Continuing Education Activity

Pulmonary Interstitial Emphysema (PIE) is an infrequently encountered yet consequential condition that primarily afflicts premature infants but can also manifest in adults. Infants born with low birth weight and prematurity are at a heightened risk for PIE, emphasizing the importance of early recognition and intervention. The pathological features of PIE involve lung damage stemming from alveolar and airway over-distention, compounded by air leaks. Clinicians must employ a comprehensive approach, incorporating exclusionary criteria, precise physical examination techniques, and targeted imaging to augment their index of suspicion.

Given the potentially severe repercussions of PIE in neonates, healthcare professionals engaged in this activity will gain insights into various treatment modalities. Notably, the activity underscores critical contraindications to mechanical ventilation, shedding light on optimal management strategies. This activity reviews the epidemiology, diagnostic intricacies, and multifaceted management approaches, enhancing clinicians' ability to contribute effectively to interprofessional teams.

Objectives:

• Identify the etiology of pulmonary interstitial emphysema.
• Determine the appropriate evaluation process for pulmonary interstitial emphysema.
• Evaluate the management options for pulmonary interstitial emphysema.
• Discuss interprofessional team strategies for improving care coordination and communication to treat pulmonary interstitial emphysema and improve outcomes.

Introduction

Pulmonary interstitial emphysema (PIE) is a rare, abnormal pathology that occurs commonly in neonates but is also prevalent in adults. The increased air pressure within the alveoli and alveolar airspaces disrupt the adjacent lung interstitial tissue, damaging the lung structure and causing linear and cystic spaces complicated by air leaks.[1] The leaked air is collected outside normal air passages and inside the interstitium or bronchovascular complexes. 

Premature infants with PIE can develop respiratory distress syndrome. The critical goal is to be able to maintain sufficient gas exchange. Without adequate gas exchange, the lungs are damaged, resulting in prolonged hypoxia, respiratory acidosis, and pulmonary hypoperfusion.[2] 

PIE is a diagnosis based on imaging and histopathology.[3] Administration of surfactant and high-frequency ventilation has decreased the incidence of PIE in premature infants. The most recent management of infants with respiratory distress syndrome is prophylaxis with synthetic surfactant and continuous positive airway pressure, with or without mechanical ventilation.[4]

Etiology

Neonatal etiologies include:[2]

• Respiratory distress syndrome
• Prematurity
• Meconium aspiration syndrome
• Positive pressure ventilation or mechanical ventilation with high peak pressures
• Pulmonary infection (pneumonia, sepsis, chorioamnionitis), amniotic fluid aspiration[5]
• Incorrect endotracheal tube placement
• Magnesium sulfate antenatal exposures[6]

Other causes in adults include:

• Asthma[7]
• Smoking[8]
• Barotrauma

Epidemiology

PIE occurs more commonly in premature infants within the first few weeks of birth. Premature infants that develop PIE within 48 hours of life usually have a grave prognosis. These infants may have associated low birth weight, premature birth, perinatal asphyxia, and sepsis.[9] In old studies, there was no difference in the development of PIE among different sexes.[10] A retrospective study showed that out of the extremely premature infants on ventilators who were treated with antenatal steroids, tocolysis, and postnatal surfactant administration, 24% had developed PIE later in their hospital course.[10][11]

The prevalence of the pathology depends on which population is studied, whether it is patients with low birth rates versus respiratory distress syndrome versus other etiologies. In one study, infants with respiratory distress syndrome were born prematurely at less than 30 weeks. PIE occurred in 3% of neonates treated early with the surfactant, 8% of neonates treated with the surfactant late, and 25% of neonates that served as control.[11]

A different study that compared surfactant administration as prophylaxis versus early treatment in premature infants showed a higher incidence of PIE in premature infants and those treated with surfactant late.[12][13] Premature infants born 25 to 29 weeks of gestation that were randomly treated with surfactant at birth resulted in PIE in 15% of the treated infants and 26% of the control infants.[12][13] 

Premature infants weighing less than 1000 g at birth showed the highest frequencies of developing PIE. Infants weighing 500 g to 799 g had an incidence of 42% of PIE, infants weighing 800 g to 899 g had an incidence of 29%, and infants weighing 900 g to 999 g had an incidence of 20%.[14][15][16][17]

