Neurogenic pulmonary edema: Pathogenesis, clinical picture, and clinical management

Neurogenic Pulmonary Edema: Pathogenesis, Clinical Picture, and Clinical Management Grigore Toma, Valery Amcheslavsky, Vladimir Zelman, Douglas S. DeWitt, and Donald S. Prough

C

urrent clinical and experimental data leave little doubt that the injured brain is highly vulnerable to secondary ischemic insults. Many insults, such as hypoxemia and hypotension, occur after patients have entered the medical care system. Consequently, prevention, early diagnosis, and effective treatment of hypoxemia and hypotension in patients with acute severe brain injury should help to limit personal, social, and economic costs. Severe brain injury disrupts multiple respiratory functions, depending on the site and extent of the neurological injury (Table 1). Importantly, each of these respiratory complications as well as other medical sequelae can contribute significantly to short- and long-term morbidity, disability, and mortality related to severe brain injury. Familiarity with important respiratory complications is an integral part of the management of critically ill patients with brain injury.1 The development of pulmonary edema in the setting of an acute neurologic event is termed neurogenic pulmonary edema (NPE) and was first described in 1908 by Shanahan in patients with epilepsy who died of postictal respiratory distress.2 Acute NPE is an uncommon, perhaps inconsistently recognized, clinical entity that can occur after virtually any form of insult to the central nervous system (CNS). Most commonly, NPE follows subarachnoid hemorrhage (SAH),3-5 but the syndrome is also associated with other acute neurologic insults such as traumatic brain injury,6 seizures,2,7 stroke,8 intracranial hemorrhage,9 infection, induction of anesthesia,10 and electroconvulsive therapy.11 CLINICAL SYNDROME

The clinical presentation of NPE is often abrupt and dramatic but resembles other forms of acute pulmonary edema. Often, the acuteness of onset of respiratory failure is the primary aspect that suggests the diagnosis. Colice12 described 2 patterns of evolution of NPE. In the early or classic form, which occurs most commonly, pulmonary edema develops within minutes to a few hours after an

acute CNS insult. The delayed form of NPE develops more slowly, progressing over 12 hours to several days after the precipitating event.12-14 Most patients present with symptoms of respiratory failure soon after the acute neurologic event (Table 2). The most common presenting signs of NPE are dyspnea, tachypnea, tachycardia, and cyanosis. One of the hallmark characteristics, though evident in only about one third of patients, is the development of pink, frothy sputum, accompanied by crackles, rales, and fever. Chest radiography demonstrates diffuse bilateral alveolar and interstitial pulmonary infiltrates (“whiteout”). The diagnosis is supported by marked hypoxemic respiratory failure and pulmonary edema with low pulmonary arterial occlusion pressure (PAOP). PAOP may be increased shortly after onset,15 but is usually normal after several hours,9,16 thereby leading many clinicians to consider NPE a form of noncardiogenic pulmonary edema. Other causes of acute respiratory failure that must be excluded include congestive heart failure, fluid overload, foreign body aspiration, gastric aspiration, and barotrauma.17 In the delayed form of NPE, the clinical presentation typically includes gradual development over several days of hypoxemia, chest radiographic abnormalities, and dyspnea. Distinguishing the delayed form of NPE from other etiologies in patients with acute neurologic insults can be challenging. In

From the Department of Anesthesiology, the University of Texas Medical Branch, Galveston, TX, USA; the Department of Neuroscience ICU, the Burdenko Neurosurgical Institute, Moscow, Russia; and the Department of Anesthesiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Address requests for reprints to Dr. Grigore Toma, Department of Anesthesiology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555-0830. E-mail: [email protected]. © 2004 Elsevier Inc. All rights reserved. 0277-0326/04/2303-0000$30.00/0 doi:10.1053/j.sane.2004.01.014

Seminars in Anesthesia, Perioperative Medicine and Pain, Vol 23, No 3 (September), 2004: pp 221-229

