Neurogenic pulmonary edema (NPE) is a relatively rare form of pulmonary

edema caused by an increase in pulmonary interstitial and alveolar fluid.

Neurogenic pulmonary edema develops within a few hours after a neurologic
insult, and diagnosis requires exclusion of other causes of pulmonary edema
(eg, high-altitude pulmonary edema).

Neurogenic pulmonary edema (NPE) adalah bentuk edema paru yang relatif jarang yang
disebabkan oleh peningkatan cairan interstisial dan alveolar paru. Edema paru neurogenik
berkembang dalam beberapa jam setelah penghinaan neurologis, dan diagnosis memerlukan
pengecualian penyebab lain edema paru (misalnya, edema paru dengan ketinggian tinggi).

General
The pathogenesis of neurogenic pulmonary edema (NPE) is not completely
understood. [1] Because the most common neurological events are associated
with increased intracranial pressure, intracranial hypertension is considered a
key etiologic factor.
Within the central nervous system, the sites responsible for the development
of neurogenic pulmonary edema are not fully elucidated. Animal studies
suggest that hypothalamic lesions, stimulation of the vasomotor centers of the
medulla, elevated intracranial pressure, and activation of the sympathetic
system have potential roles.[2, 3] Cervical spinal cord nuclei also may have a
role. Both hypothalamic lesions (paraventricular and dorsomedial nuclei) and
stimulation of the vasomotor centers of the medulla (A1 and A5, nuclei of
solitary tract, and area postrema, medial reticulated nucleus, and the dorsal
motor vagus nucleus in the medulla oblongata) can increase output along the
sympathetic trunk. Neurogenic pulmonary edema trigger zones may exist in
these structures, with specific neurologic foci or centers producing massive
sympathetic discharges that lead to neurogenic pulmonary edema. [4]
Patogenesis edema paru neurogenik (NPE) tidak sepenuhnya dipahami. [1] Karena kejadian
neurologis yang paling umum dikaitkan dengan peningkatan tekanan intrakranial, hipertensi
intrakranial dianggap sebagai faktor etiologi kunci.
Dalam sistem saraf pusat, situs yang bertanggung jawab untuk pengembangan edema paru
neurogenik tidak sepenuhnya dijelaskan. Studi pada hewan menunjukkan bahwa lesi
hipotalamus, stimulasi pusat vasomotor medulla, tekanan intrakranial yang meningkat, dan
pengaktifan sistem simpatis memiliki peran potensial. [2, 3] Inti naluri serviks serviks juga
mungkin memiliki peran. Baik lesi hipotalamus (inti paraventrikular dan dorsomedial) dan
stimulasi pusat vasomotor medula (A1 dan A5, inti saluran soliter, dan daerah postrema, inti
retikulasi medial, dan inti motorik dorsal vagus di medulla oblongata) dapat meningkatkan
output di sepanjang batang simpatik. Zona pemicu edema paru neurogenik mungkin ada
pada struktur ini, dengan fokus neurologis atau pusat khusus yang menghasilkan pelepasan
simpatik yang besar yang menyebabkan edema paru neurogenik.
Neuroanatomic structures
The medulla is believed to activate sympathetic components of the autonomic
nervous system. Experimentally, bilateral lesions of the nuclei in the medulla
produce profound pulmonary and systemic hypertension and pulmonary
edema. Alpha-adrenergic blockade (with phentolamine) and spinal cord
transection at the C7 level prevent the formation of neurogenic pulmonary
edema, suggesting an important role for sympathetic activation.
An acute neurological crisis, accompanied by a marked increase in
intracranial pressure, may stimulate the hypothalamus and the vasomotor
centers of the medulla. This, in turn, initiates a massive autonomic discharge
mediated by preganglionic centers within the cervical spine.
Medula dipercaya untuk mengaktifkan komponen simpatis dari sistem saraf otonom. Secara
eksperimental, lesi bilateral nukleus di medula menghasilkan hipertensi pulmoner dan sistemik
yang hebat dan edema paru. Blokade alfa-adrenergik (dengan phentolamine) dan transeksi
medula spinalis pada tingkat C7 mencegah pembentukan edema paru neurogenik,
menunjukkan peran penting untuk aktivasi simpatis. Krisis neurologis akut, disertai dengan
peningkatan tekanan intrakranial yang ditandai, dapat merangsang hipotalamus dan pusat
vasomotor medulla. Hal ini, pada gilirannya, memulai pelepasan otonom besar yang dimediasi
oleh pusat-pusat preganglionik di dalam tulang belakang servikal

Mechanism of edema formation

A central nervous system event produces a dramatic change in Starling
forces, which govern the movement of fluid between capillaries and the
interstitium. Both hemodynamic (cardiogenic) and nonhemodynamic
(noncardiogenic) components contribute to edema formation. Factors leading
to the development of edema in patients with subarachnoid hemorrhage are
illustrated in the flowchart below; however, these can be extrapolated to other
types of central nervous system insults.

Peristiwa sistem saraf pusat menghasilkan perubahan dramatis pada kekuatan Starling, yang
mengatur pergerakan cairan antara kapiler dan interstitium. Komponen hemodinamik
(kardiogenik) dan nonhemodinamik (nonkardiogenik) berkontribusi terhadap pembentukan
edema. Faktor-faktor yang menyebabkan perkembangan edema pada pasien dengan
perdarahan subarachnoid diilustrasikan pada diagram alir di bawah ini; Namun, ini dapat
diekstrapolasikan ke jenis penghinaan sistem saraf pusat lainnya.
actors leading to the development of neurogenic pulmonary edema in patients
with subarachnoid hemorrhage.
View Media Gallery
Changes in capillary hydrostatic pressure
Alterations in pulmonary vascular pressures appear to be the most likely
Starling force to influence the formation of neurogenic pulmonary edema.
Experimental observations suggest the following mechanisms by which
pulmonary capillary hydrostatic pressures can be increased acutely:
 An increase in left atrial pressure may occur because of increases in
sympathetic tone and venous return. Left ventricular performance may
deteriorate secondary to the direct effects of catecholamines and other
mediators, as well as transient systemic hypertension.
 Pulmonary venoconstriction occurs with sympathetic stimulation, which
may increase the capillary hydrostatic pressure and produce pulmonary
edema without affecting left atrial or pulmonary capillary wedge
pressures.
 Perubahan tekanan hidrostatik kapiler
 Perubahan pada tekanan vaskular pulmonal tampaknya merupakan kekuatan Starling
yang paling mungkin untuk mempengaruhi pembentukan edema paru neurogenik.
Pengamatan eksperimental menunjukkan mekanisme berikut dimana tekanan
hidrostatik kapiler paru dapat ditingkatkan secara akut:
  • Peningkatan tekanan atrium kiri dapat terjadi karena peningkatan nada simpatik
dan kembalinya vena. Performa ventrikel kiri dapat memburuk akibat efek langsung
katekolamin dan mediator lainnya, serta hipertensi sistemik transien.
 • Venoconstriction paru terjadi dengan stimulasi simpatis, yang dapat meningkatkan
tekanan hidrostatik kapiler dan menghasilkan edema paru tanpa mempengaruhi
tekanan baji kapiler atrium kiri atau paru-paru.

Changes in pulmonary capillary permeability

An increase in capillary permeability can result in neurogenic pulmonary
edema without elevation of pulmonary capillary hydrostatic pressure, because
causative hemodynamic alteration is inconsistent. However, evidence shows
that alpha-adrenergic blockade can protect against neurogenic pulmonary
edema. Epinephrine, norepinephrine, and even a release of secondary
mediators may directly increase pulmonary vascular permeability. Whether the
capillary leak is produced by pressure-induced mechanical injury because of
the elevated capillary hydrostatic pressure or because of some direct nervous
system control over the pulmonary capillary permeability remains uncertain.
An initial and rapid rise in pulmonary vascular pressure due to pulmonary
vasoconstriction or pulmonary blood flow can lead to pulmonary microvascular
injury. Consequently, an increase in vascular permeability results in edema
formation, as suggested by the frequent observation of pulmonary
hemorrhage in neurogenic pulmonary edema (ie, blast theory). [5, 6, 7]
Perubahan permeabilitas kapiler paru
Peningkatan permeabilitas kapiler dapat menyebabkan edema paru neurogenik tanpa
peningkatan tekanan hidrostatik kapiler paru, karena perubahan hemodinamik penyebabnya
tidak konsisten. Namun, bukti menunjukkan bahwa blokade alfa-adrenergik dapat
melindungi terhadap edema paru neurogenik. Epinephrine, norepinephrine, dan bahkan
pelepasan mediator sekunder dapat secara langsung meningkatkan permeabilitas vaskular
paru. Apakah kebocoran kapiler dihasilkan oleh cedera mekanis akibat tekanan karena
tekanan hidrostatik kapiler yang meningkat atau karena beberapa kontrol sistem saraf
langsung atas permeabilitas kapiler paru tetap tidak pasti.
Peningkatan tekanan vaskular paru yang awal dan cepat akibat vasokonstriksi paru atau
aliran darah pulmonal dapat menyebabkan cedera mikrovaskuler paru. Akibatnya,
peningkatan permeabilitas vaskular menyebabkan pembentukan edema, seperti yang
disarankan oleh pengamatan pendarahan paru yang sering terjadi pada edema paru
neurogenik (yaitu teori ledakan). [5, 6, 7]