Pathophysiology

PIE pathophysiology revealed alveolar hyperdistention and bronchial duct gland ectasia formation, leading to tissue rupture. Some causes of air leaks and alveolar rupture are insufflation (mechanical ventilation or positive pressure ventilation), uneven ventilation, and reduced lung compliance, especially since the lungs are underdeveloped and sensitive to stretch.[6][18] 

The increased transpulmonary pressure, being higher than the tensile strength of the alveoli and airways, damages the respiratory epithelium. The injury to the epithelium is where the air enters the interstitium, and the air leak into the perivascular tissue of the lung due to the high intra-alveolar pressure.[19] The air also leaks into the pleural connective tissue of the peri broncho vascular sheaths, interlobular septa, and visceral pleura.[19] The air is then trapped in the interstitium, which causes compression atelectasis of the adjacent lung.[20][21] The infant then has associated respiratory distress syndrome.[19] Surface active phospholipids are also lost from hyperinflation and overinflation.[22] 

Two common types of air leaks are intrapulmonary pneumatosis and intrapleural pneumatosis, and the former is more common. The air trapped inside the lung is underneath the pleura in the interlobular septa. Intrapleural pneumatosis occurs more commonly in mature infants with normal lungs.[2][21] The abnormal air pockets are within the visceral pleura and affect the mediastinal pleura.[7][8][23]

The complications of PIE vary from an isolated interstitial bubble to lesions of unilateral lung or lesions bilaterally. It damages the functional tissue and vascular structure with fibrotic and inflammatory changes. The pathology also results in fibroblast foci with organizing and interstitial pneumonia, granulomatous disease, and sometimes lymphangiectasia.[24] This prevents ventilation and perfusion, affecting the systemic oxygenation and perfusion of the rest of the body, which increases morbidity and mortality of the infant. The resolution of PIE can be spontaneous, resulting in pneumomediastinum, pneumothorax, or subcutaneous emphysema. Air can also leak into the pericardium or peritoneum.[8][6][25][26][24]

Histopathology

An autopsy of a previous case revealed bilateral pleural hyperinflation that inflated after the thoracic cavity was opened. There were many mucus plugs but no effusions in the pleura or pericardium. Histologically, the autopsy revealed thickening of the airway and basement membrane, along with inflammation of airway lumens and eosinophils, mimicking asthma. The airways were filled with mucus exudates. Case series revealed hyperdistention and signs of alveolar tear, parabronchial and perivascular widening, and connective tissue tearing, all indicating PIE.[7]

History and Physical

PIE is made mainly from imaging and histopathology; however, few clinical signs in history suggest this diagnosis. It is crucial to consider the risk factors for PIE, which are mainly premature birth and low birth weight. Some nonspecific clinical signs in adults and infants associated with PIE are increased oxygen requirements, which may progressively and rapidly increase carbon dioxide retention.

There are no physical exam findings specifically to help make the diagnosis. If PIE has progressed, there can be signs of air leaks, so upon physical exam, it is important to monitor for air leaks such as decreased breath sounds, crepitus heard on the affected side, or over-inflation of the chest wall.[27][28]

Evaluation

PIE is partially a radiologic diagnosis. On imaging, PIE shows the lung parenchyma filled with spherical cystic, linear, and oval air-containing lucencies. Early changes appear linear but slowly progress to more cystic formation in the interstitium. Linear radiolucencies are about 3 mm to 8 mm long and less than 2 mm wide. Cystic-like radiolucencies measure 1 mm to 4 mm in diameter. During inspiration, the lung volumes may increase, but premature lungs have decreased lung compliance, resulting in hyperdistended lungs on imaging.

Air leaks can also be seen on imaging. With air leaks, the air in the interstitium is full of large volumes of air, which reduces the gas exchange between the vascular bed and airspaces due to the increased distance.[19] Pneumothorax can form if subpleural cysts rupture. The air leak compresses the heart from the increased intrathoracic pressures and decreases venous return to the heart. Other findings seen on imaging are linear gas collections in the periphery. This is usually seen with increased demand for respiratory support and lung volumes, which are diagnostic markers for PIE.

Sometimes, early bronchopulmonary dysplasia is seen in the setting of partial bronchia obstructions. Histopathological findings in infants with bronchopulmonary dysplasia can show PIE, even if not seen on imaging.[3] A previous case study revealed a CT completed before the autopsy, which showed pleural wall thickening and constricted airways. Imaging showed pulmonary hyperinflation and localized interstitial emphysema.[7]

PIE can sometimes be seen on the anteroposterior supine chest x-ray, but it requires sequential studies to see the disease progression. There may be some difficulty differentiating lucent bronchiole overdistention from PIE, but distended airways are also round and uniform. The radiolucencies are not consistent with the normal bronchial tree.