221

222

TOMA ET AL

Table 1. Respiratory Complications of Severe Brain Injury Impaired chest wall mechanics and diaphragm function Abnormal breathing patterns Cheyne–Stokes respiration Central neurogenic hyperventilation Apneustic breathing Ataxic breathing Hypoventilation or apnea Pulmonary embolism Dysphagia, aspiration, and pneumonia Neurogenic pulmonary edema

intubated critically ill patients, atelectasis or pneumonia can produce similar hypoxemia, chest radiographic abnormalities, and dyspnea. In addition, the characteristic pattern of pulmonary edema may be less evident in portable chest radiographs. Although NPE should be suspected in any patient in whom symptoms of respiratory failure follow an acute neurologic event, the diagnosis of NPE remains one of exclusion. Therefore, the incidence of NPE is difficult to establish; given its nonspecific presentation, it is likely that the diagnosis is missed, especially in the later onset form, but also that it is applied incorrectly to patients with other reasons for respiratory compromise. The physician faced with the difficult task of caring for a patient with a combination of acute neurologic disease and respiratory complications must balance several competing priorities. As an example of the difficulties of diagnosing and treating this lifethreatening condition, we report a fatal case of NPE that was triggered by an episode of increased intracranial pressure (ICP). CASE REPORT

A 9-year-old female, 48 hours after a motorvehicle accident, was admitted to the Neuroscience Intensive Care Unit (ICU) of the Burdenko Neurosurgical Institute of the Russian Academy of Medical Sciences in Moscow, Russia. Head computed tomography (CT) showed right frontal and left temporal contusions and signs of intracranial hypertension (compression of lateral ventricles, basal cisterns, and subarachnoidal spaces). On neurological examination, the patient was found to be in a coma (Glasgow Coma Scale score 5) with signs of brainstem dysfunction, ie, increased muscle tonus with decerebrate posture, absence of pupilary and corneal reflexes, paralysis of upward gaze reflex, hyperthermia to 40°C, and severe he-

modynamic instability. The patient was intubated and ventilated with controlled mechanical ventilation. The ventilator was set at a tidal volume of 400 mL, FiO2 of 0.30 and positive end-expiratory pressure (PEEP) of 5 cm H2O. Arterial blood gas levels were the following: pH 7.55; PaCO2 42.5 mm Hg; PaO2 97.7 mm Hg; base excess (BE) ⫹20.4 mEq/L; and oxygen saturation (SaO2) 98%. ICP was less than 20 mm Hg. Jugular venous bulb sampling (right jugular vein) yielded the following findings: pH 7.44; jugular venous bulb PCO2 (PjvCO2) 51.8 mm Hg; PjvO2 32.4 mm Hg; SjvO2 56.4%. The cerebral arterio-venous difference of glucose was 0.1 mmol/L. The electrolytes were within normal limits. Pharmacologic therapy included intravenous fluid support, mannitol, antibiotics, and sedation with diazepam and morphine. By the third post-trauma day, hyperthermia had improved (core temperature, 37.5°C). Arterial blood pressure (ABP) remained near 110/70 mm Hg and heart rate was 100 to 140 beats per minute. Toward the end of day 3 (⬃70 hours after trauma), there was a spontaneous increase of ICP from 12 to 50 mm Hg, with subsequent severe cardiovascular instability (ABP decreased to 60/30 mm Hg) and hypoxemia (Fig 1). One hour 15 minutes later, a second episode of intracerebral hypertension occurred. Oxygen saturation measured by pulse oximetry gradually decreased from 98% to 80% to 70%. On physical examination, the patient was hypoxemic and pink frothy sputum was suctioned through the endotracheal tube. Pulmonary auscultation revealed bilateral diffuse crackles. The clinical diagnosis of acute NPE was made and supported by chest radiography, which demonstrated diffuse bilateral infiltrates. Intensive therapy of acute pulmonary edema included loop diuretics (furosemide 40 mg), inotro-

Table 2. Common Symptoms and Signs of Neurogenic Pulmonary Edema Hypoxemia Dyspnea Tachypnea Pink frothy sputum Pulmonary crackles, rales Angina Tachycardia

Lung findings—bilateral, diffuse interstitial/alveolar Infiltrates (“whiteout”) Normal to high pulmonary artery wedge pressure ECG—signs of cardiac ischemia Cardiovascular instability Normal to high CK-MB, troponin Leukocytosis

