negative pressure pulmonary edema ( nppe ) is an uncommon , but potentially life - threatening complication of general anesthesia .
it is usually seen during emergence from anesthesia . in healthy adults undergoing general anesthesia ,
the incidence of nppe is 0.05 to 0.1%.[13 ] it is even less common with the use of a laryngeal mask airway ( lma).[48 ] the sequelae of acute nppe can be devastating with mortality as high as 11  40% .
nppe can complicate the clinical course and outcome of otherwise healthy patients undergoing simple surgical procedures .
early recognition and institution of appropriate positive pressure ventilation is important to ensuring successful outcomes .
an unusual case of acute nppe associated with a patient forcefully biting down on the lma during emergence is presented . a review of pathophysiology , risk factors , and management strategies for nppe then follows .
a 58-year - old male presented to the emergency department with a three - day history of fever , worsening perineal erythema , and pain .
his medical history revealed only mild seasonal allergies ; his functional status was very good .
his surgical history was significant for an inguinal herniorrhaphy three years prior to his current presentation .
he was noted to have significant perineal cellulitis and pain . his preoperative chest x - ray revealed no infiltrates , pulmonary edema or cardiomegaly . computed tomography ( ct ) demonstrated extensive inflammation of the perineum and scrotum as well as subcutaneous air , consistent with the diagnosis of fournier 's gangrene .
preoperatively the patient was normotensive , but tachycardic ( heart rate 110  120 beats / minute ) .
his electrocardiogram on admission to the intensive care unit ( icu ) did not show any st , t - wave changes .
he did not demonstrate a third heart sound , peripheral edema , or jugular venous distention .
his hemoglobin and hematocrit were 14.9 g / dl and 44% , white blood cell count was 12.7  10 / ml , and platelet count was 146,000 / ml .
his electrolyte panel featured sodium of 135 mmol / l , potassium 4.3 mmol / l , chloride 99
mmol / l , hco3 26 mmol / l , blood urea nitrogen 16 mg / dl , and creatinine 1.14 mg / dl
the patient was taken to the operating room for emergency surgical debridement of the fournier 's gangrene .
he was premedicated with 2 milligrams ( mg ) of midazolam intravenously ( iv ) and anesthesia was induced with iv propofol ( 200 mg ) and fentanyl ( 100 micrograms [ mcg ] ) .
a laryngeal mask airway ( lma , size number 4 ) was placed without difficulty .
he remained hemodynamically stable throughout , but was tachypneic , with a respiratory rate of 35 breaths / minute .
surgical blood loss was ~200 ml and the procedure was otherwise uneventful . at the conclusion of surgery
immediately after lma removal , a laryngospasm was noted , with concurrent tachycardia and hypertension .
application of positive pressure via face mask ( fio2 100% ) was unsuccessful in providing effective ventilation .
intravenous propofol and succinylcholine were administered to facilitate orotracheal intubation with a 7.5 endotracheal tube ( ett ) .
he did develop a brief episode of tachycardia ( 120  130 beats per minute ) and hypertension ( 170  180 / 90  100 mmhg ) on extubation .
his arterial blood gas ( abg ) in the operating room showed ph 7.27 , paco2 59 mmhg , pao2 46 mmhg , hco3 of 16
mmol / l , base excess of 1.9 , and oxygen saturation of 75% , with a lactate of 1.27 mmol / l. he was on synchronized intermittent mechanical ventilation ( simv ) at 12 cycles / minute , tidal volume 750 ml , pressure support 10 cm h2o , with positive end - expiratory pressure ( peep ) of 10 cm h2o .
after peep was increased to 12 cm h2o , his spo2 recovered to > 90% .
of note , his peak and plateau pressures were only minimally elevated and his ability to generate a negative pressure was adequate ( > 25 cm h2o ) .
he was transferred to the intensive care unit ( icu ) where he was continued on simv , with a tidal volume of 580 ml , fio2 100% , pressure support 15 cm h2o , and peep of 12 cm h2o .
