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 Table of Contents  
Year : 2023  |  Volume : 10  |  Issue : 3  |  Page : 107-114

Ventilator-induced lung injury in children

Division of Pediatric Critical Care, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Submission04-Apr-2023
Date of Decision20-Apr-2023
Date of Acceptance25-Apr-2023
Date of Web Publication19-May-2023

Correspondence Address:
Dr. Suresh Kumar Angurana
Division of Pediatric Critical Care, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpcc.jpcc_27_23

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Mechanical ventilation is one of the common lifesaving interventions used in the care of critically ill children admitted to the pediatric intensive care unit. However, it may induce lung inflammation that can cause or aggravates lung injury. Ventilator-induced lung injury (VILI) is defined as acute lung injury inflicted or aggravated by mechanical ventilation. In the presence of preexisting lung disease (pneumonia and acute respiratory distress syndrome), the immune system hyper-reactivity may lead to cascading lung injury due to mechanical ventilation. The possible mechanisms postulated are too high tidal volume (volutrauma), excessive pressure (barotrauma), repetitive opening and closure of alveoli (atelectotrauma), inflammation (biotrauma), oxygen toxicity, adverse heart–lung interactions, deflation-related injuries, effort-related injuries, and genetic variation in expression of inflammatory mediators. Prevention is the most important strategy for VILI by using lung-protective mechanical ventilation strategies to prevent volutrauma, barotrauma, and atelectotrauma. Low tidal volume ventilation, optimal positive end-expiratory pressure and FiO2, limiting plateau pressure, neuromuscular blockers, and prone positioning are some of the important strategies to prevent and treat VILI. VILI has the potential to cause significant morbidity, mortality, and long-term pulmonary sequelae. The clinical relevance of VILI is poorly understood in critically ill children due to lack of pediatric literature, and most of the information are derived from the adult literature. In this review, we will elucidate the epidemiology, etiopathogenesis, clinical evaluation, management, and measures to attenuate or prevent VILI.

Keywords: Atelectotrauma, barotrauma, deflation-related lung injury, mechanical ventilation, volutrauma

How to cite this article:
Angurana SK, Sudeep K C, Prasad S. Ventilator-induced lung injury in children. J Pediatr Crit Care 2023;10:107-14

How to cite this URL:
Angurana SK, Sudeep K C, Prasad S. Ventilator-induced lung injury in children. J Pediatr Crit Care [serial online] 2023 [cited 2023 Jun 2];10:107-14. Available from: http://www.jpcc.org.in/text.asp?2023/10/3/107/377434

  Introduction Top

The concept of lung injury secondary to mechanical ventilation is an age-old concept, with renewed interest in recent years. In 1744, John Fothergill noted that mouth-to-mouth ventilation may be a better option than machine bellows due to uncontrolled gush of air that can damage lungs. During the polio epidemic of 1952, it was documented that mechanical ventilation can cause structural damage to lungs. Later in 1967, it was demonstrated that in patients who had received mechanical ventilation, the postmortem lung pathology showed extensive alveolar infiltrates and hyaline membrane that was termed as “respirator lung.”[1] Webb and Tierney in 1974 published their first in vivo study of ventilator-induced lung injury (VILI) in healthy rats ventilated with peak airway pressures of 45 cmH2O and 0 positive end-expiratory pressure (PEEP) who died from florid hemorrhagic pulmonary edema within 20–30 min. However, adding PEEP of 10 cmH2O to the same peak airway pressure caused minimum or no lung injury.[2] It was postulated that vascular interdependence (high hydrostatic pressure) was the cause of pulmonary edema.[2] In recent times, the Acute Respiratory Distress Syndrome Network trial (ARDSNet trial) has not only provided confirmatory evidence that VILI does occur during mechanical ventilation but also demonstrated that low tidal volume was superior to high tidal volume ventilation in adults with ARDS.[3]

