Ventilator-induced lung injury

INTRODUCTION — Lung injury can be an adverse consequence of mechanical ventilation. This injury is called ventilator-induced lung injury (VILI) and can result in pulmonary edema, barotrauma, and worsening hypoxemia that can prolong mechanical ventilation, lead to multi-system organ dysfunction, and increase mortality. Thus, adopting a ventilator strategy that reduces VILI is an important goal in ventilatory management.

The incidence, mechanisms, diagnostic evaluation, and management of VILI are discussed in this topic review. Other consequences of mechanical ventilation and the diagnosis and management of barotrauma are discussed separately. (See "Clinical and physiologic complications of mechanical ventilation: Overview" and "Diagnosis, management, and prevention of pulmonary barotrauma during invasive mechanical ventilation in adults".)

DEFINITIONS (VILI, VALI, SILI) — VILI, ventilator-associated lung injury (VALI), and self-induced lung injury (SILI) are defined below. Barotrauma is a form of VILI that is associated with alveolar rupture due to elevated transalveolar pressure; this form of VILI is discussed separately. (See "Diagnosis, management, and prevention of pulmonary barotrauma during invasive mechanical ventilation in adults", section on 'Definition'.)

●VILI – VILI is an acute lung injury affecting the airways and parenchyma that is caused by or exacerbated by mechanical ventilation.

●VALI – In clinical practice, it is often difficult to determine if the lung injury that a patient has developed was caused by the ventilatory pattern or was due to the patient's worsening underlying lung condition. As such, the term VALI is often used if a causative relationship between lung injury and the mechanical ventilator cannot be proven [1].

●SILI – Excessive tidal volume generated by spontaneous efforts can also cause lung injury [2].

Some experts propose the terms ventilation-induced or -associated lung injury as a more global way to define injury due to overdistension of the lung or alveolar stretch.

Many experts consider VILI as the "process" of injury while VALI is the end result (ie, the condition). However, despite different definitions, the terms are often used interchangeably.

INCIDENCE AND RISK FACTORS — VILI is mostly seen in patients ventilated for acute respiratory distress syndrome (ARDS) but over the past few years, it has become clear that it also occurs in patients ventilated for reasons other than ARDS.

●ARDS patients – Because the manifestations of VILI are virtually indistinguishable from ARDS, the true incidence is unknown but presumed to be higher than in patients without ARDS. Patients with ARDS are at risk of further lung injury because the lung is already injured ("primed"). In addition, the underlying pathophysiology of ARDS predisposes the lung to further injury from overdistension (because large portions of the lung are unavailable for ventilation) and from atelectrauma. (See 'Mechanisms' below.)

●Non-ARDS patients – The incidence of VILI in ventilated non-ARDS patients is also unknown. In an observational study of 332 mechanically ventilated patients who were intubated for non-ARDS causes [3], risk factors for subsequent VILI included high tidal volumes (>6 mL per kg of predicted body weight), blood product transfusions, acidemia (pH <7.35), and restrictive lung disease [3]. It is probable that similar risk factors exist in patients with ARDS.

It is thought that genetic variations place patients at increased risk for lung injury, although none are currently used as markers or therapeutic targets [4-8].

MECHANISMS — Alveolar overdistension, atelectrauma, and biotrauma are the principal mechanisms of VILI during mechanical ventilation, although the relative importance of each mechanism is unknown [9,10]. Alveolar injury results in high alveolar permeability, interstitial and alveolar edema, alveolar hemorrhage, hyaline membranes, loss of functional surfactant, and alveolar collapse (ie, findings similar to those observed in acute respiratory distress syndrome [ARDS]) [1,10,11].

Alveolar overdistension (volutrauma) — Volutrauma represents lung injury caused as lung units are overdistended with increased transpulmonary pressure [12]. Animal studies have demonstrated that high tidal volumes (or high lung volumes), rather than high airway pressure per se, cause lung injury (figure 1 and figure 2) [13,14]. In patients intubated for reasons other than ARDS, overdistension from high tidal volumes has also been shown to increase the risk for VILI (odds ratio 1.3, 95% CI 1.12-1.51, for each mL above 6 mL per kg of ideal body weight) [3]. In addition, avoiding overdistension by using low tidal volume strategies is beneficial in patients with ARDS, the details of which are provided separately. (See "Acute respiratory distress syndrome: Ventilator management strategies for adults", section on 'Low tidal volume ventilation: Initial settings'.)