PIE can sometimes be misinterpreted as pulmonary edema or aspiration syndrome if the normally aerated lung seems surrounded by exudate. Air bronchograms are signs of respiratory distress syndrome, not PIE. If an infant is on a mechanical ventilator, the airways and alveoli can appear similarly distended as in PIE. If a chest x-ray cannot differentiate, a CT scan is the next step for diagnostic imaging.[3][29][30][31]

Treatment / Management

Infants with PIE are treated in neonatal ICU as these patients are critically ill and can develop complications such as pneumothorax or pneumopericardium and require mechanical ventilation. They may also need invasive procedures such as thoracentesis. There are a few approaches to managing PIE with varying success. A high number of PIE infants tend to be premature. Using surfactants in premature infants (<30 to 32 weeks) may reduce PIE development by preventing the occurrence of respiratory distress syndrome. Secondly, if mechanical ventilation is avoidable, it should be avoided because high oxygen pressure can damage the infant's underdeveloped lungs. CPAP should be attempted first, although it can also cause PIE. Ventilator settings should be focused on reduced inspiratory time, prolonged expiratory time, and decreased pressure when adjusting PEEP. This should allow the airway to empty properly upon expiration. Affected infants require close vitals, oxygen, blood gas, and nutrition monitoring.[32] 

Conservative Management

There are a few preventive measures to prevent PIE. The prophylactic surfactant can be administered in preterm infants who are at risk of respiratory failure as it has been shown to decrease risk. The incidence of air leaks is reduced in premature infants if the surfactant is administrated early with brief ventilation.[33]

A more conservative approach is lateral decubitus positioning, which is more effective in infants with unilateral PIE. One case study showed that this approach resolved unilateral PIE within 2 to 6 days. There are low failure rates and minimal recurrence. Lateral decubitus positioning helps with bilateral PIE if one side is significantly affected. The lung that is not affected will have improved oxygen, which will decrease the ventilator settings.[34]

Surfactant

Surfactant is used in premature infants for prophylactic management of respiratory distress syndrome. Surfactant is available as natural or synthetic and administrated through intratracheal administration. Surfactant helps decrease the surface tension between air and alveolar surface, preventing the alveoli's collapse upon expiration.[11][35]

Natural surfactants are normally derived from animals, more commonly bovine than porcine, and they are similar to human surfactants. Some obstacles with surfactant use are that efficiency is inconsistent, there is a risk of pathogen contamination, lack of cost-effectiveness, and possible anaphylactic shock reaction. Currently used surfactants are the following: Survanta made of bovine lung extract, beractant made of porcine lung extract, and calfactant, a bovine broncho-alveolar extract.[12][13]

A few synthetic surfactants are therapeutic and better than natural surfactants. Colfosceril palmitate only contains phospholipids and is protein-free. Lucinactant is one of the newer surfactants that contain protein and has been studied to be better and more effective.[12][13]

High-Frequency Ventilation

In some studies, high-frequency positive pressure ventilation has been proven to be a preventive measure against air leaks and PIE compared to conventional mechanical ventilation. Still, data is limited, and others have proven no different.[36][37][38][39] Other studies have shown that elective or preventive high-frequency ventilation may prevent PIE.[14][40][41]

If an infant is in severe respiratory distress, there have been cases successively treated with selective intubation of the contralateral bronchus of patients affected by PIE.[42][43] This allows the over-distended lung tissue to decompress. That lung is prevented from being exposed to high positive oxygen pressures. Selective bronchial intubation of the left side bronchus is more complicated than the right side because the endotracheal tube needs to be inserted an additional 2 cm to 4 cm compared to the right. Upon intubation, the angle must be directed toward the bronchus of choice to increase the chance of intubating the correct bronchus.[43]

Another method that may help with intubation is turning the infant's head contralateral to the side of intubation, which may help with the intubation of the bronchus of choice.[43] A small fibrotic bronchoscope or intubation under fluoroscopy can be done. The possible complications to be aware of are atelectasis, hyperinflation of the intubated lung, upper lung collapse, acute hypoventilation or hypoxemia, injury to bronchial mucosa, or bradycardia. This is preferred over lobectomy.