  Definition Top

VILI is defined as acute lung injury (ALI) inflicted or aggravated due to mechanical ventilation. The mechanical ventilation in children with or without ARDS needs to be carefully titrated, as this lifesaving intervention can induce pulmonary inflammation that can inflict or aggravate lung injury and contribute significantly to morbidity and mortality.[4],[5],[6] It can occur both during invasive or noninvasive mechanical ventilation and in normal or diseased lungs. However, VILI most often occurs in patients with underlying physiological insults to the lungs such as pneumonia, ARDS, sepsis, major surgery, or trauma. In these situations, there are higher microscale stresses and the immune system is already primed to the cascading response to ALI due to mechanical ventilation.[4],[5],[6]

  Epidemiology Top

Data related to the incidence of VILI and the knowledge on the clinical relevance of VILI in critically ill children are limited and mainly extrapolated from experimental or adult data.[6],[7],[8] Unlike adults, pediatric lung is susceptible to mechanical VILI even in the absence of preexisting lung injury. Plötz et al.[9] demonstrated that in infants without preexisting lung injury, elective mechanical ventilation for 2 h with a tidal volume of 10 mL/kg resulted in a pro-inflammatory response.

  Etiopathogenesis Top

Pathogenesis of VILI is multifactorial and comprises a complex interplay between ventilator- and patient-related factors. The main mechanisms leading to VILI include alveolar overdistension (volutrauma), excessive pressure (barotrauma), atelectotrauma, inflammation (biotrauma), and oxidative stress.[4],[5],[7],[10],[11] Patient-related factors include immature lungs and surfactant deficiency in preterm neonates, asymmetrical/heterogeneous lung disease, lung inflammation, genetic variation in expression of inflammatory mediators, and excessive respiratory efforts[10],[12] [Figure 1]. Although there is a lack of consensus on whether volutrauma or barotrauma is the more significant determinant of lung injury, both are interrelated, and the degree of lung overinflation determines the lung injury.[12]
Figure 1: Etiopathogenesis of ventilator-induced lung injury

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High tidal volume and excessive stretch result in volutrauma. Alveolar distention and resultant injury cause increased alveolar and capillary permeability, alveolar and interstitial edema, alveolar hemorrhage, hyaline membrane formation, decreased surfactant, and alveolar atelectasis. Furthermore, volutrauma results in release of cytokines, proteases, chemokines, activation of neutrophils and macrophages leading to inflammation and lung injury.[5],[12],[13] The beneficial effects of low tidal volume ventilation in terms of improved mortality in adults were demonstrated in the landmark ARDSNet trial.[3],[14] Higher tidal volume generated due to higher spontaneous respiratory efforts of the patient has also been demonstrated to lead to lung injury termed as “patient self-inflicted lung injury” (P-SILI).[5],[10]


Lung injury due to high airway or alveolar pressure-related mechanics is called barotrauma. Heterogeneous lung and regional overdistension in ARDS are key factors for VILI. Very high pressure may lead to air-leak syndromes (pneumomediastinum and pneumothorax). Limiting the inflation pressure (i.e., plateau pressure <28–30 cm of H2O) to prevent overdistension is part of lung-protective ventilation (LPV) strategy in patients with ARDS. Transpulmonary pressure (TPP) (alveolar pressure-pleural pressure) titration helps achieve desired tidal volume by keeping airway pressure within safe limits. Bedside, plateau pressure can be used as a surrogate for TPP in the absence of actual TPP monitoring.


It occurs due to shear and stress secondary to repeated cyclical opening and closing of atelectatic alveoli during respiratory cycle. This also damages the adjacent nonatelectatic alveoli and airways.[5],[15]

Very low PEEP results in low residual volume, low functional residual capacity (FRC), and alveolar atelectasis. Alternatively, very high PEEP causes alveolar overdistension. Atelectasis causes regional volutrauma as delivered tidal volume enters the path of least resistance and distends and injures the relatively well aerated rather than the atelectatic lung. This is because the aerated lung has lower critical opening pressure than the atelectatic lung. Application of optimal PEEP prevents cycling closing and opening of collapsed alveoli and an important strategy to prevent VILI due to atelectotrauma.[5],[15]