Epidemiology
Frequency
United States
Importantly, recognize that neurogenic pulmonary edema is an
underdiagnosed condition. Patients with neurologic events often have multiple
other comorbidities, which may obscure or mimic the diagnosis of neurogenic
pulmonary edema. The lack of a standardized definition for neurogenic
pulmonary edema also makes defining its epidemiology difficult.
As many as one third of patients with status epilepticus may have evidence of
neurogenic pulmonary edema. [8] More than half the patients with severe, blunt,
or penetrating head injury have associated neurogenic pulmonary edema.
Approximately 71% of fatal cases of subarachnoid hemorrhage are
complicated by neurogenic pulmonary edema. Neurogenic pulmonary edema
may complicate subarachnoid and intercerebral hemorrhage in 30-70% of
patients and may recur after initial resolution. [9, 10]
A series of 457 patients with subarachnoid hemorrhage reported a 6%
prevalence of severe neurogenic pulmonary edema. [11] Solenski et al reported
in 1995 that increased age and a worse clinical grade of subarachnoid
hemorrhage were associated with neurogenic pulmonary edema.
International
No data suggest differences in the international incidence of neurogenic
pulmonary edema compared with the experience in the United States.
However, note that epidemiologic data on this entity in general are very
sparse because of the difficulties in recognition and diagnosis and lack of a
standardized definition.
Mortality/Morbidity
Data regarding morbidity and mortality following neurogenic pulmonary edema
(NPE) have not been well documented, given the relatively low prevalence
and likely underdiagnosis. Overall, patient outcome is usually determined by
the underlying neurological insult that led to neurogenic pulmonary edema.
Morbidity related to neurogenic pulmonary edema is reported to be in the
range of 40-50%, and reported mortality from neurogenic pulmonary edema is
low, at approximately 7%.
Race
No ethnic predisposition has been noted for neurogenic pulmonary edema.
Sex
The individual’s sex is not associated with the development of neurogenic pulmonary
edema.
Age
Age is not a specific risk factor for neurogenic pulmonary edema, other than the
increased risk for neurologic events and cardiovascular abnormalities associated with
increasing age.
History
Neurogenic pulmonary edema (NPE) characteristically presents within
minutes to hours of a severe central nervous system insult.
Sudden onset of dyspnea is the most common symptom; mild hemoptysis
also may occur.
Physical
Physical findings include the following:
 Tachypnea
 Tachycardia
 Bibasilar crackles
 Respiratory distress
 Pulmonary edema occurs but with normal jugular venous pressure and
an absence of cardiac gallop, which should raise the possibility of a
neurogenic cause
 Fever - May occur secondary to the neurological disturbance (eg,
subarachnoid hemorrhage)
Causes
Major causes
 Subarachnoid hemorrhage [12, 13, 14]
 Cerebral hemorrhage [15]
 Epileptic seizures
 Head injury [16]
Minor causes
 Multiple sclerosis with medullary involvement
 Nonhemorrhagic strokes [17]
 Bulbar poliomyelitis
 Air embolism
 Brain tumors
 Electrocoulsive therapy
 Bacterial meningitis
 Cervical spinal cord injury
 Intracranial endovascular therapy [18]
Diagnostic Considerations
Aspiration pneumonia
Aspiration frequently occurs in the setting of altered consciousness. Neurogenic
pulmonary edema (NPE) tends to develop more rapidly than aspiration pneumonia.
Although neurogenic pulmonary edema does not cause fever, the neurological insults
that result in neurogenic pulmonary edema (eg, subarachnoid hemorrhage) may be
associated with fever. Aspiration pneumonia may take 1-2 weeks to resolve, whereas
neurogenic pulmonary edema resolves within hours to several days.

Pertimbangan Diagnostik Pneumonia aspirasi Aspirasi sering terjadi pada setting

kesadaran yang berubah. Neurogenic pulmonary edema (NPE) cenderung berkembang
lebih cepat daripada pneumonia aspirasi. Meskipun edema paru neurogenik tidak
menyebabkan demam, penghinaan neurologis yang menyebabkan edema paru
neurogenik (misalnya, perdarahan subarachnoid) dapat dikaitkan dengan demam.
Pneumonia aspirasi memerlukan waktu 1-2 minggu untuk menyelesaikannya,
sedangkan edema paru neurogenik sembuh dalam beberapa jam sampai beberapa
hari.
Differential Diagnoses
 Adult Respiratory Distress Syndrome (ARDS)
 Aspiration Pneumonitis and Pneumonia
 Bacterial Pneumonia
 Cardiogenic Pulmonary Edema
Laboratory Studies
No specific laboratory study confirms the diagnosis of neurogenic pulmonary
edema (NPE). Cardiac injury enzyme levels are elevated in patients with
neurologic injury, especially subarachnoid hemorrhage. The magnitude of
elevation often correlates with the severity of the neurologic event and its
effect on cardiac function.
 In one series, 20% of patients with subarachnoid hemorrhage were
found to have serum troponin I levels greater than 1 mcg/L (range, 0.3-50
mcg/L). [19]
 Elevated natriuretic peptides, A-type and B-type, have also been
reported in patients with subarachnoid hemorrhage, with B-type
natriuretic peptide peak levels reported as 355 ± 80 pg/mL. [20]
 Tidak ada penelitian laboratorium yang spesifik yang mengkonfirmasikan diagnosis
neurogenic pulmonary edema (NPE). Tingkat enzim cidera jantung meningkat pada
pasien dengan cedera neurologis, terutama perdarahan subarachnoid. Besarnya
elevasi sering berkorelasi dengan tingkat keparahan kejadian neurologis dan
pengaruhnya terhadap fungsi jantung.
 • Dalam satu seri, 20% pasien dengan perdarahan subarachnoid ditemukan memiliki
kadar troponin I serum lebih besar dari 1 mcg / L (kisaran, 0,3-50 mcg / L). [19]
 • Peningkatan peptida natriuretik, tipe A dan tipe B, juga telah dilaporkan pada
pasien dengan perdarahan subarachnoid, dengan tingkat puncak peptida natriuretik
tipe B dilaporkan 355 ± 80 pg / mL. [20]

Imaging Studies
Chest radiographs demonstrate a bilateral alveolar filling process and a
normal-sized heart. This may mimic congestive heart failure with cephalization
of blood flow, although other features of heart failure, such as septal Kerley B
lines, are usually not evident. See the images below.
Radiografi dada menunjukkan proses pengisian alveolar bilateral dan jantung berukuran
normal. Hal ini bisa meniru gagal jantung kongestif dengan kinetisitas aliran darah,
walaupun ciri-ciri gagal jantung lainnya, seperti septal garis Kerley B, biasanya tidak jelas.
Lihat gambar di bawah in

Neurogenic pulmonary edema

in a patient with a subdural hematoma.
View Media Gallery
Progression of neurogenic pulmonary edema in the same patient in the image
above, with subdural hematoma (day 2).
Other Tests
No specific test confirms the diagnosis of neurogenic pulmonary edema.
 Initial studies of cardiac function are usually unremarkable. These
include normal ECG findings, echocardiography findings, central venous
pressure, and pulmonary artery occlusion (pulmonary artery capillary
wedge) pressure.
 Serial monitoring of cardiac function may demonstrate reduced left
ventricular function attributed to a neurogenic stress cardiomyopathy.
Findings include regional wall motion abnormalities that extend beyond a
single vascular bed. Echocardiographic findings may demonstrate a
reduced ejection fraction and large areas of akinesis in the setting of
modestly elevated serum troponin levels. Normal pulmonary artery
capillary wedge pressures may increase and approach high levels.
 Coronary angiography, if performed, shows no obstructing lesions.
 Separating the cardiac effects of the neurologic event from the effect of
therapy used in these critically ill patients may be difficult.

Studi awal tentang fungsi jantung biasanya tidak biasa. Ini termasuk temuan EKG normal,
temuan echocardiography, tekanan vena sentral, dan oklusi arteri paru (tekanan arteri
pulmonalis arteri kapiler).
• Pemantauan serial fungsi jantung dapat menunjukkan penurunan fungsi ventrikel kiri yang
dikaitkan dengan kardiomiopati tekanan neurogenik. Temuan termasuk kelainan gerak
dinding daerah yang meluas melampaui satu tempat tidur vaskular tunggal. Temuan
ekokardiografi dapat menunjukkan fraksi ejeksi yang berkurang dan area akinesis yang luas
dalam setting kadar troponin serum yang sedikit meningkat. Tekanan kapiler kapiler paru
normal dapat meningkat dan mendekati tingkat tinggi.
• Angiografi koroner, jika dilakukan, tidak menunjukkan adanya lesi yang menghalangi.
• Memisahkan efek jantung dari kejadian neurologis akibat efek terapi yang digunakan pada
pasien yang sakit kritis ini mungkin sulit dilakukan

Procedures
Hemodynamic measurements with right-sided heart catheterization (ie, Swan-
Ganz catheter) may be necessary to differentiate neurogenic pulmonary
edema from hydrostatic or cardiogenic pulmonary edema. Systemic blood
pressure, cardiac output, and pulmonary capillary wedge pressure are usually
normal by the time neurogenic pulmonary edema is diagnosed clinically.

Pengukuran hemodinamik dengan kateterisasi jantung sisi kanan (yaitu kateter Swan-
Ganz) mungkin diperlukan untuk membedakan edema paru neurogenik dari edema
paru hidrostatik atau kardiogenik. Tekanan darah sistemik, curah jantung, dan tekanan
baji kapiler paru biasanya normal pada saat neurogenic pulmonary edema didiagnosis
secara klinis.