A study found that high-frequency oscillatory ventilation is better compared to rapid-rate ventilation. These settings were found to be safe and effective for PIE in infants.[4] These settings resulted in similar oxygenation as rapid rate ventilation with lower peak and mean airway pressures.[44] Any air leaks into the mediastinum and interstitial spaces were prevented, whereas conventional ventilation resulted in respiratory failure in patients with PIE.[44] Eighty percent of the infants survived with high-frequency ventilation and required a low fraction of inspired oxygen while treated for PIE.[44][45] These patients require monitoring because high-frequency oscillatory ventilation can exacerbate gas trapping and airway collapse. Transitioning to low-frequency oscillatory ventilation has improved both unilateral and bilateral PIE.[45] 

Lobectomy

Lobectomy is considered one of the last resort therapies due to its being an invasive procedure. Lobectomies are considered when medical management fails and spontaneous resolution does not occur. This is considered in infants who have severe emphysema, as previous results are successful.[46][47]

Other Methods of Management

Few other rare case reports of other methods of management have included artificial pneumothorax,[48][49][48] chest physiotherapy with oxygen therapy,[50] steroid treatment,[51] ECMO,[25][52] and nitric oxide treatment.[53] However, these treatments are not commonly used.

Differential Diagnosis

PIE is a radiologic and histopathologic diagnosis. The following must be ruled out, which can usually be achieved by a CT scan of the chest:

• Pulmonary edema
• Pulmonary embolism
• Bronchogenic cysts
• Congenital lobar emphysema
• Air bronchograms in respiratory distress syndrome
• Aspiration pneumonia
• Diaphragmatic hernias
• Congenital cystic adenomatoid malformation

Prognosis

Diagnosis of PIE is ultimately a poor prognosis. Studies have shown high mortality rates of 53% to 67%.[9][15] Studies of infants with PIE with a low birth weight of fewer than 1600 g and severe respiratory distress syndrome have grave prognosis with a reported mortality of 80%.[54] PIE is known to cause air leaks such as pneumothorax and mediastinal emphysema, increasing the risk of mortality. If PIE appears early, it is associated with increased mortality due to severe underlying parenchymal disease.[55][54] 

It takes a few weeks for PIE to resolve with proper management. However, this leads to prolonged mechanical ventilator use and complications associated with prolonged ventilator use, such as bronchopulmonary dysplasia or chronic lobar emphysema. These may require surgical lobectomies.[56] 

One study showed that 54% of PIE survivors developed chronic lung emphysema, and 50% of these infants required surgical lobectomies.[9] Studies showed that infants with PIE also developed intraventricular hemorrhage and that PIE was still strongly associated with death.[10]

Complications

PIE is a severe disease. The following complications are associated with it.

• Respiratory insufficiency
• Mediastinal emphysema
• Other air leaks (eg, pneumomediastinum, pneumothorax, pneumopericardium, pneumoperitoneum, subcutaneous emphysema)
• Intraventricular hemorrhage
• Massive air embolism
• Chronic lung disease of prematurity
• Periventricular leukomalacia
• Death

Postoperative and Rehabilitation Care

Post-treatment monitoring is necessary for premature infants. Complications to monitor are periventricular leukomalacia, intraventricular hemorrhage, and developmental delay. Infants can develop chronic lung disease and need long-term pulmonary care. The literature is unclear regarding whether chronic lung disease benefits from bronchodilator treatment.

Consultations

Management of PIE is multidisciplinary teamwork. The following specialties are involved in the care of such patients.

• Neonatologist
• Pediatric pulmonary team
• Critical care team
• Pediatric surgery team

Deterrence and Patient Education

Preventive measures during pregnancy must be discussed in infants that are at high risk for PIE.[2]

• No smoking
• No recreational drug use (cocaine, marijuana, etc)
• No alcohol use
• Proper prenatal care

Pearls and Other Issues

Keep the following pearls in mind:

• PIE is a rare pathology that occurs more commonly in premature and underweight infants.
• PIE is commonly caused by mechanical ventilation and is associated with respiratory distress syndrome.
• Clinically, PIE can progress rapidly with increased oxygen requirements and hemodynamic instability; however, it is diagnosed through imaging and histopathology.
• PIE is usually treated with early surfactant administration and the optimal mechanical ventilator setting: high-frequency oscillation ventilation, positive end-expiratory pressure, and low inspiratory pressure. The goal is to allow proper expiration as the lungs are over-distended.
• Conservative measures include lateral decubitus positioning and CPAP if a mechanical ventilator can be avoided.
• Complications can include pulmonary air embolisms and air leaks.