his initial abg in the icu showed ph 7.6 , paco2 25 mmhg , pao2 165 mmhg , hco3 27 mmol / l , and spo2 99% ( fio2 of 80% ) .
an icu admission chest radiograph demonstrated bilateral patchy infiltrates , no pneumothoraces or effusions , and a normal heart size ; these changes were central and peripheral and not in the dependent areas of the lung [ figure 1 ] . over the subsequent 12 hours his fio2
was weaned to 40% , and his abg showed ph 7.45 , pco2 41 mmhg , pao2 78 mmhg , hco3 28 mmol / l , base excess 3.8 , and oxygen saturation 96% .
postoperatively , during the first few days he was in positive fluid balance , however , he was in a negative fluid balance thereafter .
chest x - ray one hour postoperatively the patient was taken for a planned re - debridement on postoperative day # 2 and was not extubated until postoperative day # 3 .
shortly after extubation , he complained of acute shortness of breath , with an abg showing ph 7.49 , pco2 39 mmhg , pao2 62 mmhg , hco3 29 mmol / l , and spo2 93% ( fio2 of 80% ) .
he was placed on intermittent continuous positive airway pressure ( cpap , 10 cm h2o ) via full face mask .
although the chest radiogram showed an improvement from the index postoperative film , the patchy infiltrates persisted [ figure 2 ] . after ensuring adequate volume status , furosemide ( 40 mg intravenous ) was administered , with resultant improvement in oxygenation , shortness of breath , and subsequent roentgenographic examination
the patient received two additional doses of furosemide ( 20 mg intravenous ) over the next 24 hours , as determined on the basis of clinical re - evaluation .
he was weaned off oxygen on postoperative day six as his chest radiogram showed near complete resolution of the pulmonary edema and his oxygenation was appropriate [ figure 3 ] .
the patient was doing well on follow - up at three months , and underwent uneventful skin grafting of the residual perineal wound without any general anesthesia - related complications .
ezri et al . , first reported the possible association of lma use and pulmonary edema .
shankar et al . suggested that forceful inspiration against an lma could lead to large subatmospheric pressure changes , resulting in a clinical appearance similar to that of pulmonary edema .
nppe has been previously reported after biting on an lma during emergence that resulted in dyspnea and hemoptysis .
the proseal lma has also been associated with airway obstruction and the potential for nppe .
unilateral nppe has also been reported with lma use in a patient in the lateral position . in this report ,
acute obstruction associated with forceful inspiration after biting of the lma was the most likely  trigger event for nppe .
negative pressure pulmonary edema was first described in 1927 , when researchers noted that prolonged inspiration against fixed airway obstruction resulted in pulmonary edema in the canine model .
, in three adult patients who experienced acute onset of pulmonary edema minutes to hours after severe acute upper airway obstruction .
since then , only a few case reports / series of nppe were published , and our understanding of the pathogenesis and treatment of nppe remains limited.[1221 ] negative pressure pulmonary edema has been subdivided by guffin et al . into two distinct classes .
type i , associated with forceful inspiratory effort in the context of an acute upper airway obstruction , and type ii , which occurs after the relief of chronic partial airway obstruction .
common etiologies for type i nppe include laryngospasm , epiglottitis , croup , choking / foreign body aspiration , strangulation , hanging , endotracheal tube obstruction , laryngeal tumor , goiter , postoperative vocal cord paralysis , and near drowning . of these , the laryngospasm remains the most common cause , accounting for ~50% of the reported cases .
type ii nppe can be seen after adenoidectomy / tonsillectomy , laryngeal mass resection , correction of choanal stenosis or reduction of a hypertrophic redundant uvula .
the most common clinical setting for nppe is during emergence from general anesthesia . during this critical period , upper airway obstruction
is usually followed by the rapid onset of respiratory distress , with or without hemoptysis , and clinical / radiological features consistent with bilateral pulmonary edema .
however , in some patients , the onset may be considerably delayed , up to a few hours . therefore , close postoperative observation must be considered for an extended period of time in patients experiencing respiratory difficulty or laryngospasm .