NEUROGENIC PULMONARY EDEMA

223

Fig 1. Intracerebral hypertension (arrows 1 and 2) triggers the development of neurogenic pulmonary edema with a decrease in SpO2 from 98% to 70%. Note cardiovascular instability during these episodes.

pic support (dopamine 10 ␮g/kg/min), and 4 mg of morphine. FiO2 was increased from 0.3 to 1.0 and PEEP from 5 to 10 cm H2O. Despite aggressive therapy, the patient died 4 hours after onset of NPE. On autopsy, there were bilateral frontal skull fractures, traumatic SAH, hemorrhagic contusion of the right frontal and left temporal lobes, and diffuse cerebral edema with axial dislocation. The lungs were grossly edematous.

This case report illustrates the rapid onset of cardiopulmonary insufficiency in close temporal relationship to acute intracranial hypertension. PATHOGENESIS OF NPE

NPE is characterized by an increase in extravascular lung water in patients who have sustained a sudden change in neurologic condition. The mechanism by which NPE occurs is not clear.18 Possible

224

TOMA ET AL

Fig 2. Potential pathophysiological mechanisms of neurogenic pulmonary edema initiated by increased ICP. Acute brain injury can result in sympathetic activation that causes pulmonary edema and cardiac failure (ICP, intracranial pressure; LV, left ventricular).

pathophysiological mechanisms of NPE include alterations in capillary permeability, elevations in pulmonary venous hydrostatic pressure, or left ventricular dysfunction (Fig 2). Permeability Abnormalities

In both animal and human studies of NPE, the demonstration of elevated interstitial or alveolar fluid protein concentrations suggests that increased capillary permeability contributes to pulmonary edema.19,20 Increased permeability may be caused either by hydrostatic overdistension of the pulmonary capillaries or by direct neural influences on capillary permeability. Theodore and Robin21 advanced the “blast theory,” which proposes that a neurally induced, transient rise in pulmonary intravascular pressure, caused by a massive sympathetic surge, may damage the endothelium, causing protein-rich plasma to escape into the interstitial and alveolar spaces. The high protein content in the edema fluid supports the “blast theory.”21 Investigators have speculated that this “stress failure” of

the pulmonary capillaries resembles alveolar hemorrhage seen in galloping racehorses.22 In support of this theory, high intravascular pressures have been shown to damage pulmonary capillaries, and such high pressures can develop in animals during experimental NPE.23,24 In humans, elevated PAOP has been observed in a few cases.9,25 However, pulmonary edema can develop with normal PAOP, suggesting the possibility of a neuralmediated, pressure-independent influence on capillary permeability.3,26 It is important to note that the typical sequence of NPE would be one in which acute pulmonary edema unexpectedly occurs, after which both treatment and invasive monitoring are initiated. Consequently, the acute increase in PAOP or pulmonary arterial pressure could be resolved before hemodynamic data are obtained. Neurally and humorally mediated increases in sympathetic tone after CNS injury that lead to pulmonary venoconstriction with pulmonary capillary hypertension may cause endothelial damage and increased pulmonary capillary permeability.27 Consistent with this theory, NPE in-

NEUROGENIC PULMONARY EDEMA duced experimentally by infusion of epinephrine can be attenuated by ␣-adrenergic blocking agents.28 Hydrostatic Pulmonary Edema

