosemide)Adequate ventilation: PaO2 �100 mm Hg, PaCO2 35

mm Hg, hyperventilation on demandOptimize hemodynamics (MAP, CVP, PAOP, HR),

maintain CPPTemperature control: avoid hyperthermiaCSF drainage

mprovement of oxygenationOxygen supply: via nasal mask (6 L/min); if necessary,

intubation (ventilation, PEEP �4-8 cm H2O)ecreases pre- and afterloadVasodilators (nitroglycerine, sodium nitroprusside,

blockers of �-adrenoreceptors)Diuretics: tubular (furosemide)

notropic treatment�-adrenergic drugs: dobutamine

ecessary. Although massive release of cat- m

cholamines in association with acute neurologicnjuries may contribute to ventricular injury andPE, the much smaller circulating levels associ-

ted with inotropic infusion may improve systemicemodynamics and increase systemic oxygen de-ivery. For example, dobutamine improves cardiacontractility and decreases afterload, thereby main-aining cardiac output and potentially improvingerebral perfusion while reducing sympatheticone.57

Theoretically, pharmacologic blockade of theympathetic surge associated with some acuterain injuries should limit the occurrence and se-erity of NPE. Prophylactic �-blockade with phe-oxybenzamine prevented death and pulmonarydema in rabbits infused with high doses of epi-ephrine.58 There are few data from clinical trials,ut prophylactic combined �- and �-blockade withhentolamine and propranolol may reduce pulmo-ary and myocardial injury from catecholaminesfter SAH.59 However, clinical application of thisnformation in patients with NPE is difficult. In

any patients, the acute sympathetic surge willave passed by the time NPE is recognized, andympathetic blockade would no longer be expectedo be helpful. In other patients, systemic hyperten-ion may be a response to intracranial hyperten-ion, in which case the reduction in ABP without aeduction in ICP could lead to severe brain isch-mia. In a subset of patients in whom severe sys-emic hypertension persists after control of intra-ranial hypertension, reduction of ABP is indicatedut may not have any direct effect on the course ofPE.

CONCLUSION

In patients with acute brain injury, NPE mayause life-threatening respiratory failure, develop-ng either explosively or insidiously. Although thepecific diagnosis in such patients may be elusive,PE should be included in the differential diagno-

is. Because of the extreme vulnerability of thenjured brain to hypoxemia, immediate therapeuticnterventions to improve systemic oxygenation aremperative. If possible, the precipitating intracra-ial event should be relieved by medical or surgi-al intervention. Management of ventilatory andemodynamic support must include considerationf the effects of interventions on intracranial he-

odynamics.

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