patients with a short neck , difficult intubation , endotracheal tube obstruction , history of obstructive sleep apnea , obesity , acromegaly , and upper aerodigestive tract surgery have increased susceptibility to this condition .
this syndrome is also noticed more frequently in young healthy , and muscular patients , because of their ability to generate high amounts of negative intrathoracic pressures during an obstructing event .
the pathogenesis of type 1 nppe is multifactorial.[10122128 ] the mechanism revolves around a large inspiratory force generated against an obstructed upper airway ( modified mueller maneuver ) that leads to an acute and unusual elevation of negative intrathoracic pressure .
healthy human subjects can generate very high levels of negative inspiratory pressure with a reported maximum of  140 cm h2o from a baseline of  4 cm h2o .
the first of the two proposed pathophysiological mechanisms is that nppe is a type of hydrostatic pulmonary edema caused by the significant fluid shifts from the microvasculature to the peri - microvascular interstitium .
there is alteration in the starling forces ( i.e. , intra- / extracapillary hydrostatic and oncotic pressures ) that influence the movement of fluid across the pulmonary capillaries .
negative intrathoracic pressure will be transmitted to the interstitial space and alveoli , causing an increase in the hydrostatic pressure gradient favoring transudation of the fluid from the pulmonary capillary to the pulmonary interstitial space .
it also causes an increase in the venous return to the heart resulting in an increase in the pulmonary blood volume , pulmonary venous pressures again causing an increase in the hydrostatic pressure gradient , and edema formation .
the legitimate question of whether our patient had a history of underlying heart or lung disease may arise .
he denied any history of heart or lung disease , and as mentioned previously , he had a very good functional status .
the acute onset of airway obstruction at the time of extubation , followed by desaturation , was more consistent with the clinical picture of nppe .
the concurrent development of hypoxemia during nppe triggers hypoxic pulmonary vasoconstriction and raises pulmonary vascular resistance , thus increasing transmural hydrostatic pressures .
as the right ventricular volume increases , the interventricular septum may shift leftward , indicative of reduced left ventricular diastolic compliance . simultaneously
, this negative intra - pleural pressure also has a direct depressing effect on the cardiac output by increasing the cardiac afterload .
the cardiac afterload is also increased secondary to hypoxia - induced systemic and pulmonary vasoconstriction .
the increase in afterload , in combination with hypoxemia of the myocardial muscle , leads to a decrease in the left ventricular function , which in turn increases pulmonary venous pressure and further aggravates the pulmonary edema .
the second theoretical mechanism of pathogenesis involves the loss of capillary integrity , leading to increased capillary permeability and edema formation .
the extreme elevation in transmural pressure causes mechanical stress on the alveolar capillary membrane , leading to the transudation of erythrocytes into the alveoli , a process termed as 
stress failure.[2830 ] alveolar hemorrhage , the hallmark of capillary failure has been documented by bronchoscopy and bronchoalveolar lavage during the episodes of nppe .
the classic descriptions of serosanguinous or pink frothy secretion observed in our case as well as several other case reports , indicate that this mechanism may be important in the pathogenesis of nppe .
negative pressure pulmonary edema is characterized by a rapid onset ( within minutes ) and a relatively quick resolution , with significant clinical and radiographic improvement in 12 to 24 hours .
nppe , if recognized and treated early , is usually a self - limited condition and is reversible .
removal of the obstructive event and maintaining patent airway and oxygenation should be the initial steps .
nasal bi - level positive airway pressure , mask continuous positive airway pressure ( cpap ) , and intubation and ventilation with positive end - expiratory pressure ( peep ) have been used successfully . in this case
we chose cpap because the patient did not fail to ventilate , but was hypoxemic .
however , it has been demonstrated that both biphasic intermittent positive airway pressure ( bipap ) and cpap are effective modalities for treating patients with acute pulmonary edema associated with hypercapnea .
this was because the primary problem was not fluid overload , but interstitial fluid shifts , induced by the negative intrathoracic pressure . if the patient was euvolemic , diuretic treatment was usually not required and most patients recovered quickly after the airway obstruction was resolved .