Histologic Findings
No specific histologic findings confirm the diagnosis of neurogenic pulmonary
edema.
Staging
No staging system is applicable to neurogenic pulmonary edema.
Medical Care
Neurologic disorder and neurogenic pulmonary edema (NPE)
 Focus treatment on the underlying neurologic disorder and associated
complications.
 The initial focus should be on control of the underlying neurologic insult,
which may include surgical options.
 Control neurogenic pulmonary edema with supportive and conservative
measures.
 Neurogenic pulmonary edema resolves within 48-72 hours in the
majority of affected patients.
General supportive care for neurogenic pulmonary edema
 Supplemental oxygen is required in most patients to correct hypoxemia.
 Mechanical ventilation may be necessary, either noninvasive with a face
mask or via an endotracheal tube. [21] The goals of mechanical ventilation
are to assure adequate oxygenation and ventilation and to prevent
iatrogenic lung injury. To avoid excessively high inflation pressures, tidal
volumes between 5 and 6 mL/kg or predicted body weight are used.
 With the use of low inflation volumes, positive end-expiratory pressure
(PEEP) is added to prevent compression atelectasis. The peak inspiratory
(plateau) pressure should be kept below 30-35 cm water, and eucapnia
should be maintained to avoid further increases in intracranial pressure.
 High levels of PEEP may be required to treat severe hypoxemia.
Caution is advised, however, because PEEP can inhibit cerebral venous
return and increase intracranial hypertension.
 Diuretic therapy may reduce lung water by decreasing capillary
hydrostatic pressure and increasing colloid osmotic pressure, but the
strategies to reduce lung water are not uniformly successful. The use of
diuretics to minimize or reduce fluid overload seems a more reasonable
approach, but adequate cardiac output and cerebral perfusion pressure
must be maintained.
  The goal of management in respiratory failure is to achieve an adequate
level of oxygenation in the vital organs. Swan-Ganz catheterization may
be helpful in guiding fluid and hemodynamic management, particularly if
diuretics are used.
 To maintain adequate tissue oxygenation, sufficient cardiac output
(cardiac index >2.2 L/min/m 2) and hemoglobin (>10 g/L) are required to
ensure optimal oxygen delivery. Because cardiac output depends on
cardiac filling pressures (central venous pressure and wedge pressure),
meticulous monitoring of intravascular volume is mandatory. See
the Cardiac Output calculator.
Gangguan neurologis dan edema paru neurogenik (NPE) • Fokus perawatan pada
kelainan neurologis yang mendasarinya dan komplikasi yang terkait. • Fokus awal harus
dikendalikan dari penghinaan neurologis yang mendasarinya, yang mungkin mencakup
pilihan operasi. • Kontrol edema paru neurogenik dengan tindakan suportif dan
konservatif. • Edema paru neurogenik sembuh dalam waktu 48-72 jam pada sebagian
besar pasien yang terkena. Perawatan suportif umum untuk edema paru neurogenik •
Oksigen tambahan diperlukan pada kebanyakan pasien untuk memperbaiki hipoksemia. •
Ventilasi mekanis mungkin diperlukan, tidak invasif dengan masker wajah atau melalui
tabung endotrakea. [21] Tujuan ventilasi mekanis adalah untuk menjamin oksigenasi dan
ventilasi yang memadai dan untuk mencegah cedera paru iatrogenik. Untuk menghindari
tekanan inflasi yang terlalu tinggi, volume tidal antara 5 dan 6 mL / kg atau berat badan
yang diprediksi digunakan. • Dengan penggunaan volume inflasi rendah, tekanan ekspres
akhir positif (PEEP) ditambahkan untuk mencegah atelektasis kompresi. Tekanan puncak
inspirasi (dataran tinggi) harus dijaga di bawah air 30-35 cm, dan eucapnia harus dijaga
agar tidak terjadi peningkatan tekanan intrakranial lebih lanjut. • Tingkat PEEP yang tinggi
mungkin diperlukan untuk mengobati hipoksemia berat. Perhatian disarankan, karena
PEEP dapat menghambat kembalinya serebral vena dan meningkatkan hipertensi
intrakranial. • Terapi diuretik dapat mengurangi air paru-paru dengan menurunkan tekanan
hidrostatik kapiler dan meningkatkan tekanan osmotik koloid, namun strategi untuk
mengurangi air paru tidak berhasil secara merata. Penggunaan diuretik untuk
meminimalkan atau mengurangi kelebihan cairan tampaknya merupakan pendekatan
yang lebih masuk akal, namun curah jantung yang cukup dan tekanan perfusi serebral
harus dijaga. • Tujuan manajemen dalam kegagalan pernafasan adalah mencapai tingkat
oksigenasi yang memadai pada organ vital. Kateterisasi Swan-Ganz bisa membantu
dalam menuntun manajemen fluida dan hemodinamika, terutama jika diuretik digunakan. •
Untuk menjaga oksigenasi jaringan yang adekuat, curah jantung yang cukup (indeks
jantung> 2,2 L / menit / m 2) dan hemoglobin (> 10 g / L) diperlukan untuk memastikan
pemberian oksigen optimal. Karena curah jantung tergantung pada tekanan pengisian
jantung (tekanan vena sentral dan tekanan baji), pemantauan volume intravaskular sangat
teliti adalah wajib. Lihat kalkulator Cardiac Output.

Pharmacological therapy for neurogenic pulmonary edema: Pharmacological

agents are not used routinely in the treatment of neurogenic pulmonary
edema. Several agents, such as alpha-adrenergic antagonists, beta-
adrenergic blockers, dobutamine, and chlorpromazine, are advocated by
some authors, but assessment of their effectiveness is difficult because
neurogenic pulmonary edema is usually a self-limited condition that resolves
spontaneously.
 Alpha-adrenergic antagonists (eg, phentolamine) can prevent
neurogenic pulmonary edema or hasten its resolution in experimental
models. However, no human trials have established the safety and
efficacy of these agents. These agents may be used to treat concomitant
systemic hypertension, if present, but care must be taken to avoid
significant hypotension that can diminish cerebral perfusion. [22]

 Beta-adrenergic agonists, in theory, are used to counteract the alpha-

adrenergic–induced increase in systemic vascular resistance by
increased inotropic effect with reflex-mediated decrease in afterload.
Some studies have used dobutamine and shown a distinct improvement
in myocardial function in patients with neurogenic pulmonary edema. [23] A
more recent study looked at patients with neurogenic pulmonary edema
who were taking lower doses of dopamine (< 6 mcg/min/kg) and showed
this to be a reasonable alternative to dobutamine. Recommendations
against using higher doses of dopamine have also been published, given
the possible effects on increased afterload.
Terapi farmakologis untuk edema paru neurogenik: Agen farmakologis tidak digunakan
secara rutin dalam pengobatan edema paru neurogenik. Beberapa agen, seperti
antagonis alfa-adrenergik, penghambat beta-adrenergik, dobutamin, dan klorpromazin,
dianjurkan oleh beberapa penulis, namun penilaian keefektifannya sulit dilakukan karena
edema paru neurogenik biasanya merupakan kondisi self-limited yang dapat sembuh
secara spontan. • Antagonis alfa-adrenergik (misalnya, phentolamine) dapat mencegah
edema paru neurogenik atau mempercepat resolusinya dalam model eksperimental.
Namun, tidak ada percobaan manusia yang telah menetapkan keamanan dan kemanjuran
agen ini. Agen ini dapat digunakan untuk mengobati hipertensi sistemik bersamaan, jika
ada, namun perawatan harus dilakukan untuk menghindari hipotensi yang signifikan yang
dapat mengurangi perfusi serebral. [22] • Agonis beta-adrenergik, secara teori, digunakan
untuk melawan peningkatan resistensi vaskular sistemik alfa-adrenergik dengan
meningkatkan efek inotropik dengan penurunan afterload yang dimediasi secara refleks.
Beberapa penelitian telah menggunakan dobutamin dan menunjukkan peningkatan fungsi
miokard yang berbeda pada pasien dengan edema paru neurogenik. [23] Sebuah studi
yang lebih baru melihat pasien dengan edema paru neurogenik yang memakai dosis
dopamin dosis rendah (<6 mcg / min / kg) dan menunjukkan ini sebagai alternatif yang
masuk akal untuk dobutamin. Rekomendasi melawan penggunaan dosis dopamin dosis
tinggi juga telah dipublikasikan, mengingat kemungkinan efek pada peningkatan afterload
Surgical Care
Surgical management is directed at the neurologic insult (eg, intracerebral
hemorrhage, subdural hematoma) because neurogenic pulmonary edema has
no direct surgical treatment.
Manajemen bedah diarahkan pada penghinaan neurologis (misalnya, perdarahan
intraserebral, hematoma subdural) karena edema paru neurogenik tidak memiliki
perawatan bedah langsung.

Consultations
Consultations may include the following:
 Critical care medicine specialist or intensivist for ongoing intensive care
 Neurosurgeon and/or neurologist for evaluation and management of any
underlying precipitating event
 Interventional radiologist for some specific neurologic vascular issues
 Konsultasi dapat mencakup hal-hal berikut:
 • Spesialis perawatan kesehatan kritis atau intensivis untuk perawatan intensif yang
sedang berlangsung
 • Ahli bedah saraf dan / atau ahli saraf untuk evaluasi dan pengelolaan peristiwa
pengendapan yang mendasari
 • Ahli radiologi intervensional untuk beberapa masalah pembuluh darah neurologis
tertentu

Diet
No specific dietary recommendations are needed for patients with neurogenic
pulmonary edema.
Activity
Patients with neurogenic pulmonary edema usually have limited mobility as a
result of their neurologic condition. No specific restrictions on activity are
needed, except those required for treatment of the neurologic condition,
especially patients undergoing neurologic surgery. Early ambulation and
rehabilitation are crucial for recovery.
Medication Summary
No targeted or specific medications treat neurogenic pulmonary edema
(NPE), other than those that have been discussed in Medical Care. These
include alpha-adrenergic antagonists (eg, phentolamine) and Beta-adrenergic
agonists (eg, dobutamine, dopamine, norepinephrine).

Diet Tidak ada rekomendasi diet khusus yang diperlukan untuk pasien dengan edema
paru neurogenik. Aktivitas Pasien dengan neurogenic pulmonary edema biasanya
memiliki mobilitas terbatas akibat kondisi neurologisnya. Tidak ada pembatasan
aktivitas khusus yang diperlukan, kecuali yang diperlukan untuk perawatan kondisi
neurologis, terutama pasien yang menjalani operasi neurologis. Ambulasi awal dan
rehabilitasi sangat penting untuk pemulihan. Ringkasan Obat Tidak ada obat spesifik
atau target yang mengobati edema paru neurogenik (NPE), selain yang telah dibahas di
Perawatan Kesehatan. Ini termasuk antagonis alfa-adrenergik (misalnya, phentolamine)
dan agonis Beta-adrenergik (misalnya dobutamin, dopamin, norepinephrine).

Further Outpatient Care

No specific recommendations for outpatient follow up are needed for persons
who have been treated for neurogenic pulmonary edema. Patients who
recover should probably follow up with a physician in an outpatient setting as
clinically indicated; however, no specific guidelines are available regarding the
appropriate time interval following discharge from the hospital. In general,
patients with neurogenic pulmonary edema do not present as outpatients and
should not be treated in an outpatient setting.

Perawatan Rawat Jalan lebih lanjut

Tidak ada rekomendasi khusus untuk tindak lanjut rawat jalan yang diperlukan untuk orang-
orang yang telah diobati untuk edema paru neurogenik. Pasien yang sembuh mungkin harus
menindaklanjuti dengan dokter di tempat rawat jalan sebagaimana ditunjukkan secara
klinis; Namun, tidak ada panduan spesifik mengenai interval waktu yang sesuai setelah
dikeluarkan dari rumah sakit. Secara umum, pasien dengan neurogenic pulmonary edema
tidak hadir sebagai pasien rawat jalan dan tidak boleh dirawat di tempat rawat jalan.