Large tidal volumes are not always required for alveolar overdistension. When there is heterogeneous consolidation or atelectasis (eg, patient with ARDS), a disproportionate volume from each breath is delivered to the open alveoli. This can cause regional alveolar overdistension and VILI despite delivery of conventional tidal volumes that are based upon body weight [15]. A similar process is at play when lung compliance is reduced such as severe fibrosis or during single lung ventilation when a tidal breath is distributed to only one lung as opposed to two.

Atelectrauma — Animal models have demonstrated that cyclic alveolar expansion (during inspiration) and collapse (during expiration) creates shear forces that distend and cause injury to adjacent alveoli and airways (figure 3) [16-18]. Specifically, non-atelectatic alveoli are exposed to the injurious impact of neighboring atelectatic alveoli that are opening and collapsing during tidal breathing. This process is referred to as cyclical atelectasis, or atelectrauma. Surfactant depletion or dysfunction may play a role in atelectrauma [19]. Strategies aimed at limiting atelectrauma (eg, high positive end-expiratory pressure and open lung ventilation) have had mixed effects in human trials and are discussed separately. (See "Acute respiratory distress syndrome: Ventilator management strategies for adults", section on 'Open lung ventilation'.)

Biotrauma (inflammation) — Biotrauma is characterized by ventilator-induced release of inflammatory mediators from cells within the injured lung [20-22]. Both alveolar overdistension and atelectrauma have been shown in animals to result in an increase in inflammatory mediators (from neutrophils, macrophages, and likely alveolar epithelial cells) including tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-8, matrix metalloproteinase-9, and transcription factor nuclear factor (NF)-kB [23-26]. In patients with ARDS, similar inflammatory mediators are elevated and several randomized trials that show a mortality benefit to low tidal volume ventilation (LTVV), also report a concurrent reduction in lavage and serum cytokines with LTVV strategies [27,28]. Another study demonstrated that the changes in serum cytokine levels can occur within one hour of a change in ventilatory strategy, suggesting that even relatively short periods of injurious ventilation may be deleterious [29-31]. There is also evidence that injurious ventilatory strategies may lead to the subsequent development of pulmonary fibrosis (in animals) [32] and to the development of multi-organ failure (in humans) [33,34], although the precise mechanisms are unclear. However, many of the strategies that target inflammation in ARDS/VILI have not been successful, although corticosteroids may be of value in select circumstances. (See "Acute respiratory distress syndrome: Ventilator management strategies for adults", section on 'Low tidal volume ventilation: Initial settings' and "Acute respiratory distress syndrome: Investigational or ineffective therapies in adults", section on 'Anti-inflammatory therapies' and "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults", section on 'Glucocorticoids'.)

CLINICAL FEATURES AND DIAGNOSTIC EVALUATION — The clinical presentation and diagnostic evaluation of patients with ventilator-associated lung injury (VALI) is similar to patients with progressive acute respiratory distress syndrome (ARDS) with the major difference being that the features develop while on mechanical ventilation itself. (See "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults".)

Clinical presentation — While on mechanical ventilation, patients typically develop worsening hypoxemia or require a greater fraction of inspired oxygen (FiO₂) to maintain the same arterial oxygen tension (PaO₂) or arterial oxyhemoglobin saturation (SaO₂). Patients become more tachypneic and tachycardic. The chest radiograph typically shows new or increased bilateral interstitial or alveolar opacities of any severity (image 1). Computed tomography (CT) of the chest demonstrates heterogeneous consolidation and atelectasis, as well as focal hyperlucent areas that represent overdistended lung (image 2). VALI may also be associated with new organ failure [35]. (See "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults", section on 'Clinical features'.)

Diagnostic evaluation — VALI is a clinical diagnosis based upon the features described above (see 'Clinical presentation' above) and the exclusion of alternative causes of respiratory deterioration and/or ARDS (table 1) in mechanically ventilated patients. The approach is similar to that in patients with suspected ARDS (see "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults"). However, there are some features that are different, the details of which are discussed in this section.