Hydrostatically induced pulmonary edema can occur without endothelial damage. One possible sequence leading to NPE is acutely increased sympathetic tone that abruptly increases left ventricular afterload and causes intense venoconstriction, thereby elevating left ventricular filling pressures and inducing pulmonary capillary hypertension. This is consistent with the finding that cardiac filling pressures are normal in some patients with NPE and elevated in others. Active pulmonary venoconstriction can increase pulmonary capillary pressure and produce hydrostatic edema. In canine studies, induced intracranial hypertension resulted in pulmonary venoconstriction and hydrostatic pulmonary edema.29 In isolated lung models, induced intracranial hypertension resulted in venoconstriction and elevated resistance to pulmonary blood flow, perhaps due to increased circulating catecholamines, predominantly epinephrine.29,30 Pulmonary venoconstriction could result in increased capillary hydrostatic pressure that is reflected in increased pulmonary systolic and diastolic pressure but not in increased PAOP. During balloon occlusion, no flow would enter the occluded vascular segment and normal left atrial pressure would be measured. Such a mechanism could explain both the observed variance in pulmonary edema protein concentration in the presence of normal PAOP in patients with NPE. In a series of 12 patients with NPE, Smith27 observed that 7 of 12 patients apparently had a hydrostatic mechanism for NPE with edema fluid to plasma protein ratios ⬍0.65. Once again, it is important to note that pulmonary arterial catheterization after an acute episode of NPE could be too late to document increased PAOP. It is likely that a combination of factors in differing proportions produces NPE and that explains the differing clinical presentations. The role that adrenergic tone might play in the cardiac response of NPE is also potentially important. In experimental animal models, extreme sympathetic nervous system overactivity can generate acute hemodynamic derangements, acute left ventricular failure, and pulmonary edema. ␣-Adrenergic antagonists have been shown to prevent NPE.31

225 Other Possible Mechanisms

Various forms of noncardiac pulmonary edema have been explained on the basis of hypoxic pulmonary vasoconstriction leading to pulmonary hypertension, arterial wall rupture, and leakage of protein-rich fluid into the interstitium and alveoli.32 An alternative theory is that damaged arterial walls attract fibrin and platelets, which form thrombi and microemboli, producing pulmonary capillary hypertension, capillary rupture, and edema formation. Activated intravascular clotting or fibrinolysis may have an important role in NPE, as well as in other forms of noncardiac pulmonary edema.33 The clinical and pathologic features of NPE are quite similar to those of other forms of acute respiratory distress syndrome. Moss et al34,35 postulate that acute respiratory distress syndrome in many clinical situations has a common cerebral cause—the initiating trauma interferes with hypothalamic cellular metabolism, which leads to autonomically mediated increased pulmonary venular resistance. This condition results in increased capillary pressures and vascular congestion, interstitial and intraalveolar edema and hemorrhage, and right-to-left shunting. The transudate of plasma and resulting hyaline membrane formation inactivate surfactant and predispose to atelectasis. This is an attractive unifying theory to explain posttraumatic pulmonary insufficiency and acute respiratory distress syndrome, as well as the varied forms of noncardiac pulmonary edema such as NPE. MEDIATORS OF NPE

Although brain injury results in NPE in scattered clinical cases and in a variety of experimental models, the mechanisms through which CNS injury produces NPE are unclear. Experimental studies provide evidence for direct sympathetic mechanisms as well as circulating mediators. The high-pressure component of NPE is probably mediated both by circulating vasoactive agents and by direct stimulation of sympathetic nerves leading to pulmonary vessels. The pulmonary vasculature is richly innervated by sympathetic nerves, and stimulation of the stellate ganglion causes pulmonary venous and arterial spasm.34-39 Studies with isolated lung lobes have shown that a vasoactive agent, released into the venous circulation after CNS injury, is an important mediator of pulmonary hypertension.40 This agent is probably

226 a catecholamine, because ␣-adrenergic blockers inhibited its effect. Catecholamines increase dramatically within seconds of a variety of brain injuries.37,38,41 After SAH, the concentrations of epinephrine, norepinephrine, and dopamine increase almost immediately to 1,200, 145, and 35 times the normal limits, respectively.42 Furthermore, epinephrine can remain increased in the circulation for at least 10 days.43 This could explain why NPE can occur as much as 14 days after a CNS insult. After CNS insults, ␣-adrenergic blockers also prevent systemic hypertension, suggesting that increased circulating catecholamines are responsible for systemic as well as pulmonary and vascular constriction.44 A pulmonary vascular membrane permeability defect in NPE might be mediated by the increase in circulating catecholamines, release of noncatecholamine mediators after the massive ␣-adrenergic discharge, direct ␣-adrenergic effects on endothelial cells, or some alteration in ␤-adrenergic tone. ␣-Adrenergic blockers prevent changes in lymph protein clearance after intracranial hypertension and stellate ganglion stimulation, suggesting a catecholamine-mediated change in pulmonary endothelial permeability.45 The role of ␤-adrenergic tone in altering pulmonary endothelial permeability is unclear. ␤-Adrenergic agonists prevented experimental histamineinduced permeability abnormalities, but ␤-adrenergic antagonists seem to influence pulmonary transendothelial protein flux by changing vascular surface area.46,47 CNS Involvement