Enhancing Healthcare Team Outcomes

Premature infants who are at high risk for PIE must be monitored closely in the NICU. These infants need a strong interprofessional team to coordinate the care among pediatricians, pulmonologists, intensivists, and surgeons. CPAP and synthetic surfactants are currently the latest management for the prevention of PIE in patients with respiratory distress syndrome. Patients must be monitored closely by pediatricians and pulmonologists after recovery for any long-term effects. With appropriate communication, these critical patients can be managed appropriately.

Review Questions

• Access free multiple choice questions on this topic.
• Click here for a simplified version.
• Comment on this article.

References

1.

Tachibana Y, Taniguchi H, Kondoh Y, Kataoka K, Hamada N, Hashiguchi T, Ichikado K, Kishaba T, Sato S, Udo E, Hashisako M, Fukuoka J. Pulmonary interstitial emphysema is a risk factor for poor prognosis and a cause of air leaks. Respir Investig. 2019 Sep;57(5):444-450. [PubMed: 31043328]

2.

Gronbach J, Ehrhardt H, Zimmer KP, Waitz M. Early Pulmonary Interstitial Emphysema in Preterm Neonates-Respiratory Management and Case Report in Nonventilated Very Low Birth Weight Twins. AJP Rep. 2018 Apr;8(2):e99-e105. [PMC free article: PMC5951786] [PubMed: 29765788]

3.

Jabra AA, Fishman EK, Shehata BM, Perlman EJ. Localized persistent pulmonary interstitial emphysema: CT findings with radiographic-pathologic correlation. AJR Am J Roentgenol. 1997 Nov;169(5):1381-4. [PubMed: 9353462]

4.

Keszler M, Donn SM, Bucciarelli RL, Alverson DC, Hart M, Lunyong V, Modanlou HD, Noguchi A, Pearlman SA, Puri A. Multicenter controlled trial comparing high-frequency jet ventilation and conventional mechanical ventilation in newborn infants with pulmonary interstitial emphysema. J Pediatr. 1991 Jul;119(1 Pt 1):85-93. [PubMed: 1906102]

5.

Aiyoshi T, Masumoto K, Shinkai T, Tanaka Y, Fujii S, Sasaki T, Chiba F, Sakamoto N, Gotoh C, Urita Y, Nakao M, Takayasu H, Tanaka H, Imai H. Pulmonary interstitial emphysema due to respiratory syncytial virus infection. Pediatr Int. 2016 Sep;58(9):916-9. [PubMed: 27435178]

6.

Greenough A, Dixon AK, Roberton NR. Pulmonary interstitial emphysema. Arch Dis Child. 1984 Nov;59(11):1046-51. [PMC free article: PMC1628820] [PubMed: 6508339]

7.

Mauad T, Nascimento FBPD, Dolhnikoff M, Picka MCM, Saldiva PHN., BIAS. Pulmonary interstitial emphysema in fatal asthma: case report and histopathological review. BMC Pulm Med. 2018 Mar 20;18(1):50. [PMC free article: PMC5859394] [PubMed: 29554886]

8.

Margaritopoulos GA, Harari S, Caminati A, Antoniou KM. Smoking-related idiopathic interstitial pneumonia: A review. Respirology. 2016 Jan;21(1):57-64. [PubMed: 26138798]

9.

Gaylord MS, Thieme RE, Woodall DL, Quissell BJ. Predicting mortality in low-birth-weight infants with pulmonary interstitial emphysema. Pediatrics. 1985 Aug;76(2):219-24. [PubMed: 4022695]

10.

Verma RP, Chandra S, Niwas R, Komaroff E. Risk factors and clinical outcomes of pulmonary interstitial emphysema in extremely low birth weight infants. J Perinatol. 2006 Mar;26(3):197-200. [PubMed: 16493434]

11.

Kendig JW, Notter RH, Cox C, Aschner JL, Benn S, Bernstein RM, Hendricks-Munoz K, Maniscalco WM, Metlay LA, Phelps DL. Surfactant replacement therapy at birth: final analysis of a clinical trial and comparisons with similar trials. Pediatrics. 1988 Nov;82(5):756-62. [PubMed: 3054783]

12.

Dunn MS, Shennan AT, Zayack D, Possmayer F. Bovine surfactant replacement therapy in neonates of less than 30 weeks' gestation: a randomized controlled trial of prophylaxis versus treatment. Pediatrics. 1991 Mar;87(3):377-86. [PubMed: 2000278]

13.