Biotrauma is due to release of mediators of inflammation (cytokines and chemokines) either locally from injured lungs or systemically in response to volutrauma, barotrauma, atelectotrauma, oxygen toxicity, and sepsis, aggravating the initial injury. Alveolar macrophages and epithelial cells, neutrophils, and macrophages secrete several inflammatory mediators (tumor necrosis factor-alpha, interleukin [IL]-6, IL-8, transcription factor nuclear factor-kappa B [NK-κβ], and matrix metalloproteinase-9) which lead to local lung damage, distant organ injury, and multiple organ dysfunction syndrome (MODS).[4]

Oxidative stress

Oxygen is frequently used in children with hypoxemic respiratory failure. However, excess oxygen (hyperoxia) leads to lung injury, particularly in preterm neonates due to underdeveloped antioxidant mechanisms. Oxidative stress is caused by the generation of reactive oxygen species which oxidize cell membrane lipids, proteins, nucleic acids, and enzymes, causing cell death and tissue damage.[4],[5],[12],[16]

Adverse heart-lung interactions

It contributes to VILI, especially in setting of high tidal volume and low PEEP. During inspiration (mechanical breath), there is a decrease in pulmonary blood flow due to squeezing of right ventricle by the expanding lung and vice versa during expiration. This cycle of low flow-high flow-low flow in pulmonary circulation damages the pulmonary capillary endothelium (capillary stress failure) resulting in increased capillary permeability, leakage of water and proteins, and pulmonary edema.[17] Overtime, right ventricular failure ensues and its dilatation pushes the interventricular septum toward the left ventricle leading to increased left ventricular end-diastolic pressure, further aggravating pulmonary edema.[10],[17]

Lung deflation injury

Sudden loss of PEEP as in abrupt disconnection of mechanical ventilator (for suctioning, extubation, or sudden stopping noninvasive ventilation [NIV]) causes lung deflation injury. During sustained inflation, there is a decrease in cardiac output which is usually compensated by increased systemic vascular resistance (SVR) to maintain blood pressure. During sudden deflation, the cardiac output increases, but the heart faces significant afterload due to increased SVR, leading to increased left ventricular end-diastolic pressure and resultant pulmonary edema. Furthermore, high pulmonary blood flow during sudden deflation causes a sudden increase in capillary pressure causing capillary injury.[18] These altered hemodynamic factors during sudden deflation result in increased lung water, capillary stress failure, microvascular leakage, inflammation, poor lung compliance, atelectasis, and poor oxygenation leading to VILI.

These effects can be mitigated by avoiding open suction, accidental disconnection from ventilator, and unplanned extubation; gradual lowering of PEEP in patients with ARDS; and avoiding abrupt disconnection from NIV.[4],[10],[17],[18]

Effort-induced lung injury

Early neuromuscular paralysis in ventilated patients with ARDS has been shown to improve lung functions and mortality.[19] It has been demonstrated that NIV in patients with severe ARDS was associated with worse outcomes as compared to invasive mechanical ventilation.[20] In children with ARDS, airway pressure release ventilation, promoting spontaneous ventilation, has been associated with increased mortality.[21] Results of these studies show that spontaneous breathing during mechanical ventilation is deleterious, especially in presence of underlying diseased lungs. This concept has been labeled as P-SILI.

Postulates for P-SILI include increased negative intrapleural pressure (during spontaneous efforts) leading to higher TPP and higher tidal volume (TV), pendelluft mechanisms resulting in tidal recruitment of already injured alveoli, and increased transvascular pressure leading to pulmonary edema, and patient–ventilator asynchrony worsening lung injury.[4],[10]

At the same time, the beneficial effects of spontaneous breathing (not excessive) include maintaining diaphragmatic tone and function (helpful during weaning), increased right ventricular preload, and reduced right ventricular afterload (improved lung perfusion). Therefore, it is important to maintain a balance between adequate and excessive spontaneous efforts at bedside. Selection of proper ventilation mode and settings, adequate sedoanalgesia, neuromuscular blockers, adequate recruitment (which flattens diaphragm and reduces the degree of efforts), minimizing patient–ventilator asynchrony, prone position, correction of acidosis, esophageal manometry, and extracorporeal CO2 removal are important steps in facilitating the balance.