New pulmonary infection and pulmonary edema are the most common etiologies that need to be excluded. However, additional etiologies that occur as a consequence of being critically ill or mechanically ventilated also need to be considered; these include sepsis, aspiration, barotrauma, auto-positive end-expiratory pressure (auto-PEEP), drug or transfusion reactions, venous, fat, air, or amniotic fluid embolism, intra-abdominal distension, endotracheal tube displacement, lobar collapse, pleural effusion, and acute coronary syndromes. We suggest the following general approach:

●Patients should be re-examined for evidence of infection, bronchoconstriction, fluid overload (eg, crackles, edema, elevated jugular venous pulse), barotrauma (eg, unilateral reduced air entry, crepitus), venous thrombosis (lower extremity swelling or erythema), or abdominal hypertension limiting respiration (tense abdomen, ileus). (See "Assessment of respiratory distress in the mechanically ventilated patient" and "Abdominal compartment syndrome in adults", section on 'Clinical presentation'.)

●A drug history (allergy or drug reaction) and blood product transfusion history (eg, pulmonary edema or transfusion-related lung injury) should be obtained. (See "Transfusion-related acute lung injury (TRALI)" and "Approach to the patient with a suspected acute transfusion reaction".)

●Ventilator settings should be assessed for tidal volume settings >6 mL/kg/min and the presence of auto-PEEP, high peak and plateau pressures (although high peak pressures can occur in the context of increased airway resistance, and high plateau pressures can also be due to a stiff chest wall). Ventilator equipment should also be examined for faulty expiratory valves and heat moisture exchangers. (See "Diagnosis, management, and prevention of pulmonary barotrauma during invasive mechanical ventilation in adults", section on 'Barotrauma diagnosis and management'.)

●Patients should also undergo routine laboratory testing (including lipase, coagulation studies, cardiac enzymes), arterial blood gas analysis, chest radiography (eg, new infiltrates, lobar collapse, mainstem intubation, pneumothorax, pleural effusion), and electrocardiography (ST segment changes, new rhythm disturbance).

Most etiologies should be identified with initial testing. Further testing should be targeted at the suspected etiology and may include computed tomography (CT) chest, blood and other body fluids culture, echocardiography, lower extremity Doppler studies, and rarely CT pulmonary angiography, bronchoscopy, or lung biopsy. Pulmonary artery catheterization is almost never required unless volume status is unclear. (See "Pulmonary artery catheterization: Indications, contraindications, and complications in adults", section on 'Indications'.)

PREVENTION AND MANAGEMENT — VILI is often an iatrogenic disease; its prevention in ventilated patients is critical. For patients with suspected ventilator-associated lung injury (VALI), we adjust ventilator settings to follow lung protective ventilation used in patients with acute respiratory distress syndrome (ARDS) to prevent further lung injury. (See "Acute respiratory distress syndrome: Ventilator management strategies for adults", section on 'Low tidal volume ventilation: Initial settings'.)

First line strategies — The prevention and management of VALI is the same as for patients with ARDS.

●Patients with ARDS – In patients with ARDS, alveolar overdistension is mitigated (but not always prevented) by using small tidal volumes of 6 mL/kg predicted body weight (PBW) and maintaining a plateau pressure of ≤30 cm H₂O using a positive end-expiratory pressure (PEEP) strategy outlined in the table (table 2 and table 3 and table 4). Some data suggest that a key ventilatory variable determining outcome is the driving pressure (driving pressure = plateau pressure - PEEP) [36], or the mechanical power delivered to the respiratory system [37]. Retrospective analysis of data from previous clinical trials suggest a combination of driving pressure and respiratory rate is somewhat more predictive of mortality than the more complex calculation of mechanical power. However, there are no prospective studies demonstrating whether ventilatory strategies should specifically aim to reduce either of these variables [38]. (See "Acute respiratory distress syndrome: Ventilator management strategies for adults".)

●Patients without ARDS – In patients who do not have ARDS, we typically choose a protective ventilatory strategy similar to those with ARDS. This approach is based upon a few trials that have examined the effect of low tidal volume ventilation (LTVV) in this population. Other strategies targeted at atelectrauma (eg, high PEEP, open lung) have not been studied in patients without ARDS. Data to support LTVV in patients without ARDS are discussed separately. (See "Overview of initiating invasive mechanical ventilation in adults in the intensive care unit", section on 'Tidal volume'.)