Kattwinkel J, Bloom BT, Delmore P, Davis CL, Farrell E, Friss H, Jung AL, King K, Mueller D. Prophylactic administration of calf lung surfactant extract is more effective than early treatment of respiratory distress syndrome in neonates of 29 through 32 weeks' gestation. Pediatrics. 1993 Jul;92(1):90-8. [PubMed: 8516091]

14.

Moriette G, Paris-Llado J, Walti H, Escande B, Magny JF, Cambonie G, Thiriez G, Cantagrel S, Lacaze-Masmonteil T, Storme L, Blanc T, Liet JM, André C, Salanave B, Bréart G. Prospective randomized multicenter comparison of high-frequency oscillatory ventilation and conventional ventilation in preterm infants of less than 30 weeks with respiratory distress syndrome. Pediatrics. 2001 Feb;107(2):363-72. [PubMed: 11158471]

15.

Hart SM, McNair M, Gamsu HR, Price JF. Pulmonary interstitial emphysema in very low birthweight infants. Arch Dis Child. 1983 Aug;58(8):612-5. [PMC free article: PMC1628320] [PubMed: 6351760]

16.

Amini E, Nayeri FS, Hemati A, Esmaeilinia T, Nili F, Dalili H, Aminnejad M. Comparison of High Frequency Positive Pressure Mechanical Ventilation (HFPPV) With Conventional Method in the Treatment of Neonatal Respiratory Failure. Iran Red Crescent Med J. 2013 Mar;15(3):183-6. [PMC free article: PMC3745744] [PubMed: 23983995]

17.

Yu VY, Wong PY, Bajuk B, Szymonowicz W. Pulmonary interstitial emphysema in infants less than 1000 g at birth. Aust Paediatr J. 1986 Aug;22(3):189-92. [PubMed: 3767787]

18.

Berk DR, Varich LJ. Localized persistent pulmonary interstitial emphysema in a preterm infant in the absence of mechanical ventilation. Pediatr Radiol. 2005 Dec;35(12):1243-5. [PubMed: 16086158]

19.

Kim HR, Yoo SM, Lee HY, Han JH, Frazier AA, White CS. Presence of subpleural pulmonary interstitial emphysema as an indication of single or multiple alveolar ruptures on CT in patients with spontaneous pneumomediastinum. Acta Radiol. 2016 Dec;57(12):1483-1489. [PubMed: 26868169]

20.

Plenat F, Vert P, Didier F, Andre M. Pulmonary interstitial emphysema. Clin Perinatol. 1978 Sep;5(2):351-75. [PubMed: 747902]

21.

Richter A, Tegtmeyer FK, Möller J. Air embolism and pulmonary interstitial emphysema in a preterm infant with hyaline membrane disease. Pediatr Radiol. 1991;21(7):521-2. [PubMed: 1771121]

22.

Wyszogrodski I, Kyei-Aboagye K, Taeusch HW, Avery ME. Surfactant inactivation by hyperventilation: conservation by end-expiratory pressure. J Appl Physiol. 1975 Mar;38(3):461-6. [PubMed: 1097385]

23.

Freysdottir D, Olutoye O, Langston C, Fernandes CJ, Tatevian N. Spontaneous pulmonary interstitial emphysema in a term unventilated infant. Pediatr Pulmonol. 2006 Apr;41(4):374-8. [PubMed: 16447182]

24.

Barcia SM, Kukreja J, Jones KD. Pulmonary interstitial emphysema in adults: a clinicopathologic study of 53 lung explants. Am J Surg Pathol. 2014 Mar;38(3):339-45. [PubMed: 24525504]

25.

Toledo Del Castillo B, Gordillo I, Rubio García E, Fernández Lafever SN, Gonzalez Cortés R, Urbano Villaescusa J, López González J, Solana García MJ, López-Herce Cid J. Diffuse persistent pulmonary interstitial emphysema secondary to mechanical ventilation in bronchiolitis. BMC Pulm Med. 2016 Nov 03;16(1):139. [PMC free article: PMC5094036] [PubMed: 27809884]

26.

Nuñez-Ramiro A, Aguar M, Cernada M, Parra-Llorca A, Vento M. Oxygen needs during resuscitation and surfactant to achieve stabilisation were independent risks factors for pulmonary interstitial emphysema in preterm infants. Acta Paediatr. 2018 Jan;107(1):28-32. [PubMed: 28851119]

27.