Further Inpatient Care

Neurological insults severe enough to cause neurogenic pulmonary edema
(NPE) always warrant admission to hospital. Most patients require close
cardiac monitoring, requiring initial admission to a monitored bed. A telemetry
unit or step-down unit bed may suffice for less severe cases. Intensive care
admission may be required if patients develop increasingly severe hypoxemia
or respiratory distress, or if invasive monitoring is required.
Perawatan Rawat Jalan lebih lanjut
Tidak ada rekomendasi khusus untuk tindak lanjut rawat jalan yang diperlukan untuk orang-
orang yang telah diobati untuk edema paru neurogenik. Pasien yang sembuh mungkin harus
menindaklanjuti dengan dokter di tempat rawat jalan sebagaimana ditunjukkan secara
klinis; Namun, tidak ada panduan spesifik mengenai interval waktu yang sesuai setelah
dikeluarkan dari rumah sakit. Secara umum, pasien dengan neurogenic pulmonary edema
tidak hadir sebagai pasien rawat jalan dan tidak boleh dirawat di tempat rawat jalan.

Inpatient & Outpatient Medications

No specific recommendations for outpatient medications are needed for
neurogenic pulmonary edema. See Medical Care.
Transfer
Patients with neurogenic pulmonary edema generally have multiple
comorbidities that dictate the setting in which they are receiving care. Transfer
between levels of acute care (ie, ICU to transitional care units, and
subsequently to general medical/surgical ward) is influenced by a variety of
factors. The most important of these is likely the underlying neurological insult
that led to the development of pulmonary edema. Once this is managed and
stabilized, further transitions between level of care are dictated by clinical
circumstances. These include an ongoing need for mechanical ventilation,
hemodynamic parameters, and the need for regular neurologic monitoring.

Perawatan Rawat Jalan lebih lanjut

Tidak ada rekomendasi khusus untuk tindak lanjut rawat jalan yang diperlukan untuk orang-
orang yang telah diobati untuk edema paru neurogenik. Pasien yang sembuh mungkin harus
menindaklanjuti dengan dokter di tempat rawat jalan sebagaimana ditunjukkan secara
klinis; Namun, tidak ada panduan spesifik mengenai interval waktu yang sesuai setelah
dikeluarkan dari rumah sakit. Secara umum, pasien dengan neurogenic pulmonary edema
tidak hadir sebagai pasien rawat jalan dan tidak boleh dirawat di tempat rawat jalan.

Deterrence/Prevention
Prevention is primarily aimed at interventions that help avoid or relieve the
neurological insults that subsequently lead to pulmonary edema. Current
understanding is limited as to which patients are likely to develop pulmonary
edema as a result of neurological injury. Given this lack of understanding,
predicting who will develop pulmonary edema and determining what
measures can then be undertaken to prevent its occurrence are difficult.
Pencegahan / Pencegahan
Pencegahan terutama ditujukan pada intervensi yang membantu menghindari atau
menghilangkan penghinaan neurologis yang kemudian menyebabkan edema paru.
Pemahaman saat ini terbatas dimana pasien cenderung mengembangkan edema paru
akibat cedera neurologis. Mengingat kurangnya pemahaman ini, memprediksi siapa yang
akan mengembangkan edema paru dan menentukan tindakan apa yang bisa dilakukan
untuk mencegah terjadinya sulit.

Complications
Complications include but are not limited to the following:
 Prolonged hypoxic respiratory failure
 Hemodynamic instability
 Nosocomial infections (ie, related to prolonged mechanical ventilation
and hospitalization)
 Death
Prognosis
Neurogenic pulmonary edema usually is generally well tolerated by the
patient, although some patients require ventilatory support. The neurogenic
pulmonary edema usually resolves within 48-72 hours. Prognosis is
determined more by the course of the underlying neurological problem than by
the neurogenic pulmonary edema, unless significant respiratory complications
develop.
Neurogenic pulmonary edema biasanya ditoleransi dengan baik oleh pasien, walaupun
beberapa pasien memerlukan dukungan ventilasi. Edema paru neurogenik biasanya sembuh
dalam waktu 48-72 jam. Prognosis lebih ditentukan oleh jalannya masalah neurologis yang
mendasarinya dibandingkan dengan edema paru neurogenik, kecuali komplikasi pernapasan
yang signifikan.

Patient Education
For excellent patient education resources, visit eMedicineHealth's Brain and
Nervous System Center. Also, see eMedicineHealth's patient education
article Stroke.

The pathophysiology linking the neurologic, cardiac, and pulmonary conditions in NPE has been subject
to debate and controversy since the recognition of NPE as a clinical entity. A common thread among all
case descriptions of NPE is the severity and acuity of the precipitating CNS event. Neurologic conditions
that cause abrupt, rapid, and extreme elevation in intracranial pressure (ICP) appear to be at greatest
risk of being associated with NPE [18,19]. Elevated ICP levels correlate with increased levels of
extravascular lung water (EVLW) and NPE [2,20]. The abrupt increase in ICP leading to neuronal
compression, ischemia or damage is believed to give rise to an intense activation of the sympathetic
nervous system and the release of catecholamines [2,21]. This fundamental role of catecholamines is
supported by the fact that the blockade of sympathetic activity in animal models via intrathecal
lidocaine, phentolamine infusion, or pretreatment with phenoxybenzamine mitigates the pathologic
neuro-pulmonary process [22,23] (Table (Table1).1). In addition to pharmacologic intervention,
anatomical interruption of the nervous system pathway (e.g., spinal cord transection) has also been
Patofisiologi yang menghubungkan kondisi neurologis, jantung, dan paru di NPE telah
menjadi bahan perdebatan dan kontroversi sejak pengakuan NPE sebagai entitas klinis.
Sebuah benang merah di antara semua deskripsi kasus NPE adalah tingkat keparahan dan
ketajaman peristiwa CNS yang mengendap. Kondisi neurologis yang menyebabkan elevasi
mendadak, cepat, dan ekstrem pada tekanan intrakranial (ICP) tampaknya berisiko terbesar
terkait dengan NPE [18,19]. Peningkatan kadar ICP berkorelasi dengan peningkatan kadar air
paru-paru ekstravaskuler (EVLW) dan NPE [2,20]. Peningkatan ICP yang tiba-tiba yang
menyebabkan kompresi neuron, iskemia atau kerusakan diyakini dapat menyebabkan
pengaktifan sistem saraf simpatik dan pelepasan katekolamin secara signifikan [2,21]. Peran
dasar katekolamin ini didukung oleh fakta bahwa blokade aktivitas simpatik pada model
hewan melalui lidokain intratekal, infus phentolamine, atau pretreatment dengan
fenoksibenzamin mengurangi proses patologis neuro-pulmoner [22,23] (Tabel (Tabel 1) .1) .
Selain intervensi farmakologis, gangguan anatomi jalur sistem saraf (misalnya, transeksi
medula spinalis) juga telah terjadi.

shown to protect against the formation of NPE (Table (Table1).1). In one animal model, NPE was
prevented by removal of one lung followed by reimplantation. This was in contrast to the pulmonary
edema that developed in the innervated intrinsic lung [24]. In a human example, NPE has been reported
in soldiers who died suddenly after gunshot wounds to the head. The soldiers with concomitant cervical
spinal cord injury (and presumably severed neuronal connection) did not have evidence of pulmonary
edema on post-mortem exam [1]. Pulmonary edema has also been reported in patients with
pheochromocytoma, presumably from catecholamine surge [25].
ditunjukkan untuk melindungi terhadap pembentukan NPE (Tabel (Table1) .1). Dalam satu
model hewan, NPE dicegah dengan mengeluarkan satu paru yang diikuti dengan
reimplantasi. Hal ini berbeda dengan edema paru yang berkembang di paru intrinsik yang
diinervasi [24]. Dalam contoh manusia, NPE telah dilaporkan pada tentara yang meninggal
mendadak setelah luka tembak di kepala. Para prajurit dengan cedera sumsum tulang
belakang serviks bersamaan (dan koneksi neuron yang diputus mungkin) tidak memiliki
bukti edema paru pada pemeriksaan post-mortem [1]. Edema paru juga telah dilaporkan
pada pasien dengan pheochromocytoma, mungkin dari lonjakan katekolamin [25].

Introduction
Neurogenic pulmonary edema (NPE) is a clinical syndrome characterized by the acute onset of
pulmonary edema following a significant central nervous system (CNS) insult. The etiology is
thought to be a surge of catecholamines that results in cardiopulmonary dysfunction. A myriad of
CNS events, including spinal cord injury, subarachnoid hemorrhage (SAH), traumatic brain
injury (TBI), intracranial hemorrhage, status epilepticus, meningitis, and subdural hemorrhage,
have been associated with this syndrome [1-5]. Although NPE was identified over 100 years ago,
it is still underappreciated in the clinical arena. Its sporadic and relatively unpredictable nature
and a lack of etiologic-specific diagnostic markers and treatment modalities may in part be
responsible for its poor recognition at the bedside. In this manuscript, we will review the
anatomical origin of NPE, outline the various possible pathophysiologic mechanisms responsible
for its development, and propose a clinical framework for the classification of NPE.
Neurogenic pulmonary edema (NPE) adalah sindroma klinis yang ditandai dengan onset akut
edema paru setelah penghinaan sistem saraf pusat yang signifikan (CNS). Etiologi dianggap
sebagai gelombang katekolamin yang menyebabkan disfungsi kardiopulmoner. Sejumlah
kejadian CNS, termasuk cedera sumsum tulang belakang, perdarahan subarachnoid (SAH),
cedera otak traumatis (TBI), perdarahan intrakranial, status epilepticus, meningitis, dan
perdarahan subdural, telah dikaitkan dengan sindrom ini [1-5]. Meskipun NPE diidentifikasi
lebih dari 100 tahun yang lalu, namun tetap kurang dihargai di arena klinis. Sifat sporadis
dan relatif tidak dapat diprediksi dan kurangnya tanda diagnostik spesifik etiologi dan
modalitas perawatan mungkin sebagian bertanggung jawab atas pengakuan buruknya di sisi
tempat tidur. Dalam manuskrip ini, kami akan meninjau asal anatomis NPE, menjelaskan
berbagai mekanisme patofisiologis yang mungkin bertanggung jawab atas
perkembangannya, dan mengusulkan kerangka klinis untuk klasifikasi NPE

Historical background
The syndrome of NPE has been recognized for over a century. In 1903, Harvey Williams
Cushing, described the connection between CNS injury and hemodynamic dysfunction [6]; and,
in 1908, W. T. Shanahan reported 11 cases of acute pulmonary edema as a complication of
epileptic seizures [7]. Francois Moutier described the sudden onset of pulmonary edema among
soldiers shot in the head in World War I [8]. Similar reports exist of observed alveolar edema and
hemorrhage in the lungs of 17 soldiers dying after isolated bullet head wounds in the Vietnam
War [1].