The specific neurologic loci or pathways that generate NPE remain conjectural and controversial, with somewhat contradictory animal data and limited human data. Based primarily on animal data, multiple “edemagenic” sites that have been postulated as the origin of the pathophysiologic process include the hypothalamus and several loci in the medulla oblongata.12 The posterior medulla, which forms the inferior aspect of the floor of the fourth ventricle, includes adrenergic areas 1 and 5 and the nucleus of the solitary tract. Nerve fibers pass from area 5 to the intermediolateral cell column of the thoracolumbar spinal cord (the site of sympathetic outflow) and from area 1 to the hypothalamus. In experimental animals, stimulation of these areas generated NPE.48

TOMA ET AL Clinical evidence suggesting specific anatomic sites has necessarily been anecdotal. Because NPE is extremely rare in patients with cervical spinal cord lesions, the CNS regions responsible for NPE are assumed to be supraspinal. Brain-imaging techniques provide evidence that derangements of the medulla (which contains the vasomotor center) contribute to NPE. Simon et al49 described a woman with multiple sclerosis who had recurrent pulmonary edema associated with a lesion in the posterior aspect of the rostral medulla involving the floor of fourth ventricle. Keegan and Lanier50 described a 21-year-old man who developed NPE in association with surgical resection of a perimedullary brain tumor. These anecdotal reports support the concept that medullary disease can generate NPE in humans, and that NPE can occur in these cases in the absence of systemic hypertension.50 By causing sympathetic activation, posterior hypothalamic lesions also can precipitate NPE in humans.51,52 In a series of 106 patients dying from SAH, 65 had hypothalamic lesions that had histological evidence of ischemia, microhemorrhages, massive hemorrhage, or a combination of ischemia and hemorrhage.53 The hypothalamus probably is part of an integrated response, also involving portions of the medulla, that initiates NPE. Several studies have shown that the hypothalamus, along with the nucleus tractus solitarius and ventrolateral medulla, plays an important role in regulating cardiovascular responses by the autonomic nervous system.54,55 CLINICAL MANAGEMENT OF NPE

There are no specific treatments for NPE, other than immediate management of such precipitating causes as intracranial hypertension or evacuation of intracranial space-occupying lesions. Maintenance of intentional hypocarbia, diuretics, and mannitol may also be helpful in controlling ICP, at least temporarily. Management of respiratory compromise is largely supportive and does not differ substantially from supportive care of acute respiratory failure caused by other factors. Respiratory support consists of various combinations of supplemental oxygen therapy, mechanical ventilation, judicious fluid management and, possibly, sodium nitroprusside, which may be useful for its ability to directly dilate peripheral and pulmonary vessels (Table 3).1,56,57 Care should be taken with the

NEUROGENIC PULMONARY EDEMA Table 3. Management of Patients with Neurogenic Pulmonary Edema Methods to control intracranial hypertension Position to improve cerebral venous return (neutral, head-up position) Avoiding drugs that increase ICP Diuretics: osmotic (mannitol, hypertonic saline); tubular (furosemide) Adequate ventilation: PaO2 ⬎100 mm Hg, PaCO2 35 mm Hg, hyperventilation on demand Optimize hemodynamics (MAP, CVP, PAOP, HR), maintain CPP Temperature control: avoid hyperthermia CSF drainage Improvement of oxygenation Oxygen supply: via nasal mask (6 L/min); if necessary, intubation (ventilation, PEEP ⬍4-8 cm H2O) Decreases pre- and afterload Vasodilators (nitroglycerine, sodium nitroprusside, blockers of ␣-adrenoreceptors) Diuretics: tubular (furosemide) Inotropic treatment ␤-adrenergic drugs: dobutamine

