Malcolm LemyzeJihad Mallat

Understanding negative pressure pulmonaryedema

Received: 4 March 2014Accepted: 15 April 2014Published online: 6 May 2014

� The Author(s) 2014. This article ispublished with open access atSpringerlink.com

M. Lemyze and J. Mallat contributedequally to this work.

Electronic supplementary materialThe online version of this article(doi:10.1007/s00134-014-3307-7) containssupplementary material, which is availableto authorized users.

M. Lemyze ()) � J. MallatDepartment of Respiratory and Critical CareMedicine, Schaffner Hospital, 99 route de laBassee, 62300 Lens, Francee-mail: malcolmlemyze@yahoo.fr

J. MallatDepartment of Anesthesiology, SchaffnerHospital, Lens, France

Abbreviations

NPPE Negative pressurepulmonary edema

PE Pulmonary edemaUAO Upper airway obstructionICU Intensive care unitARDS Acute respiratory distress

syndromeNIV Noninvasive positive

pressure ventilation

Negative pressure pulmonary edema (NPPE) is a form ofnoncardiogenic pulmonary edema (PE) that results fromthe generation of high negative intrathoracic pressure(NIP) needed to overcome upper airway obstruction(UAO). NPPE is a potentially life-threatening complica-tion that develops rapidly after UAO in otherwise healthyyoung persons who are capable of producing largemarkedly NIPs. The incidence of NPPE, in patientsdeveloping acute UAO, has been estimated to be up to12 % [1]. The true incidence, however, is not known andmay be higher than has been suggested, since many casesmay have been misdiagnosed because of a lack offamiliarity with the syndrome. All causes of obstructedupper airway may lead to NPPE [2]. However, the mostcommonly reported etiology of NPPE in adults is laryn-gospasm during intubation or in the postoperative periodafter anesthesia (50 % of cases of NPPE) [3]. Neverthe-less, NPPE may be more common in ICU patients than isthought; For instance, ventilation with low tidal volumeduring the acute phase of ARDS in patients with increasedrespiratory drive can lead to patient–ventilator asyn-chrony that causes increased breathing effort and the

generation of high NIPs that will further worsen PE. Also,strong inspiratory efforts in the presence of increasedresistive work of breathing will lead to negative alveolarpressures mimicking the cardiothoracic relationshipspresent during NPPE, and may contribute to extubationfailure in some patients.

Understanding the pulmonary fluid homeostasis iscrucial to comprehend the mechanisms responsible forpulmonary edema formation. In the normal lung, the netfluid transfer across the pulmonary capillaries depends onthe net difference between hydrostatic and colloidosmotic pressures, as well as on the permeability of thecapillary membrane (Starling’s law). Under normal con-ditions, most of this filtered fluid is removed from theinterstitium through the lymphatic system to return to thesystemic circulation [4]. The alveolar epithelium, becauseof its tight intercellular junctions, acts as an effectivebarrier limiting water intrusion into alveolar spaces.However, when the hydrostatic pressure in the pulmonarycapillary bed increases and/or the lung interstitial pressuredecreases, the rate of transvascular fluid filtration rises,causing edema in the perimicrovascular interstitial spaces,

Intensive Care Med (2014) 40:1140–1143DOI 10.1007/s00134-014-3307-7 UNDERSTANDING THE DISEASE

and maybe alveolar flooding if a critical quantity ofedema fluid in the interstitial space has been reached [4,5].

What is the pathophysiology of NPPE? Two differentmechanisms have been suggested to explain the patho-genesis of PE during UAO. One belief is that NPPE isdeveloped by substantial fluid shifts due to swings inintrathoracic pressure [6]. Markedly NIP is generated bydeep inspiratory efforts against an occluded airway or aclosed glottis (modified Muller maneuver). Young healthysubjects can generate very high levels of negative inspi-ratory pressure with a maximum of -140 cmH2O [7].This NIP is transmitted by the same amount to theintrapleural spaces, resulting in augmentation of venous

return to the right side of the heart, and pulmonary venouspressures, while decreasing perivascular interstitialhydrostatic pressure, which favors movement of fluidfrom the pulmonary capillaries into the interstitium andalveolar spaces [8] (Fig. 1). Also, the hyperadrenergicstate associated with catastrophic UAO can causeperipheral vasoconstriction and an increase in venousreturn, which could further increase pulmonary bloodflow, contributing to edema. Furthermore, the NIPincreases left ventricular afterload by increasing thetransmural left ventricular pressure, thus raising ventric-ular wall tension [9]. The increase in afterload depressesleft ventricular ejection. In addition, the resulting hyp-oxemia decreases myocardial contractility and increases