Dominguez MC, Pires CDS, Stopiglia MCS, Mezzacappa MAMDS, Alvares BR. Bilateral pulmonary interstitial emphysema in a preterm infant on continuous positive airway pressure: clinical and radiological correlation. Radiol Bras. 2018 Mar-Apr;51(2):137-138. [PMC free article: PMC5935420] [PubMed: 29743753]

28.

Demura Y, Ishizaki T, Nakanishi M, Ameshima S, Itoh H. Persistent diffuse pulmonary interstitial emphysema mimicking pulmonary emphysema. Thorax. 2007 Jul;62(7):652. [PMC free article: PMC2117240] [PubMed: 17600299]

29.

Campbell RE. Intrapulmonary interstitial emphysema: a complication of hyaline membrane disease. Am J Roentgenol Radium Ther Nucl Med. 1970 Nov;110(3):449-56. [PubMed: 5489682]

30.

Langlet B, Dournes G, Laurent F. CT features of pulmonary interstitial emphysema. Diagn Interv Imaging. 2019 Dec;100(12):825-826. [PubMed: 31053558]

31.

Donnelly LF, Lucaya J, Ozelame V, Frush DP, Strouse PJ, Sumner TE, Paltiel HJ. CT findings and temporal course of persistent pulmonary interstitial emphysema in neonates: a multiinstitutional study. AJR Am J Roentgenol. 2003 Apr;180(4):1129-33. [PubMed: 12646469]

32.

Gessler P, Toenz M, Gugger M, Pfenninger J. Lobar pulmonary interstitial emphysema in a premature infant on continuous positive airway pressure using nasal prongs. Eur J Pediatr. 2001 Apr;160(4):263-4. [PubMed: 11317654]

33.

Rojas-Reyes MX, Morley CJ, Soll R. Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev. 2012 Mar 14;(3):CD000510. [PubMed: 22419276]

34.

Schwartz AN, Graham CB. Neonatal tension pulmonary interstitial emphysema in bronchopulmonary dysplasia: treatment with lateral decubitus positioning. Radiology. 1986 Nov;161(2):351-4. [PubMed: 3763899]

35.

Stevens TP, Harrington EW, Blennow M, Soll RF. Early surfactant administration with brief ventilation vs. selective surfactant and continued mechanical ventilation for preterm infants with or at risk for respiratory distress syndrome. Cochrane Database Syst Rev. 2007 Oct 17;2007(4):CD003063. [PMC free article: PMC8554819] [PubMed: 17943779]

36.

Pohlandt F, Saule H, Schröder H, Leonhardt A, Hörnchen H, Wolff C, Bernsau U, Oppermann HC, Obladen M, Feilen KD. Decreased incidence of extra-alveolar air leakage or death prior to air leakage in high versus low rate positive pressure ventilation: results of a randomised seven-centre trial in preterm infants. Eur J Pediatr. 1992 Dec;151(12):904-9. [PubMed: 1473544]

37.

Greenough A, Rossor TE, Sundaresan A, Murthy V, Milner AD. Synchronized mechanical ventilation for respiratory support in newborn infants. Cochrane Database Syst Rev. 2016 Sep 01;9(9):CD000456. [PMC free article: PMC6457687] [PubMed: 27581993]

38.

Cools F, Henderson-Smart DJ, Offringa M, Askie LM. Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants. Cochrane Database Syst Rev. 2009 Jul 08;(3):CD000104. [PubMed: 19588317]

39.

Goel S, Mondkar J, Panchal H, Hegde D, Utture A, Manerkar S. Nasal Mask Versus Nasal Prongs for Delivering Nasal Continuous Positive Airway Pressure in Preterm Infants with Respiratory Distress: A Randomized Controlled Trial. Indian Pediatr. 2015 Dec;52(12):1035-40. [PubMed: 26713987]

40.

Bhuta T, Henderson-Smart DJ. Rescue high frequency oscillatory ventilation versus conventional ventilation for pulmonary dysfunction in preterm infants. Cochrane Database Syst Rev. 2000;1998(2):CD000438. [PMC free article: PMC7032669] [PubMed: 10796364]

41.

Bhuta T, Henderson-Smart DJ. Elective high frequency jet ventilation versus conventional ventilation for respiratory distress syndrome in preterm infants. Cochrane Database Syst Rev. 2000;1998(2):CD000328. [PMC free article: PMC7043304] [PubMed: 10796194]

42.