administration of sodium nitroprusside because of its potential for increasing ICP. Mechanical ventilation with PEEP rapidly improves both oxygenation and radiographic evidence of NPE. PEEP is titrated to attain an acceptable balance between systemic hemodynamics, arterial oxygenation, and FiO2. An assisted mode of ventilation, such as intermittent mandatory ventilation or pressure control ventilation, with PEEP is often sufficient to resolve NPE, and weaning can be achieved fairly rapidly in many patients.1 The use of PEEP to improve oxygenation may increase ICP in some patients with brain injury by increasing cerebral venous pressure. PEEP may further decrease cerebral perfusion pressure by decreasing cardiac output and ABP. Excessive reduction of cerebral perfusion pressure could aggravate neurologic injury. If PEEP is required for management of hypoxemia, ICP should be monitored concomitantly. PEEP therapy may need to be reduced or combined with head elevation if PEEP is associated with increasing ICP or neurological deterioration. In patients with considerable hemodynamic instability, assessment of cardiac function with pulmonary arterial catheterization, transesophageal echocardiography, or esophageal Doppler may help to guide therapy. Inotropic support may be necessary. Although massive release of cat-

227 echolamines in association with acute neurologic injuries may contribute to ventricular injury and NPE, the much smaller circulating levels associated with inotropic infusion may improve systemic hemodynamics and increase systemic oxygen delivery. For example, dobutamine improves cardiac contractility and decreases afterload, thereby maintaining cardiac output and potentially improving cerebral perfusion while reducing sympathetic tone.57 Theoretically, pharmacologic blockade of the sympathetic surge associated with some acute brain injuries should limit the occurrence and severity of NPE. Prophylactic ␣-blockade with phenoxybenzamine prevented death and pulmonary edema in rabbits infused with high doses of epinephrine.58 There are few data from clinical trials, but prophylactic combined ␣- and ␤-blockade with phentolamine and propranolol may reduce pulmonary and myocardial injury from catecholamines after SAH.59 However, clinical application of this information in patients with NPE is difficult. In many patients, the acute sympathetic surge will have passed by the time NPE is recognized, and sympathetic blockade would no longer be expected to be helpful. In other patients, systemic hypertension may be a response to intracranial hypertension, in which case the reduction in ABP without a reduction in ICP could lead to severe brain ischemia. In a subset of patients in whom severe systemic hypertension persists after control of intracranial hypertension, reduction of ABP is indicated but may not have any direct effect on the course of NPE. CONCLUSION

In patients with acute brain injury, NPE may cause life-threatening respiratory failure, developing either explosively or insidiously. Although the specific diagnosis in such patients may be elusive, NPE should be included in the differential diagnosis. Because of the extreme vulnerability of the injured brain to hypoxemia, immediate therapeutic interventions to improve systemic oxygenation are imperative. If possible, the precipitating intracranial event should be relieved by medical or surgical intervention. Management of ventilatory and hemodynamic support must include consideration of the effects of interventions on intracranial hemodynamics.