Fig. 1 As shown in the left part of the illustration, breathingthrough the normally open upper airway requires minimaldiaphragmatic efforts (thin black arrow) that generate small levels(-2 to -8 cmH2O) of negative pleural pressure (PPL) duringinspiration. In normal conditions, the alveolar–capillary pressuregradient is small, and when hydrostatic pressures slightly increasein the pulmonary capillary bed, the fluid overload may be offset byincreased lymphatic drainage. Conversely, inspiration against anobstructed upper airway—as represented by closed vocal cords in

the right side of the illustration—requires forceful diaphragmaticefforts (large black arrow) generating high levels (-50 to -140 cmH2O) of negative PPL that increase venous return to theright side of the heart (large blue arrow). This may result in higherhydrostatic pressures in the pulmonary capillaries and a suddendrop of pressures in the alveolar spaces, creating a huge pressuregradient across the pulmonary capillary wall and disruption of thealveolar–capillary membrane, leading to alveolar flooding andpulmonary edema (yellow arrows)

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pulmonary arterial resistance. The fall in left ventricularejection fraction augments in succession end-diastolicpressure, left atrial pressure, and pulmonary venouspressure, further increasing the pulmonary capillaryhydrostatic pressures that promote the formation of PE[9]. Therefore, the combination of increased preload andafterload associated with a decrease in pulmonary inter-stitial pressure cause a high increase in the hydrostaticpulmonary pressure gradient (disturbance of the Starlingequilibrium), allowing transudation of fluid out of thepulmonary capillary into the lung interstitium, resulting inPE. This mechanism of NPPE is similar to hydrostatic PEas observed in patients suffering from congestive heartfailure or volume overload states.

The second suggested mechanism is that the mechan-ical stress developed from respiration against anobstructed upper airway may induce breaks in the alveolarepithelial and pulmonary microvascular membranes,resulting in increased pulmonary capillary permeabilityand protein-rich PE [7, 10]. This theory is based on theconcept of wall stress failure developed more than20 years ago by West et al. [11], in which increasingtransmural pulmonary capillary pressures cause disrup-tion of the alveolar–capillary membrane with resultanthigh-permeability PE. In animals, when pulmonary cap-illaries are subjected to increased transmural pressure,ultrastructural damage of the walls of the capillaries andalveolar epithelium is observed under scanning electronmicroscope [12]. Stress failure of pulmonary capillarieshas been suggested to be involved in several conditionscausing PE and hemorrhage, including neurogenic andhigh-altitude PE [13], and following intense exercise inelite human athletes [14]. This indicates that acute

increases in transmural pulmonary capillary pressures asobserved in NPPE may lead to high-permeability PE [15].However, Fremont et al. [2], in 10 NPPE patients, found alow PE fluid-to-serum protein ratio with normal alveolarfluid clearance, further supporting a hydrostatic mecha-nism for edema fluid formation. Nevertheless, we believethat the pathogenesis of NPPE is probably multifactorial,ranging from transudative to high-permeability edemawhen a very high transmural pulmonary capillary pressurehas been produced.

Treatment of NPPE generally includes maintaining apatent airway, and oxygen supplementation with additionof positive end-expiratory pressure or noninvasive posi-tive pressure ventilation (NIV) as guided by physicalexamination and arterial blood gas analysis. Mechanicalventilation should be reserved for severe patients who donot respond to NIV. Diuretics are often used; however,there is no evidence of their utility, and they may exac-erbate hypovolemia and hypoperfusion. Ultimately,NPPE usually has a rapidly resolving clinical course in12–48 h when recognized early and treated immediately.

Understanding the pathophysiological mechanismscontributing to PE can help in distinguishing NPPE fromother causes of noncardiogenic PE, thus preventing use ofinappropriate and dangerous treatment for patients withNPPE.

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