Brooks JG, Bustamante SA, Koops BL, Hilton S, Cooper D, Wesenberg RL, Simmons MA. Selective bronchial intubation for the treatment of severe localized pulmonary interstitial emphysema in newborn infants. J Pediatr. 1977 Oct;91(4):648-52. [PubMed: 908990]

43.

Chalak LF, Kaiser JR, Arrington RW. Resolution of pulmonary interstitial emphysema following selective left main stem intubation in a premature newborn: an old procedure revisited. Paediatr Anaesth. 2007 Feb;17(2):183-6. [PubMed: 17238893]

44.

Clark RH, Gerstmann DR, Null DM, Yoder BA, Cornish JD, Glasier CM, Ackerman NB, Bell RE, Delemos RA. Pulmonary interstitial emphysema treated by high-frequency oscillatory ventilation. Crit Care Med. 1986 Nov;14(11):926-30. [PubMed: 3769502]

45.

Squires KA, De Paoli AG, Williams C, Dargaville PA. High-frequency oscillatory ventilation with low oscillatory frequency in pulmonary interstitial emphysema. Neonatology. 2013;104(4):243-9. [PubMed: 24060678]

46.

Ahluwalia JS, Rennie JM, Wells FC. Successful outcome of severe unilateral pulmonary interstitial emphysema after bi-lobectomy in a very low birthweight infant. J R Soc Med. 1996 Mar;89(3):167P-8P. [PMC free article: PMC1295705] [PubMed: 8683524]

47.

Martinez-Frontanilla LA, Hernandez J, Haase GM, Burrington JD. Surgery of acquired lobar emphysema in the neonate. J Pediatr Surg. 1984 Aug;19(4):375-9. [PubMed: 6481581]

48.

Dear PR, Conway SP. Treatment of severe bilateral interstitial emphysema in a baby by artificial pneumothorax and pneumonotomy. Lancet. 1984 Feb 04;1(8371):273-5. [PubMed: 6143009]

49.

Dördelmann M, Schirg E, Poets CF, Ure B, Glüer S, Bohnhorst B. Therapeutic lung puncture for diffuse unilateral pulmonary interstitial emphysema in preterm infants. Eur J Pediatr Surg. 2008 Aug;18(4):233-6. [PubMed: 18704893]

50.

Leonidas JC, Hall RT, Rhodes PG. Conservative management of unilateral pulmonary interstitial emphysema under tension. J Pediatr. 1975 Nov;87(5):776-8. [PubMed: 1185348]

51.

Mahapatra S, Scottoline B. Steroid-induced resolution of refractory pulmonary interstitial emphysema. J Matern Fetal Neonatal Med. 2016 Dec;29(24):4092-5. [PubMed: 26952563]

52.

Magarakis M, Nguyen DM, Macias AE, Rosenkranz ER. Lobectomy with ECMO Support in an Infant Who Developed Pulmonary Interstitial Emphysema Following Repair of Hypoplastic Aortic Arch. Braz J Cardiovasc Surg. 2018 Sep-Oct;33(5):528-530. [PMC free article: PMC6257528] [PubMed: 30517264]

53.

Phatak RS, Pairaudeau CF, Smith CJ, Pairaudeau PW, Klonin H. Heliox with inhaled nitric oxide: a novel strategy for severe localized interstitial pulmonary emphysema in preterm neonatal ventilation. Respir Care. 2008 Dec;53(12):1731-8. [PubMed: 19025710]

54.

Morisot C, Kacet N, Bouchez MC, Rouland V, Dubos JP, Gremillet C, Lequien P. Risk factors for fatal pulmonary interstitial emphysema in neonates. Eur J Pediatr. 1990 Apr;149(7):493-5. [PubMed: 2347343]

55.

Heneghan MA, Sosulski R, Alarcon MB. Early pulmonary interstitial emphysema in the newborn: a grave prognostic sign. Clin Pediatr (Phila). 1987 Jul;26(7):361-5. [PubMed: 3595042]

56.

Demir OF, Hangul M, Kose M. Congenital lobar emphysema: diagnosis and treatment options. Int J Chron Obstruct Pulmon Dis. 2019;14:921-928. [PMC free article: PMC6507121] [PubMed: 31118601]

Disclosure: Ruchi Jalota Sahota declares no relevant financial relationships with ineligible companies.

Disclosure: Fatima Anjum declares no relevant financial relationships with ineligible companies.