Mechanical power, stress, and strain

Mechanical power is defined as amount of energy transferred from ventilator to the lungs per unit time (joules per minute). The risk of VILI is directly proportional to the amount and duration of energy delivered to the lungs which in turn depends on the set ventilatory parameters (tidal volume, respiratory rate, and PEEP).[22],[23],[24] The risk of VILI is directly proportional to lung size and severity of lung disease. Lungs with large surface area and uniform mechanical properties will experience less intense transfer of energy. On the other hand, the risk of VILI will be significantly higher (for the same mechanical power delivered) in small and heterogeneous lungs with varying mechanical properties.[24] Gattinoni et al.[23] proposed that mechanical power can be used as a single variable for the ventilator-related etiology of lung injury. It can be computed and analyzed at bedside from tidal volume/driving pressure, flow, PEEP, and respiratory rate by using special software.

Lung stress is defined as force per unit area (expressed in the same units as pressure) and lung strain is defined as change in lung volume caused by lung stress. Lung stress and strain are important mediators of VILI in heterogeneous lung as strain and stress are concentrated in regions between atelectatic and aerated lung units. The applied tidal volume preferentially enters and overdistends the adjacent normal lungs, which are constrained by the nonexpandable atelectatic lungs. This focused stress at these regions can be more than two times greater than the TPP applied to the whole lung. In addition, the risk for VILI also depends on whether strain on lungs is dynamic or static. Dynamic strain is caused by the lung volume change mediated by tidal volume and static strain is caused by the volume change mediated by PEEP. The dynamic strain is more harmful to the lungs than static strain.[25],[26]

  Consequences Of Ventilator-Induced Lung Injury Top

VILI is characterized by lung inflammation and diffuse alveolar damage. Pathology shows disruption of alveolarization and vasculogenesis, endothelial activation, endothelial and epithelial dysfunction, alveolar–capillary membrane disruption, increased capillary permeability, recruitment of inflammatory cells, release of inflammatory mediators, and accumulation of protein-rich fluid in the lungs (pulmonary edema). These changes increase the distance between the alveolar epithelial cells and capillary endothelial cells, surfactant dysfunction and deficiency, hyaline membrane formation, and atelectasis leading to abnormalities in gas exchange. The inflammatory mediators and lung bacterial flora translocate to systemic circulation leading to systemic inflammatory response syndrome, sepsis, and MODS. Persistent lung injury leads to suboptimal repair and chronic lung damage[4],[5],[10] [Figure 1].

  Clinical Assessment Top

The diagnosis of VILI is mainly clinical. The typical presentation includes a patient on ventilator developing worsening hypoxemia. It requires a high index of suspicion, detailed history and physical examination, review of oxygenation and ventilation status, ventilator parameters, chest radiograph, laboratory investigations, and ruling out close mimickers of hypoxemia in ventilated patients.

Clinical assessment include eliciting history of recent onset fever, volume of fluids received or fluid balance, blood product transfusion, and drug allergy. Examine for new-onset crackles or bronchospasm, evidence of pneumothorax, pleural effusion, limb edema, ascites, and intra-abdominal hypertension.

Laboratory investigations include markers of inflammation (total leukocyte count and differential leukocyte count, platelet count, C-reactive protein, and procalcitonin) and cultures (blood and bronchoalveolar lavage fluid). Cardiac enzymes, lipase levels, fiber-optic bronchoscopy, lower limb Doppler, and pulmonary angiography may be needed in certain cases.[4] Chest radiograph in VILI may be like ARDS and common findings include diffuse alveolar/interstitial infiltrates without cardiomegaly. Computed tomography chest is not required or possible in all cases, but it may show bilateral heterogeneous areas of consolidation and atelectasis with focal areas of hyperlucencies suggestive of alveolar overdistension.[4]

  Differential Diagnosis Top

The common differential diagnosis of VILI include new-onset pulmonary infection, cardiogenic pulmonary edema, aspiration, air leak syndrome (pneumothorax), pleural effusion, auto-PEEP, endobronchial intubation, abdominal distension, transfusion-associated lung injury, burns and inhalation injuries, severe pancreatitis, and postcardiopulmonary bypass and major surgeries; and special situation in adults including acute coronary syndrome, and embolism (fat, amniotic fluid, air).[4]