228

TOMA ET AL REFERENCES

1. Wijdicks EFM, Borel CO: Respiratory management in acute neurological illness. Neurology 50:11-20, 1998 2. Shanahan WT: Acute pulmonary edema as a complication of epileptic seizures. NY Med J 37:54-56, 1908 3. Mayer SA, Fink ME, Homma S, et al: Cardiac injury associated with neurogenic pulmonary edema following subarachnoid hemorrhage. Neurology 44:815-820, 1994 4. Ciongoli AK, Poser CM: Pulmonary edema secondary to subarachnoid hemorrhage. Neurology 22:867-870, 1972 5. Demling R, Riessen R: Pulmonary dysfunction after cerebral injury. Crit Care Med 18:768-774, 1990 6. Simmons RL, Martin AJ, Heisterkamp CD, et al: Respiratory insufficiency in combat casualities: II. Pulmonary edema following head injury. Ann Surg 170:39-44, 1969 7. Darnell JC, Jay SJ: Recurrent postictal pulmonary edema: A case report and review of the literature. Epilepsia 23:71-83, 1982 8. Cohen JA, Abraham E: Neurogenic pulmonary edema: A sequel of non-hemorrhagic cerebrovascular accidents. Angiology 27:280-292, 1976 9. Carlson RW, Schaeffer RJ, Michaels SG, et al: Pulmonary edema following intracranial hemorrhage. Chest 75:731-734, 1979 10. Braude N, Lundgrove T: Neurogenic pulmonary edema precipitated by induction of anaesthesia. Br J Anaesthesia 62: 101-103, 1989 11. Buisseret P: Acute pulmonary oedema following grand mal epilepsy and as a complication of electric shock therapy. Br J Ch Dis 71:194-198, 1982 12. Colice GL: Neurogenic pulmonary edema. Clin Chest Med 6:473-489, 1985 13. Fein IA, Rackow EC: Neurogenic pulmonary edema. Chest 81:318-320, 1982 14. Fisher A, Agoul–Nasr HT: Delayed nonfatal pulmonary edema following subarachnoid hemorrhage. J Neurosurg 51: 856-859, 1979 15. Simon RP, Bayne LL, Naughton MP: Left atrial pressure elevation recreates the altered lung lymph flow of seizures. J Appl Physiol 53:432-435, 1982 16. Touho H, Karasawa J, Shishido H, et al: Neurogenic pulmonary edema in the acute stage of hemorrhagic cerebrovascular disease. Neurosurgery 25:762-768, 1989 17. Ingram RH, Jr, Braunwald E: Dyspnea and pulmonary edema, in Fauci AS, Braunwald E, Isselbacher KJ, et al (eds): Harrison’s Principles of Internal Medicine, vol 1, 14th ed. New York, McGraw-Hill, 1998, pp 190-194 18. Malik A: Mechanisms of neurogenic pulmonary edema. Crit Res 57:1, 1985 19. Hoff JT, Nishimura M, Garcia-Uria J, et al: Experimental neurogenic pulmonary edema: I. The role of systemic hypertension. J Neurosurg 54:627-631, 1981 20. Kowalski ML, Didier A, Kaliner MA: Neurogenic inflammation in the airways: I. Neurogenic stimulation induces plasma protein extravasation into the rat airway lumen. Am Rev Respir Dis 140:101-109, 1989 21. Theodore J, Robin E: Speculations on neurogenic pulmonary edema. Am Rev Respir Dis 113:405, 1976 22. West JB, Mathieu–Costello O: Stress failure of pulmonary capillaries, in Crystal RG, West JB, Weibel ER, Barnes PJ

(eds): The Lung: Scientific Foundations, vol 2, 2nd ed. Philadelphia, Lippincott Raven, 1997, pp 1493-1501 23. Maron MB: Analysis of airway fluid protein concentration in neurogenic pulmonary edema. J Appl Physiol 62:470476, 1987 24. Johnston SC, Horn JK, Valente J, et al: The role of hypoventilation in a sheep model of epileptic sudden death. Ann Neurol 37:531-537, 1995 25. Wray NP, Nicotra MB: Pathogenesis of neurogenic pulmonary edema. Am Rev Respir Dis 118:783-786, 1978 26. Yabumoto M, Kuriyama T, Iwamoto M, et al: Neurogenic pulmonary edema associated with ruptured intracranial aneurysm: Case report. Neurosurgery 19:300-304, 1986 27. Smith WS, Matthay MA: Evidence for a hydrostatic mechanism in human neurogenic pulmonary edema. Chest 111: 1326-1333, 1997 28. Simon RP: Neurogenic pulmonary edema. Neurol Clin 11:309-323, 1993 29. Maron M, Dawson C: Pulmonary venoconstriction caused by elevated cerebrospinal fluid pressure in the dog. J Appl Physiol 49:73, 1980 30. Maron MB: Pulmonary vasoconstriction in a canine model of neurogenic pulmonary edema. J Appl Physiol 68:912918, 1990 31. Brasher RE, Ross JC: Hemodynamic effects of elevated cerebrospinal fluid pressure: Alterations with adrenergic blockade. J Clin Invest 49:1324-1333, 1970 32. Karliner JS: Noncardiogenic forms of pulmonary edema. Circulation 46:212-215, 1972 33. Singth I: High altitude pulmonary edema. Am Heart J 70:435-439, 1965 34. Moss G, Staunton C, Stein AA: Cerebral etiology of the shock lung syndrome. J Trauma 12:885-890, 1972 35. Moss G: The role of the central nervous system in shock: the centroneurogenic etiology of the respiratory distress syndrome. Crit Care Med 2:181-185, 1974 36. Richardson JB: Nerve supply to the lungs. Am Rev Respir Dis 119:785-799, 1979 37. Dauber IM, Weil JV: Lung injury edema in dogs: Influence of sympathetic ablation. J Clin Invest 72:1977-1986, 1983 38. Hakim TS, Van der Zee H, Malik AB: Effects of sympathetic nerve stimulation on lung fluid and protein exchange. J Appl Physiol 51:68-72, 1981 39. Chen HI, Lin JD, Liao JF: Participation of regional sympathetic outflows in the centrogenic pulmonary pathology. Am J Physiol 240:H109-H115, 1981 40. Maron MB, Davidson CA: Adrenal component to pulmonary hypertension induced by elevated cerebrospinal fluid pressure. J Appl Physiol 47:153-160, 1979 41. Beckman DL, Iams SG: Circulating catecholamines in cats before and after lethal head injury. Proc Soc Exp Biol Med 160:200-202, 1979 42. Graf CJ, Rossi NP: Catecholamine response to intracranial hypertension. J Neurosurg 49:862-868, 1978 43. Naredi S, Lambert G, Eden E, et al: Increased sympathetic nervous activity in patients with nontraumatic subarachnoid hemorrhage. Stroke 31:901-906, 2000 44. Bean JW, Beckman DL: Centrogenic pulmonary pathology in mechanical head injury. J Appl Physiol 27:807-812, 1969