Epidemiology
Because much of the clinical information on NPE has been derived from case reports and
autopsy series, the true incidence of NPE is unknown and is likely underreported. Any acute
CNS insult, including spinal cord trauma, can result in pulmonary edema. In patients with SAH,
reports of NPE incidence range from 2% to 42.9% [3,9,10]. Clinically, the likelihood of
developing NPE following SAH correlates with increasing age, delay to surgery, vertebral artery
origin, and the severity of clinical and radiographic presentation (e.g., Hunt-Hess and Fischer
grades) [10,11]. Patients with SAH who develop NPE have a higher mortality rate, nearing 10%
[3]. In patients with TBI, the incidence of NPE has been estimated to be up to 20% [12]. Rogers
et al. examined a large autopsy and inpatient database on patients with acute head injury in an
effort to better characterize NPE in this patient population. The authors found that the incidence
of NPE in patients with TBI who died at the scene was 32%. Among the TBI patients who died
within 96 hours, the incidence of NPE rose to 50% [2]. There was a direct correlation between
decreasing cerebral perfusion pressure (CPP) and reduced PaO2/FiO2 ratios in the TBI patients
[2]. NPE in patients who suffer seizures is rare; however, up to 80 to 100% of epileptics who die
unexpectedly of seizures are also found to have NPE [13]. In other series, close to one-third of
patients with status epilepticus also developed NPE [14]. Other conditions, including aqueductal
glioma, multiple sclerosis, medication overdose, arteriovenous malformations,
meningitis/encephalitis and spinal cord infarction, have been reported and linked to the
formation of NPE [5,15-17].

Pathophysiology
The pathophysiology linking the neurologic, cardiac, and pulmonary conditions in NPE has been
subject to debate and controversy since the recognition of NPE as a clinical entity. A common
thread among all case descriptions of NPE is the severity and acuity of the precipitating CNS
event. Neurologic conditions that cause abrupt, rapid, and extreme elevation in intracranial
pressure (ICP) appear to be at greatest risk of being associated with NPE [18,19]. Elevated ICP
levels correlate with increased levels of extravascular lung water (EVLW) and NPE [2,20]. The
abrupt increase in ICP leading to neuronal compression, ischemia or damage is believed to give
rise to an intense activation of the sympathetic nervous system and the release of catecholamines
[2,21].
Patofisiologi yang menghubungkan kondisi neurologis, jantung, dan paru di NPE telah
menjadi bahan perdebatan dan kontroversi sejak pengakuan NPE sebagai entitas klinis.
Sebuah benang merah di antara semua deskripsi kasus NPE adalah tingkat keparahan dan
ketajaman peristiwa CNS yang mengendap. Kondisi neurologis yang menyebabkan elevasi
mendadak, cepat, dan ekstrem pada tekanan intrakranial (ICP) tampaknya berisiko terbesar
terkait dengan NPE [18,19]. Peningkatan kadar ICP berkorelasi dengan peningkatan kadar air
paru-paru ekstravaskuler (EVLW) dan NPE [2,20]. Peningkatan ICP yang tiba-tiba yang
menyebabkan kompresi neuron, iskemia atau kerusakan diyakini dapat menyebabkan
pengaktifan sistem saraf simpatik dan pelepasan katekolamin secara signifikan [2,21].

This fundamental role of catecholamines is supported by the fact that the blockade of
sympathetic activity in animal models via intrathecal lidocaine, phentolamine infusion, or
pretreatment with phenoxybenzamine mitigates the pathologic neuro-pulmonary process [22,23]
(Table (Table1).1). In addition to pharmacologic intervention, anatomical interruption of the
nervous system pathway (e.g., spinal cord transection) has also been shown to protect against the
formation of NPE (Table (Table1).1). In one animal model, NPE was prevented by removal of
one lung followed by reimplantation. This was in contrast to the pulmonary edema that
developed in the innervated intrinsic lung [24]. In a human example, NPE has been reported in
soldiers who died suddenly after gunshot wounds to the head. The soldiers with concomitant
cervical spinal cord injury (and presumably severed neuronal connection) did not have evidence
of pulmonary edema on post-mortem exam [1]. Pulmonary edema has also been reported in
patients with pheochromocytoma, presumably from catecholamine surge [25].

Peran dasar katekolamin ini didukung oleh fakta bahwa blokade aktivitas simpatik pada
model hewan melalui lidokain intratekal, infus phentolamine, atau pretreatment dengan
fenoksibenzamin mengurangi proses patologis neuro-pulmoner [22,23] (Tabel (Tabel
1) .1) . Selain intervensi farmakologis, gangguan anatomi jalur sistem saraf (misalnya,
transeksi medula spinalis) juga telah terbukti melindungi terhadap pembentukan NPE
(Tabel (Tabel 1) .1). Dalam satu model hewan, NPE dicegah dengan mengeluarkan satu
paru yang diikuti dengan reimplantasi. Hal ini berbeda dengan edema paru yang
berkembang di paru intrinsik yang diinervasi [24]. Dalam contoh manusia, NPE telah
dilaporkan pada tentara yang meninggal mendadak setelah luka tembak di kepala. Para
prajurit dengan cedera sumsum tulang belakang serviks bersamaan (dan koneksi
neuron yang diputus mungkin) tidak memiliki bukti edema paru pada pemeriksaan post-
mortem [1]. Edema paru juga telah dilaporkan pada pasien dengan pheochromocytoma,
mungkin dari lonjakan katekolamin [25].

Table 1

Animal studies assessing possible therapeutic interventions for neurogenic pulmonary edema (NPE)

Anatomical origin of NPE

Although the exact source of sympathetic outflow has not been identified, certain centers in the
brain have been implicated. These 'NPE trigger zones' include the hypothalamus and the
medulla, specifically area A1, A5, nuclei of solitary tract and the area postrema [5]. Area A1 is
located in the ventrolateral aspect of the medulla and is composed of catecholamine neurons
which project into the hypothalamus [5]. The neurons from area A5, located in the upper portion
of the medulla, project into the preganglionic centers for spinal cord sympathetic outflow [5].
Injury to Area A1 or disruption of the efferent pathway between A5 and the cervical cord has
been shown to result in the formation of pulmonary edema [26]. Stimulation of area A5 also
causes increases in systemic blood pressure [27]. The nuclei of solitary tract and the area
postrema of the medulla have also been linked to the formation of NPE. These areas are related
to respiratory regulation and receive input from the carotid sinus. In animal models, bilateral
irritation of the nuclei solitary tract causes severe hypertension and NPE [23]. Unilateral
stimulation of the area postrema also results in profound hemodynamic changes, including
increased cardiac output, peripheral vascular resistance, and hypertension [5]. Finally, NPE was
shown to develop after lesions were induced in the hypothalamus of laboratory animals [28]. In a
case series of 22 patients suffering from NPE, 11 of the patients had significant radiographic
abnormalities in the hypothalamus. The presence of hypothalamic lesions among these NPE
patients conferred a worse prognosis [29].
Meskipun sumber pasti arus keluar simpatis belum teridentifikasi, beberapa pusat di otak
telah terlibat. 'Zona pemicu NPE' ini mencakup hipotalamus dan medula, khususnya area A1,
A5, inti saluran soliter dan daerah postrema [5]. Area A1 terletak pada aspek ventrolateral
medula dan terdiri dari neuron katekolamin yang memproyeksikan hipotalamus [5]. Neuron
dari daerah A5, terletak di bagian atas medula, diproyeksikan ke pusat preganglionik untuk
aliran keluar simpatis spinalis [5]. Cedera pada Area A1 atau terganggunya jalur eferen
antara A5 dan tali serviks telah terbukti menyebabkan pembentukan edema paru [26].
Stimulasi daerah A5 juga menyebabkan peningkatan tekanan darah sistemik [27]. Inti dari
saluran soliter dan daerah postrema medula juga telah dikaitkan dengan pembentukan NPE.
Daerah ini terkait dengan regulasi pernafasan dan mendapat masukan dari sinus karotid.
Pada model hewan, iritasi bilateral saluran soliter nujum menyebabkan hipertensi berat dan
NPE [23]. Rejimen unilateral dari daerah postrema juga menyebabkan perubahan
hemodinamik yang mendalam, termasuk peningkatan curah jantung, resistensi vaskular
perifer, dan hipertensi [5]. Akhirnya, NPE terbukti berkembang setelah lesi diinduksi di
hipotalamus hewan laboratorium [28]. Dalam rangkaian kasus 22 pasien yang menderita
NPE, 11 pasien memiliki kelainan radiografi yang signifikan pada hipotalamus. Adanya lesi
hipotalamus di antara pasien NPE ini memberikan prognosis yang lebih buruk [29].

Pathogenesis
It is the prevailing view that the autonomic response to elevated ICP plays an important role in
the pathogenesis of NPE. However, what occurs mechanistically at the level of the pulmonary
vascular endothelium remains enigmatic and theoretical. Several clinicopathologic paradigms
have been proposed to explain the clinical syndrome of NPE: 1) Neuro-cardiac; 2) Neuro-
hemodynamic; 3) "blast theory"; and 4) pulmonary venule adrenergic hypersensitivity.

Ini adalah pandangan yang berlaku bahwa respons otonom terhadap ICP yang
meningkat memainkan peran penting dalam patogenesis NPE. Namun, apa yang terjadi
secara mekanis pada tingkat endotelium vaskular paru tetap misterius dan teoretis.
Beberapa paradigma klinis telah ditunjukkan untuk menjelaskan sindrom klinis NPE: 1)
Neuro-jantung; 2) Neuro-hemodinamik; 3) "teori ledakan"; dan 4) hipersensitifitas
adenenergi venula pulmonal.