  Treatment Top

Prevention is the most important strategy for VILI. The use of NIV in appropriately selected cases; selection of the most appropriate ventilation setting that prevents overdistension of alveoli and resulting volutrauma, barotrauma, and atelectotrauma; and early liberation from mechanical ventilation are important preventive strategies. For prevention of P-SILI, adequate sedation, neuromuscular blockade, adequate recruitment, treatment of acidosis, prone positioning, and avoiding double triggering are important measures[17] [Figure 2].
Figure 2: Measure to prevent and treat ventilator-induced lung injury

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The “baby lung” concept in ARDS represents relatively preserved small areas of aerated lung (just the size of a baby's lung). This part of the lung needs to be protected from the injury during mechanical ventilation. In ARDS, most of the lung is collapsed and nonaerated. Delivering large tidal volume will overinflate the “baby lung” causing injury to this part as well. The ideal tidal volume is one which is required to ventilate the “baby lung.” However, the “baby lung” is not a fixed anatomical structure as there is redistribution of atelectatic lung units during the disease progression/improvement and positioning.[4],[5]

Lung-protective ventilation strategy

The LPV strategy has been put forth with focus on delivery of small tidal volume (to avoid volutrauma) and optimal PEEP (to prevent alveolar collapse). Optimizing recruitment of lung, keeping it open, and ensuring that the lungs receive uniform distribution of delivered tidal volume (open lung concept) are the basic principles of LPV strategy. It has been demonstrated that in adults with ARDS, VILI can be mitigated by employing LPV strategies. The ARDSNet trial showed that low tidal volume strategy (6 mL/kg of predicted body weight and plateau pressure <30 cmH2O) resulted in lower mortality than higher tidal volume (12 mL/kg of predicted body weight and plateau pressure <50 cmH2O).[3] Even in non-ARDS patients, low tidal volume (6–8 mL/kg of predicted body weight) was associated with improved survival.[27] The findings of ARDSNet trial are important clinical translations of the above concepts.

PEEP is an important component of ARDS ventilation. It leads to alveolar recruitment, protects from atelectotrauma, and leads to better oxygenation. However, PEEP needs to be carefully titrated as very high PEEP and low PEEP can cause overdistension and alveolar collapse, respectively. Optimal PEEP depends on FiO2 (as per PEEP selection criteria of ARDSNet trial), analysis of pressure-volume loop, TPP, and lung ultrasound analysis.

As far as pediatric literature is concerned, there are no randomized controlled trials on the effect of mechanical ventilation settings and outcomes. The issue of optimal tidal volume is a matter of debate. Available pediatric studies (retrospective and prospective) have demonstrated mixed results, some showing the beneficial effect of larger tidal volume and others demonstrating no relationship between tidal volume and patient outcome.[28],[29],[30] In a meta-analysis of 7 studies (n = 1756), not a single tidal volume threshold could be identified that was associated with increased mortality irrespective of the presence or absence of ALI/ARDS.[31] The lack of association between tidal volume and outcome in children possibly explains the poor adherence to LPV strategies in children.[32],[33] However, a direct relationship between peak inspiratory pressure and mortality has been demonstrated in several observational studies among children with ALI.[34],[35] Similarly, the data on optimal PEEP in ALI/ARDS in children are limited. Pediatric intensivists tend to use lower PEEP and accept higher FiO2 for the fear of hemodynamic compromise.[36] However, deviations in approach from the ARDS Network protocol have been associated with poor outcome in children with ARDS.[33]

Driving pressure (plateau pressure-PEEP or tidal volume/static compliance) is the physical variable that has been correlated best with mortality.[35] A driving pressure-based mechanical ventilation strategy to prevent VILI in patients with ARDS is a matter of debate in recent years.[37],[38]

Neuromuscular blockers given for 48 h in patients with ARDS (n = 340) have been shown to reduce mortality (10% mortality benefit at day 28 and day 90) (ACURASYS trial).[19] The morality benefit attributed in the neuromuscular blockers is possibly due to reduction in cytokine levels, decreased biotrauma, and decrease in multiorgan dysfunction.[39]