NEUROGENIC PULMONARY EDEMA 45. Van der Zee H, Malik AB, Lee BC, et al: Lung fluid and protein exchange during intracranial hypertension and role of sympathetic mechanisms. J Appl Physiol 48:273-280, 1980 46. Persson CGA, Ekman M, Erjefalt I: Vascular anti-permeability effects of beta-receptor agonists and theophylline in the lung. Acta Pharmacol Toxicol 44:216-220, 1979 47. Minnear FL, Malik AB: Mechanisms of neurogenic pulmonary edema. Ann NY Acad Sci 384:169-190, 1982 48. Blessing WW, West MJ, Chalmers J: Hypertension, bradycardia, and pulmonary edema in the conscious rabbit after brainstem lesions coinciding with the A1 group of catecholamine neurons. Circ Res 49:849-958, 1981 49. Simon RP, Gean-Marton AD, Sandler JE: Medullary lesion inducing pulmonary edema: A magnetic resonance imaging study. Ann Neurol 30:727-730, 1991 50. Keegan MT, Lanier WL: Pulmonary edema after resection of a fourth ventricle tumor: Possible evidence for a medullamediated mechanism. Mayo Clinic Proc 74:264-268, 1999 51. Maire FW, Patton HD: Neural structures involved in the genesis of preoptic pulmonary edema, gastric erosions and behavior changes. Am J Physiol 184:345-350, 1956 52. Nathan MA, Reis DJ: Fulminating arterial hypertension with pulmonary edema from release of adrenomedullary cat-

229 echolamines after lesions of the anterior hypothalamus in the rat. Circ Res 37:226-235, 1975 53. Crompton MR: Hypothalamic lesions following the rupture of cerebral berry aneurysms. Brain 86:301-318, 1963 54. Loewy AD, McKellar S: The neuroanatomical basis of central cardiovascular control. Fed Proc 39:2495-2503, 1980 55. Sawchenko PE, Swanson LW: Central noradrenergic pathways for the integration of hypothalamic neuroendocrine and autonomic responses. Science 214:685-687, 1981 56. Cohn JN, Franciosa JA: Vasodilator therapy of cardiac failure. N Engl J Med 297:254-258, 1991 57. Knudsen F, Jensen HP, Petersen PL: Neurogenic pulmonary edema: treatment with dobutamine. Neurosurgery 29:269270, 1991 58. Siwadlowski W, Aravanis C, Worthen M, et al: Mechanisms of adrenalin pulmonary edema and its prevention by narcotics and autonomic blockers. Chest 57:554-557, 1970 59. Walter P, Neil-Dwyer G, Cruickshank JM: Beneficial effects of adrenergic blockade in patients with subarachnoid haemorrhage. BMJ 284:1661-1664, 1982