Neuro-cardiac NPE
Whereas NPE has traditionally been described as a 'non-cardiogenic' form of pulmonary edema,
there is evidence that, in at least a subset of patients, neurologic insult leads to direct myocardial
injury and the development of pulmonary edema. Takotsubo's cardiomyopathy is a reversible
condition characterized by depressed cardiac contractility following a neurologically 'stressful'
event. The transiently diminished lusitropy, diastolic dysfunction, and global hypokinesis of the
Takotsubo heart can render these patients susceptible to cardiogenic pulmonary edema [30].
Connor was one of the first investigators to describe the myocytolysis and contraction-band
necrosis on myocardial biopsies of neurosurgical patients with pulmonary edema [31]. Since this
original report, several cases of cardiac injury associated with pulmonary edema following a
CNS event have been described. In a retrospective analysis, patients with no previous cardiac
history developed acute onset of pulmonary edema in association with a SAH. The patients all
demonstrated segmental wall motion abnormalities on echocardiogram, mildly elevated cardiac
enzymes, electrocardiogram (EKG) abnormalities, and elevated pulmonary artery occlusion
pressures (PAOPs). These patients were noted to have focal myocardial necrosis, yet had no
evidence of infarction and had normal coronary arteries [32]. Similar descriptions of reversible
cardiac dysfunction have been reported among patients with TBI and NPE [30].
As with all forms of NPE, massive sympathetic discharge following CNS insult is thought to be
the precipitating factor. More specifically, in this subset of patients with 'neuro-cardiac' NPE, it is
catecholamines that induce direct myocyte injury. This is supported by the fact that the wall
motion abnormalities seen on echocardiogram in patients with neurogenic stunned myocardium
follow a pattern of sympathetic nerve innervation [33]. Similarly, myocardial lesions have been
shown in patients with pheochromocytoma, supporting the role of catecholamine surge in the
pathogenesis of stunned myocardium [34].

Sedangkan NPE secara tradisional digambarkan sebagai bentuk edema paru non-
kardiogenik, ada bukti bahwa, setidaknya sebagian pasien, penghinaan neurologis
menyebabkan cedera miokard langsung dan perkembangan edema paru. Kardiomiopati
Takotsubo adalah kondisi reversibel yang ditandai dengan kontraksi jantung tertekan
setelah peristiwa 'stres' yang neurologis. Lusitropi yang berkurang sementara, disfungsi
diastolik, dan hipokinesis global jantung Takotsubo dapat membuat pasien ini rentan
terhadap edema paru kardiogenik [30]. Connor adalah salah satu peneliti pertama yang
mendeskripsikan myocytolysis and contraction-band necrosis pada biopsi miokard pada
pasien bedah saraf dengan edema paru [31]. Sejak laporan awal ini, beberapa kasus
cedera jantung berhubungan dengan edema paru setelah kejadian CNS telah
dijelaskan. Dalam analisis retrospektif, pasien tanpa riwayat jantung sebelumnya
mengalami onset akut edema paru yang berhubungan dengan SAH. Semua pasien
menunjukkan kelainan gerak dinding segmental pada ekokardiogram, peningkatan
enzim jantung ringan, kelainan elektrokardiogram (EKG), dan tekanan oklusi arteri paru
yang meningkat (PAOP). Pasien-pasien ini diketahui memiliki nekrosis miokard fokal,
namun tidak memiliki bukti adanya infark dan memiliki arteri koroner normal [32].
Gambaran serupa tentang disfungsi jantung reversibel telah dilaporkan di antara pasien
dengan TBI dan NPE [30]. Seperti semua bentuk NPE, pelepasan simpatik yang besar
setelah penghinaan SSP dianggap sebagai faktor pengendapan. Lebih khusus lagi,
pada subset pasien dengan NPE 'neuro-jantung' ini, katekolamin yang menyebabkan
luka miokard langsung. Hal ini didukung oleh fakta bahwa kelainan gerak dinding yang
terlihat pada ekokardiogram pada pasien dengan neurogenik tertegun miokardium
mengikuti pola persarafan saraf simpatik [33]. Demikian pula, lesi miokard telah
ditunjukkan pada pasien dengan pheochromocytoma, yang mendukung peran lonjakan
katekolamin dalam patogenesis miokardium tertegun [34].

Neuro-hemodynamic NPE
Unlike the direct toxic effects to the myocardium as detailed above, the 'neuro-hemodynamic'
theory posits that ventricular compliance is indirectly altered by the abrupt increases in systemic
and pulmonary pressures following CNS injury. In the original studies by Sarnoff and Sarnoff,
substantial increases in aortic and pulmonary pressures were observed following the injection of
thrombin into the intracisterna magna of dogs and rabbits [35]. The authors noted that following
the sympathetic surge, the left ventricle had reached its workfailure threshold and failed to
effectively pump against the systemic pressures. A translocation of blood flow from the highly
resistant systemic circulation to the low resistance pulmonary circuit subsequently ensued,
leading to a hydrostatic form of pulmonary edema. The increased sizes of the left atrium and
pulmonary veins in the animals were well documented in this study, and the authors
subsequently coined the term "neuro-hemodynamic pulmonary edema" [35]. Several other
animal models have documented large elevations in left atrial, systemic and pulmonary pressures
associated with NPE [18,22,36]. One study induced graded levels of ICP in chimpanzees. All of
the animals developed systemic hypertension, but only those with a marked increase in left atrial
pressure and a decrease in cardiac output developed pulmonary edema [18].
Tidak seperti efek toksik langsung terhadap miokardium seperti yang dijelaskan di atas, teori
'neuro-hemodinamik' menyatakan bahwa kepatuhan ventrikel secara tidak langsung diubah
oleh peningkatan tiba-tiba tekanan sistemik dan pulmonal setelah cedera SSP. Dalam studi
awal oleh Sarnoff dan Sarnoff, peningkatan substansial tekanan aorta dan pulmonal diamati
setelah injeksi trombin ke magna intracisterna anjing dan kelinci [35]. Para penulis mencatat
bahwa setelah lonjakan simpatik, ventrikel kiri telah mencapai ambang batas workfailure
dan gagal memompa secara efektif terhadap tekanan sistemik. Sebuah translokasi aliran
darah dari sirkulasi sistemik yang sangat resisten ke sirkuit paru resistensi rendah kemudian
terjadi, yang mengarah ke bentuk hidrostatik edema paru. Peningkatan ukuran atrium kiri
dan vena pulmonal pada hewan didokumentasikan dengan baik dalam penelitian ini, dan
kemudian penulis menciptakan istilah "edema paru neuro-hemodinamik" [35]. Beberapa
model hewan lainnya telah mendokumentasikan elevasi yang besar pada tekanan atrium
kiri, sistemik dan pulmonal yang terkait dengan NPE [18,22,36]. Satu studi menginduksi
kadar ICP pada simpanse. Semua hewan mengembangkan hipertensi sistemik, namun
hanya mereka yang memiliki peningkatan tekanan atrium kiri yang nyata dan penurunan
output jantung mengembangkan edema paru [18].

Blast theory
The neuro-cardiac and neuro-hemodynamic theories outlined above both suggest that alterations
in hydrostatic and Starling forces are central to the formation of pulmonary edema following
CNS injury. Although hydrostatic pressures may play a role in the pathogenesis, this mechanism
alone cannot explain the presence of red blood cells (RBCs) and protein observed in the alveolar
fluid in many NPE subjects [37,38]. The exudative properties of the pulmonary fluid imply that
alterations in vascular permeability play a role in the pathogenesis of NPE. In order to explain
the presence of both hydrostatic factors and vascular leak, Theodore and Robin introduced the
"blast theory" of NPE [39]. Similar to the neuro-hemodynamic model, the "blast theory" posits
that the severe abrupt increases in systemic and pulmonary pressures following the
catecholamine surge result in a net shift of blood volume from the systemic circulation to the low
resistance pulmonary circulation. This increase in pulmonary venous pressure leads to the
development of transudative pulmonary edema. The "blast theory" further posits that the acute
rise in capillary pressure induces a degree of barotrauma capable of damaging the capillary-
alveolar membrane. The structural damage to the pulmonary endothelium ultimately leads to
vascular leak and persistent protein-rich pulmonary edema [39]. The pulmonary edema
according to the "blast theory" is thus the result of two mechanisms which act synergistically: A
high-pressure hydrostatic influence and pulmonary endothelial injury. Several pre-clinical
models support this mechanism [40,41]. Maron showed that barotrauma and vascular
permeability occurred when pulmonary pressures exceeded 70 torr following CNS injury in dogs
[40]. In another study, EVLW was observed when pulmonary artery pressures reached 25 torr or
greater in rabbits [41]. The authors concluded that some degree of pulmonary hypertension is
required for the development of pulmonary edema, and that the degree of permeability is
"pressure dependent" [41].
Teori neuro-jantung dan neuro-hemodinamik yang diuraikan di atas keduanya menunjukkan
bahwa perubahan pada kekuatan hidrostatik dan Starling sangat penting bagi pembentukan
edema paru setelah cedera SSP. Meskipun tekanan hidrostatik dapat berperan dalam
patogenesis, mekanisme ini sendiri tidak dapat menjelaskan adanya sel darah merah (RBC)
dan protein yang diamati pada cairan alveolar di banyak subyek NPE [37,38]. Sifat eksudatif
cairan paru menyiratkan bahwa perubahan permeabilitas vaskular berperan dalam
patogenesis NPE. Untuk menjelaskan adanya faktor hidrostatik dan kebocoran vaskular,
Theodore dan Robin memperkenalkan "teori ledakan" NPE [39]. Serupa dengan model
neuro-hemodinamik, "teori ledakan" menunjukkan bahwa peningkatan tekanan sistemik dan
pulmonal yang parah tiba-tiba mengikuti gelombang katekolamin menghasilkan pergeseran
volume darah dari sirkulasi sistemik ke sirkulasi paru resistensi rendah. Peningkatan tekanan
vena pulmonal ini menyebabkan perkembangan edema paru transudatif. "Teori ledakan"
selanjutnya menyatakan bahwa kenaikan tekanan kapiler akut menginduksi derajat
barotrauma yang mampu merusak membran alveolar kapiler. Kerusakan struktural pada
endothelium paru akhirnya menyebabkan kebocoran vaskular dan edema paru yang kaya
protein padat [39]. Edema paru sesuai dengan "teori ledakan" adalah hasil dari dua
mekanisme yang bertindak secara sinergis: Pengaruh hidrostatik tekanan tinggi dan cedera
endotel paru. Beberapa model pra-klinis mendukung mekanisme ini [40,41]. Maron
menunjukkan bahwa barelrauma dan permeabilitas vaskular terjadi ketika tekanan paru-
paru melebihi 70 torr setelah cedera SSP pada anjing [40]. Dalam studi lain, EVLW diamati
ketika tekanan arteri pulmonal mencapai 25 torr atau lebih pada kelinci [41]. Penulis
menyimpulkan bahwa beberapa tingkat hipertensi pulmonal diperlukan untuk
pengembangan edema paru, dan tingkat permeabilitasnya adalah "tekanan tergantung"
[41].