Second line strategies — Other strategies that may be used when first line strategies fail include:

●High PEEP – Other ventilator strategies including open lung ventilation, monitoring driving pressure, and recruitment maneuvers which are discussed separately. (See "Acute respiratory distress syndrome: Ventilator management strategies for adults" and "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults".)

●Paralysis – Neuromuscular blockers may be required in select circumstance when sedation has failed to correct conditions that confer a predisposition to VILI (eg, breath stacking) [39]. (See "Neuromuscular blocking agents in critically ill patients: Use, agent selection, administration, and adverse effects" and "Acute respiratory distress syndrome: Ventilator management strategies for adults", section on 'Neuromuscular blockers' and "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults", section on 'Paralysis (neuromuscular blockade)'.)

●Prone positioning – Prone positioning has been shown to be effective in patients with severe ARDS and is discussed separately. (See "Prone ventilation for adult patients with acute respiratory distress syndrome".)

●Extracorporeal membrane oxygenation (ECMO) – One strategy to decrease the physical stress induced by mechanical ventilation is to use ECMO or extracorporeal CO₂ removal (ECCO₂R) to achieve gas exchange. However, although preliminary data suggest that ECMO may reduce mortality in patients with very severe ARDS [40-42], the use of ECMO or ECCO₂R as an initial strategy to prevent VILI is unproven. (See "Acute respiratory distress syndrome: Investigational or ineffective therapies in adults" and "Extracorporeal life support in adults in the intensive care unit: Overview".)

INVESTIGATIONAL THERAPIES — Several strategies have been used by experts without success, many of which are discussed separately. (See "Acute respiratory distress syndrome: Investigational or ineffective therapies in adults".)

High frequency ventilation should be avoided as an initial strategy in most patients with acute respiratory distress syndrome. (See "High-frequency ventilation in adults".)

The value of sedatives such as ketamine is unclear [43].

SUMMARY AND RECOMMENDATIONS

●Ventilator-induced lung injury (VILI) is the process of acute lung injury that develops during mechanical ventilation. Ventilator-associated lung injury (VALI) is an iatrogenic disease that results from VILI and exists if a causative relationship cannot be proven. Self-induced lung injury is that due to excessive tidal volume due to spontaneous breaths. (See 'Definitions (VILI, VALI, SILI)' above.)

●VALI is commonly seen in patients receiving mechanical ventilation for acute respiratory distress syndrome (ARDS). However, VALI can occur in patients who are receiving mechanical ventilation for reasons other than ARDS. Other risk factors include large tidal volumes, blood product transfusions, acidemia, and restrictive lung disease. (See 'Incidence and risk factors' above.)

●Alveolar overdistension, atelectrauma, and biotrauma are the principal mechanisms of VILI, although the relative contribution of each is unknown [9]. Alveolar injury results in high alveolar permeability, interstitial and alveolar edema, alveolar hemorrhage, hyaline membranes, loss of functional surfactant, and alveolar collapse (ie, ARDS) [1,10,11].

●VALI is a clinical diagnosis based upon the clinical features of ARDS and the exclusion of alternative causes of respiratory deterioration and/or ARDS (table 1) in mechanically ventilated patients. (See 'Clinical features and diagnostic evaluation' above.)

•The clinical presentation and diagnostic evaluation of patients with suspected VALI is similar to patients with progressive ARDS with the major difference being that the features develop while on mechanical ventilation itself. (See "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults" and 'Clinical presentation' above.)

•New pulmonary infection and pulmonary edema are the most common etiologies that need to be distinguished from VALI. However, additional etiologies that occur as a consequence of being critically ill or mechanically ventilated also need to be considered (eg, sepsis, aspiration, barotrauma, auto-positive end-expiratory pressure [auto-PEEP], drug or transfusion reactions, venous, fat, air, or amniotic fluid embolism, intra-abdominal distension [ascites, ileus, or intra-abdominal hypertension], endotracheal tube displacement, lobar collapse, pulmonary effusion, and acute coronary syndromes). (See "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults" and 'Clinical features and diagnostic evaluation' above.)

●Patients with VALI are managed in an identical fashion to patients with ARDS (table 2 and table 3 and table 4). Therapies that target biotrauma have largely not been evaluated to date. (See 'Prevention and management' above and "Acute respiratory distress syndrome: Ventilator management strategies for adults" and "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults" and 'Investigational therapies' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Arthur S Slutsky, MD, who contributed to earlier versions of this topic review.