Prone position ventilation leads to improvement in oxygenation by increasing the homogeneity of ventilation and protection against lung injury. PROSEVA trial demonstrated that in patients with severe ARDS with PaO2/FiO2 <150 (n = 466), prone positioning was associated with a 16.8% reduction in 28-day mortality.[40]

Prevention of accidental disconnection of mechanical ventilation and unplanned extubation; sudden weaning of high PEEP or fast weaning from NIV; and use of closed suction catheters prevents alveolar derecruitment and lung deflation injury.

Recruitment maneuvers were once thought to reduce VILI; however, due to complications (hemodynamic compromise and pneumothorax), and uncertain clinical benefit, these are not used routinely.

High-frequency oscillatory ventilation (HFOV) provides very low tidal volume, a continuous distending pressure (thereby preventing atelectrauma), and delivers small superimposed pressure oscillations (preventing volutrauma). Theoretically, HFOV qualifies for an ideal lung-protective mode of ventilation as it may prevent VILI.

However, two large trials (OSCILLATE and OSCAR trials) failed to demonstrate the survival benefits of HFOV in adults with ARDS.[41],[42] Arnold et al.[43] demonstrated that in children with acute hypoxemic respiratory failure (n = 58), the mortality was same in two groups; however, children in HFOV group had improvement in oxygenation over time and lower requirement of supplemental oxygen at day 30, suggestive of less lung injury in HFOV group. Gupta et al.[44] in a retrospective study demonstrated higher mortality and morbidity in children managed with HFOV compared with conventional mechanical ventilation. Recently, Bateman et al.[45] in a post hoc analysis and propensity matching (for the severity of illness) (data from the Randomized Evaluation of Sedation Titration for Respiratory Failure and RESTORE study) demonstrated that early HFOV (initiated within 24–48 h of intubation) was associated with a longer duration of mechanical ventilation but not with mortality compared with conventional mechanical ventilation or late HFOV.

Extracorporeal support is a promising intervention in reducing VILI; however, there are limited data on clinical benefits of extracorporeal support. Anti-inflammatory drugs and mesenchymal stem cells have been used in animal models to reduce VILI. However, clinical studies are limited. Ketamine and propofol have been used as anti-inflammatory agents in reduction of IL-1β, caspase-1, and NF-κB, with ketamine found superior to propofol.[46]

  Prognosis Top

VILI is associated with increased morbidity and mortality. MODS secondary to biotrauma is a major contributing factor. The complications of VILI include pulmonary edema, barotrauma, and worsening hypoxemia resulting in prolongation of mechanical ventilation. VILI is associated with extensive inflammation and severe lung injury, and extensive fibrosis which can lead to long-term respiratory disability, recurrent pulmonary infections, and cor pulmonale among survivors.[4]

Future directions

Limited data on VILI in children opens doors for well-designed clinical studies to elucidate the epidemiology and pathogenesis of VILI; optimal and physiological use of mechanical ventilation; and effect of tidal volume, PEEP, and other interventions in children with or without ARDS. Till that time, pediatric intensivists should use mechanical ventilation judiciously based on guidelines and suggestion from the Paediatric Mechanical Ventilation Consensus Conference and the Paediatric ALI Consensus Collaborative.[47],[48],[49],[50]

  Conclusion Top

Although mechanical ventilation is lifesaving in critically ill children, it can lead to VILI by complex interplay of airway (high plateau pressure and tidal volume) and vascular forces (vascular shearing from adverse heart–lung interactions). It is possible to prevent or mitigate VILI in mechanically ventilated children by using LPV strategies. Avoiding end-inspiratory alveolar overdistension, maintaining adequate FRC, and targeting just acceptable levels of gas exchange (not entirely normal) with the least damaging ventilation are important principles. In all cases requiring ventilation, it is important to first ascertain the feasibility of NIV before intubation.


The authors are grateful to Prof. Jayashree Muralidharan for guidance and critically reviewing this manuscript.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2]


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