Theodore and Robin in the "blast theory" acknowledged that it is rare to document elevated
systemic and pulmonary pressures in human cases of NPE. According to their theory, this can be
explained by the fact that the sympathetic surge and subsequent hemodynamic instability occurs
at the time of the inciting event when hemodynamic monitoring is rare [39]. During the later
stages of NPE, systemic and pulmonary pressures can return to normal, whereas the endothelial
injury and vascular leak may persist [39]. A few case reports have been able to document this
sequence of events in human subjects, lending credence to the "blast theory". One case study
described a patient who had hemodynamic monitoring at the time of a seizure that led to NPE.
Within minutes of the seizure, marked increases in systemic, pulmonary and pulmonary artery
occlusion pressures were recorded. The hemodynamics quickly normalized and two hours later,
pulmonary edema developed, which was determined to be high in protein content [37]. In
another case report of a patient with an intracranial hemorrhage, extreme increases in systemic
and mean pulmonary pressures (410/200 mmHg and 48 mmHg, respectively) lasted 4 minutes.
This was followed by a dramatic decrease in the patient's oxygen levels. The patient's pulmonary
edema did not clear on radiograph for 72 hours following the last episode of transient systemic
and pulmonary hypertension. The authors concluded that persistent vascular leak was the basis
for these findings [42].
Theodore dan Robin dalam "teori ledakan" mengakui bahwa jarang mendokumentasikan
tekanan sistemik dan paru yang meningkat pada kasus manusia NPE. Menurut teori mereka,
ini dapat dijelaskan oleh fakta bahwa lonjakan simpatik dan ketidakstabilan hemodinamik
berikutnya terjadi pada saat kejadian menghasut ketika pemantauan hemodinamik jarang
terjadi [39]. Selama tahap selanjutnya dari NPE, tekanan sistemik dan pulmonal dapat
kembali normal, sedangkan cedera endotel dan kebocoran vaskular mungkin berlanjut [39].
Beberapa laporan kasus telah mampu mendokumentasikan urutan peristiwa ini dalam
subjek manusia, memberikan kepercayaan pada teori ledakan. Satu studi kasus
menggambarkan pasien yang melakukan pemantauan hemodinamika pada saat kejang
yang menyebabkan NPE. Dalam beberapa menit kejang, ditandai dengan adanya tekanan
oklusi arteri, paru-paru dan pulmonal. Hemodinamika dengan cepat dinormalisasi dan dua
jam kemudian, edema paru berkembang, yang bertekanan tinggi kandungan protein [37].
Dalam kasus lain, laporan pasien dengan perdarahan intrakranial, peningkatan tekanan paru
sistemik dan rata-rata yang ekstrem (410/200 mmHg dan 48 mmHg) berlangsung 4 menit.
Hal ini diikuti oleh penurunan dramatis pada tingkat oksigen pasien. Edema paru pasien
tidak jelas pada radiografi selama 72 jam setelah episode terakhir dari hipertensi sistemik
dan pulmonal transien. Penulis menyimpulkan bahwa kebocoran vaskular persisten
merupakan dasar untuk temuan ini [42].

Pulmonary venule adrenergic hypersensitivity

Many reports of NPE fail to consistently demonstrate the hypertensive surges and changes in left
atrial pressures as described in the theories above. This suggests that systemic hypertension and
its effect on cardiac contractility may not always contribute to the development of NPE. An
alternative hypothesis is that the massive sympathetic discharge following CNS
injury directly affects the pulmonary vascular bed, and that the edema develops regardless of any
systemic changes. We refer to this as the 'pulmonary venule adrenergic hypersensitivity' theory.
This concept of neurally induced changes to endothelial integrity is made plausible by the fact
that pulmonary vascular beds contain α- and β-adrenergic receptors [43]. In a well designed
study by McClellan et al. [44], CNS injury and elevated ICP was induced in dogs by cisternal
saline infusion. Autonomic activation following the CNS insult was evidenced by an increase in
systemic and pulmonary vascular pressures. The pulmonary edema developed in the dogs and
was proven to be exudative in content. When the same degree of pulmonary hypertension and
increased left atrial pressure was induced with a left atrial balloon in the control group,
pulmonary edema did not develop. The authors concluded that neurologic insult resulted in acute
lung injury (ALI), which could not be explained by hemodynamic changes, but rather
by direct neurological influences on the pulmonary endothelium [44]. In other studies of
intracranial lesions induced in sheep, pulmonary edema developed despite normal or only mildly
increased left atrial and systemic pressures [38,45]. In one of these studies, α-adrenergic
blockade prevented the formation of pulmonary edema with little systemic effect, further
supporting the role of direct adrenergic influence [38]. In human examples, continuous cardiac
monitoring during the development of NPE in patients with SAH and brain tumor resection
failed to demonstrate preceding hemodynamic changes [46-48]. These findings suggest that
isolated pulmonary venoconstriction or endothelial disruption following CNS injury may be
responsible for the formation of pulmonary edema [47,48].

Banyak laporan tentang NPE gagal untuk secara konsisten menunjukkan lonjakan hipertensi
dan perubahan tekanan atrium kiri seperti yang dijelaskan dalam teori di atas. Hal ini
menunjukkan bahwa hipertensi sistemik dan pengaruhnya terhadap kontraktilitas jantung
mungkin tidak selalu berkontribusi terhadap perkembangan NPE. Hipotesis alternatif adalah
bahwa pelepasan simpatik yang besar setelah cedera SSP secara langsung mempengaruhi
ranjang vaskular pulmonal, dan edema berkembang terlepas dari perubahan sistemik
apapun. Kami menyebut ini sebagai teori 'hiperensitifitas venula venula adenenergi'. Konsep
perubahan yang disebabkan oleh neurik terhadap integritas endotel ini dibuat masuk akal
oleh fakta bahwa tempat tidur vaskular paru mengandung reseptor α dan β-adrenergik [43].
Dalam sebuah studi yang dirancang dengan baik oleh McClellan dkk. [44], cedera SSP dan
ICP yang meningkat diinduksi pada anjing dengan infus salin kismis. Aktivasi otonom setelah
penghinaan SSP dibuktikan dengan peningkatan tekanan vaskular sistemik dan pulmonal.
Edema paru berkembang pada anjing dan terbukti eksudatif dalam kandungan. Bila tingkat
hipertensi pulmoner yang sama dan peningkatan tekanan atrium kiri diinduksi dengan balon
atrium kiri pada kelompok kontrol, edema paru tidak berkembang. Penulis menyimpulkan
bahwa penghinaan neurologis mengakibatkan cedera paru akut (ALI), yang tidak dapat
dijelaskan oleh perubahan hemodinamik, melainkan oleh pengaruh neurologis langsung
pada endothelium paru [44]. Dalam studi lain tentang lesi intrakranial yang diinduksi pada
domba, edema paru dikembangkan meskipun secara normal atau hanya sedikit
meningkatkan tekanan atrium dan sistemik kiri [38,45]. Dalam salah satu penelitian ini,
blokade α-adrenergik mencegah pembentukan edema paru dengan sedikit efek sistemik,
yang selanjutnya mendukung peran pengaruh adrenergik langsung [38]. Dalam contoh
manusia, pemantauan jantung terus menerus selama pengembangan NPE pada pasien
dengan SAH dan reseksi tumor otak gagal menunjukkan perubahan hemodinamik
sebelumnya [46-48]. Temuan ini menunjukkan bahwa venoconstriction paru terisolasi atau
gangguan endotel setelah cedera SSP mungkin bertanggung jawab atas pembentukan
edema paru [47,48].

Clinical characteristics
Two distinct clinical forms of NPE have been described. The early form of NPE is most common
and is characterized by the development of symptoms within minutes to hours following
neurologic injury. In contrast, the delayed form develops 12 to 24 hours after the CNS insult [5].
The abrupt nature of respiratory distress is an impressive feature of NPE. Typically, the patient
becomes acutely dyspneic, tachypneic, and hypoxic within minutes. Pink, frothy sputum is
commonly seen and bilateral crackles and rales are appreciated on auscultation. Sympathetic
hyperactivity is common and the patient may be febrile, tachycardic, and hypertensive, and
leukocytosis may occur. Chest radiograph will reveal bilateral hyperdense infiltrates consistent
with acute respiratory distress syndrome (ARDS) [5]. Symptoms often spontaneously resolve
within 24 to 48 hours; however, in patients with ongoing brain injury and elevated ICP, the NPE
often persists.
Dua bentuk klinis NPE yang berbeda telah dijelaskan. Bentuk awal NPE paling umum dan
ditandai dengan perkembangan gejala dalam beberapa menit sampai beberapa jam setelah
cedera neurologis. Sebaliknya, bentuk tertunda berkembang 12 sampai 24 jam setelah
penghinaan SSP [5]. Sifat mendadak dari gangguan pernafasan adalah ciri khas NPE.
Biasanya, pasien menjadi akut dyspneic, tachypneic, dan hypoxic dalam hitungan menit.
Pink, sputum berbusa biasanya terlihat dan kerutan bilateral dan rales dihargai pada
auskultasi. Hiperaktivitas simpatis umum terjadi dan pasien mungkin demam, takikardik,
dan hipertensi, dan leukositosis mungkin terjadi. Radiografi dada akan mengungkapkan
infiltrat hipertensi bilateral yang konsisten dengan sindrom distres pernafasan akut (ARDS)
[5]. Gejala sering diatasi secara spontan dalam waktu 24 sampai 48 jam; Namun, pada
pasien dengan cedera otak dan ICP yang sedang naik daun, NPE sering terjadi.