diuretic therapy was an essential component in treating hydrostatic pulmonary edema , and it was also used in some patients with acute lung injury .
another complicating factor in our patient was that he had a septic focus , and therefore , had an increased risk for septic shock and had just undergone surgery . as his chest radiogram failed to improve as expected , and the patient was still requiring cpap support on postoperative day three , furosemide was cautiously given .
it did improve his oxygenation , and was therefore continued for an additional 24 hours .
bronchodilators were often used and were shown to be beneficial ( our patient was treated with albuterol nebulization ) .
patients with nppe could have wheezing secondary to interstitial edema - induced narrowing of the bronchial lumina . in vitro and in vivo studies in human and animal models
had shown that beta agonists could increase the rate of alveolar fluid clearance via increased active cation transport , which accelerated the regression of symptoms of pulmonary edema .
the theory of vascular leak and the use of diuresis in patients with acute lung injury was tied to this case .
demonstrated that when a critical volume of fluid collected interstitially , alveolar flooding commenced . here , we administered a diuretic on the third day to improve oxygenation , with good result , after three days of cautious observation .
in a patient developing acute onset of perioperative pulmonary edema , other causes of pulmonary edema should be considered .
the differential diagnosis should include cardiogenic edema , neurogenic edema , aspiration pneumonitis , acute respiratory distress syndrome ( ards ) , pulmonary embolism , anaphylaxis , drug - induced non - cardiogenic pulmonary edema , and postoperative residual curarization .
in nppe , an increase in extravascular lung water decreased the compliance and increased shunting .
our patient was on a spontaneous mode of ventilation , and prior to that had received high doses of narcotics intraoperatively .
he had no history of cardiac pathology in the past and had a good functional status , and his electrocardiogram was normal .
there were no other features of anaphylaxis . as he had a rapid onset of bilateral diffuse infiltrates on chest x - ray , aspiration pneumonitis was unlikely .
postoperative residual curarization was also identified as one of the risk factors for upper airway obstruction , as it typically impaired the upper airway dilator muscle strength , while preserving inspiratory muscle function .
this patient did have an increased risk for acute lung injury ( ali ) or ards , secondary to his underlying infectious process .
patients with nppe can develop diffuse alveolar injury through damage to the pulmonary capillaries by mechanical disruption of the alveolar - capillary membrane .
many of these patients may fulfill the clinical , physiological , and radiographic criteria for ali / ards .
his pao2/ fio2 was indeed < 200 and his chest x - ray did show bilateral infiltrates .
however , he did not develop bacteremia , he did not develop septic shock , and he was oxygenating adequately throughout the case .
the current case illustrates the development of nppe as a complication of intermittent obstruction of lma upon emergence from general anesthesia .
the favorable outcome was likely due to early recognition and appropriate nppe - directed therapy .
the majority of the cases of nppe in the literature are in association with endotracheal tube use , and the incidence in association with lmas seems low .
however , some patients emerging from anesthesia ( especially in the second stage ) have a tendency to bite on the airway , and if this obstruction is not relieved promptly , nppe may develop .
the increasing use of lmas in the administration of anesthetics will provide more scenarios where nppe can manifest .
we encourage our colleagues to be vigilant in the recognition of nppe , while using an lma , and to be aware of the treatment modalities available to them , as well as the differential diagnoses involved when such a scenario is encountered .
 negative pressure pulmonary edema ( nppe ) following the use of the laryngeal mask airway ( lma ) is an uncommon and under - reported event . 
 we present a case of a 58-year - old male , who developed nppe following lma use . after biting vigorously on his lma , 
 the patient developed stridor upon emergence , with concurrent appearance of blood - tinged , frothy sputum and pulmonary edema . 
 he subsequently required three days of mechanical ventilation . 
 after discontinuation of mechanical ventilation the patient continued to require additional pulmonary support using continuous positive airway pressure , with a full facemask , to correct the persistent hypoxemia . 
 his roentgenographic findings demonstrated an accelerated improvement with judicious administration of intravenous furosemide . 
INTRODUCTION
CASE REPORT
DISCUSSION
CONCLUSIONS