Differential diagnosis
Because alternative conditions are common, NPE is a difficult diagnosis to establish. The
diagnosis of 'pure' NPE is a diagnosis of exclusion and, by traditional definition, requires
documentation of non-cardiogenic pulmonary edema in the setting of neurological injury.
Aggressive fluid hydration is frequently administered to neurologically injured patients. Large
volume resuscitation is especially common in SAH patients suspected of having vasospasm, thus
rendering these patients at risk for volume overload and pulmonary edema [9]. Aspiration
pneumonia is also common among CNS injured patients and must be excluded. Aspiration
pneumonia differs from NPE by the presence of clinical clues (vomiting, gastric contents in the
oropharynx, witnessed aspiration) and the distribution of alveolar disease in dependent portions
of the lungs. In contrast, NPE is characterized by a frothy, often blood-tinged sputum and more
centrally distributed alveolar disease on radiograph [5].
Karena kondisi alternatif yang umum, NPE adalah diagnosis yang sulit untuk ditetapkan.
Diagnosis NPE 'murni' adalah diagnosis pengecualian dan, menurut definisi tradisional,
memerlukan dokumentasi edema paru non-kardiogenik dalam pengaturan cedera
neurologis. Hidrasi cairan agresif sering diberikan pada pasien yang mengalami cedera
neurologis. Resusitasi volume besar sangat umum terjadi pada pasien SAH yang dicurigai
mengalami vasospasme, sehingga membuat pasien ini berisiko kelebihan volume dan
edema paru [9]. Pneumonia aspirasi juga umum terjadi pada pasien yang cedera SSP dan
harus dikeluarkan. Pneumonia aspirasi berbeda dengan NPE dengan adanya petunjuk klinis
(muntah, kandungan lambung pada orofaring, aspirasi yang disaksikan) dan distribusi
penyakit alveolar pada bagian paru-paru yang bergantung. Sebaliknya, NPE ditandai oleh
sputum yang berbusa, sering dilumuri darah dan penyakit alveolar terdistribusi secara
terpusat pada radiografi [5].

Previous treatment in humans

Although numerous case reports have described the various precipitating CNS insults and
clinical scenarios associated with NPE, few studies have identified specific treatment modalities
for this condition. The management of NPE to date has largely focused on treating the
underlying neurologic condition in order to quell the sympathetic discharge responsible for
causing the lung injury. Treatment efforts to reduce ICP, including decompression and clot
evacuation, osmotic diuretics, anti-epileptics, tumor resection, and steroids have all been
associated with improvements in oxygenation [3,16,28]. Pharmacological intervention,
specifically anti-α-adrenergic agents, which potentially interrupt the vicious cycle of
hemodynamic instability and subsequent respiratory failure, has shown promise in animal
models. However, there are few reports documenting its use in humans. In one case report, a
patient with TBI developed sudden onset of bilateral infiltrates and hypoxia in the setting of
elevated blood pressures, sinus tachycardia and normal central venous pressure (CVP). This
patient was successfully treated with the α-blocking agent, chlorpromazine, as evidenced by
rapid improvement in oxygenation and hemodynamics; catecholamine levels were not measured
in this report [49].
Meskipun banyak laporan kasus telah menggambarkan berbagai penghinaan SSP yang
memicu pencetus dan skenario klinis yang terkait dengan NPE, beberapa penelitian telah
mengidentifikasi modalitas pengobatan spesifik untuk kondisi ini. Pengelolaan NPE sampai
saat ini sebagian besar berfokus pada penanganan kondisi neurologis yang mendasarinya
untuk mengatasi pelepasan simpatik yang menyebabkan cedera paru-paru. Upaya
pengobatan untuk mengurangi ICP, termasuk evakuasi dekompresi dan klem, diuretik
osmotik, anti-epilepsi, reseksi tumor, dan steroid semuanya telah dikaitkan dengan
perbaikan oksigenasi [3,16,28]. Intervensi farmakologis, khususnya agen anti-α-adrenergik,
yang berpotensi mengganggu siklus setan ketidakstabilan hemodinamik dan kegagalan
pernafasan berikutnya, telah menunjukkan harapan pada model hewan. Namun, ada
beberapa laporan yang mendokumentasikan penggunaannya pada manusia. Dalam satu
laporan kasus, seorang pasien dengan TBI mengembangkan onset infiltrat bilateral dan
hipoksia secara tiba-tiba dalam pengaturan tekanan darah tinggi, sinus takikardia dan
tekanan vena sentral normal (CVP). Pasien ini berhasil diobati dengan agen penghambat α,
chlorpromazine, yang terbukti dengan peningkatan oksigenasi dan hemodinamika yang
cepat; Tingkat katekolamin tidak diukur dalam laporan ini [49].

Proposed clinical framework, diagnostic criteria, and management of NPE

NPE is an exotic form of pulmonary edema and can be considered a form of ARDS per the
consensus definition. While all cases of NPE follow a CNS event and likely originate from
sympathetic activation, downstream effects on the cardiopulmonary system vary. Some patients
may have direct myocardial injury resulting in left ventricular failure and pulmonary edema.
Others develop pulmonary edema from a non-cardiogenic mechanism as described in the
pulmonary venule hypersensitivity models. Differentiating between 'cardiogenic involvement'
and 'non-cardiogenic' mechanisms is essential in the clinical realm, as there are clear therapeutic
implications. In order for this clinical entity to be effectively studied and treated, a definition that
captures a subset of patients with NPE who may benefit from sympathetic interference would be
helpful. We, therefore, propose the following diagnostic criteria for this subset of NPE: 1)
Bilateral infiltrates; 2) PaO2/FiO2 ratio < 200; 3) no evidence of left atrial hypertension; 4)
presence of CNS injury (severe enough to have caused significantly increased ICP); 5) absence
of other common causes of acute respiratory distress or ARDS (e.g., aspiration, massive blood
transfusion, sepsis). For those patients who meet the above NPE criteria, measurement of serum
catecholamines may be helpful. In those patients in whom blood pressure permits, a trial of an α-
adrenergic blocking agent, such as phentolamine, can be considered.
NPE adalah bentuk edema paru eksotis dan dapat dianggap sebagai bentuk ARDS per
definisi konsensus. Sementara semua kasus NPE mengikuti acara CNS dan
kemungkinan berasal dari aktivasi simpatik, efek hilir pada sistem kardiopulmoner
bervariasi. Beberapa pasien mungkin mengalami luka miokard langsung akibat
kegagalan ventrikel kiri dan edema paru. Yang lain mengembangkan edema paru dari
mekanisme non-kardiogenik seperti yang dijelaskan pada model hiperensitifitas venula
paru. Membedakan antara 'keterlibatan kardiogenik' dan mekanisme 'non-kardiogenik'
sangat penting di ranah klinis, karena ada implikasi terapeutik yang jelas. Agar entitas
klinis ini dipelajari dan dirawat secara efektif, definisi yang menangkap subset pasien
dengan NPE yang mungkin mendapat manfaat dari gangguan simpatik akan sangat
membantu. Oleh karena itu, kami mengusulkan kriteria diagnostik berikut untuk subset
NPE ini: 1) infiltrat bilateral; 2) rasio PaO2 / FiO2 <200; 3) tidak ada bukti hipertensi
atrium kiri; 4) adanya luka SSP (cukup parah sehingga menyebabkan ICP meningkat
secara signifikan); 5) tidak adanya penyebab umum lainnya dari gangguan pernafasan
akut atau ARDS (mis., Aspirasi, transfusi darah masif, sepsis). Bagi pasien yang
memenuhi kriteria NPE di atas, pengukuran katekolamin serum mungkin membantu.
Pada pasien yang diberi tekanan darah, percobaan agen pemblokir α-adrenergik,
seperti phentolamine, dapat dipertimbangkan
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Conclusion
Despite decades of scientific experiments and case descriptions, the diagnosis and management
of NPE remains controversial and challenging. Although this syndrome has been described for
over a millennium, it remains underdiagnosed and underappreciated. The exact pathophysiology
of NPE is still debated and the wide variety of clinical situations in which it occurs can obfuscate
diagnosis. The sudden development of hypoxemic respiratory failure following a catastrophic
CNS event, which cannot be attributed to other causes of ARDS, is the only universally agreed
upon characteristic of NPE. A common denominator in all cases of NPE is likely a surge in
endogenous serum catecholamines that may result in changes in cardiopulmonary hemodynamics
and Starling forces. It appears that the specific clinical manifestations of this surge may vary
depending on the individual circumstance. In some patients, cardiac dysfunction may
predominate; in others, capillary leak is the primary manifestation. These patterns have obvious
implications for the diagnosis and treatment of individual cases, including cardiac evaluation,
fluid management, and choice of inotropic or vasoactive substances such as α-adrenergic
blockade.
dari NPE tetap kontroversial dan menantang. Meskipun sindrom ini telah digambarkan
selama lebih dari satu milenium, namun sindrom ini masih kurang terdiagnosis dan kurang
mendapat penghargaan. Patofisiologi yang tepat dari NPE masih diperdebatkan dan
berbagai situasi klinis di mana hal itu terjadi dapat menyamarkan diagnosis. Perkembangan
tiba-tiba kegagalan pernapasan hipoksemik setelah kejadian SSP yang dahsyat, yang tidak
dapat dikaitkan dengan penyebab ARDS lainnya, adalah satu-satunya karakteristik NPE yang
disepakati secara universal. Sebuah common denominator dalam semua kasus NPE
kemungkinan merupakan lonjakan katekolamin serum endogen yang dapat menyebabkan
perubahan hemodinamik kardiopulmoner dan kekuatan Starling. Tampaknya manifestasi
klinis spesifik dari gelombang ini dapat bervariasi, tergantung pada keadaan individu. Pada
beberapa pasien, disfungsi jantung bisa terjadi; Pada orang lain, kebocoran kapiler
merupakan manifestasi utama. Pola ini memiliki implikasi yang jelas untuk diagnosis dan
perawatan kasus individual, termasuk evaluasi jantung, penanganan cairan, dan pilihan zat
inotropik atau vasoaktif seperti blokade α-adrenergik.

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Abbreviations
ALI: acute lung injury; ARDS: acute respiratory distress syndrome; CNS: central nervous
system; CPP: cerebral perfusion pressure; CSF: cerebrospinal fluid; CVP: central venous
pressure; EKG: electrocardiogram; EVLW: extravascular lung water; ICP: intracranial pressure;
NPE: neurogenic pulmonary edema; PAOPs: pulmonary artery occlusion pressures; PVR:
pulmonary vascular resistance; Qs/Qt: pulmonary shunt; RBCs: red blood cells; SAH:
subarachnoid hemorrhage; TBI: traumatic brain injury; VD: dead space.
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Competing interests
The authors declare that they have no competing interests.
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Note
This article is one of eleven reviews selected from the Annual Update in Intensive Care and
Emergency Medicine 2012 (Springer Verlag, DOI: 10.1007/978-3-642-25716-2) and co-
published as a series in Critical Care. Other articles in the series can be found online
at http://ccforum.com/series/annualupdate2012. Further information about the Annual Update in
Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901.