NEW YORK--Mechanical ventilation may be the mainstay of treatment for acute respiratory distress syndrome (ARDS), but recent studies show that how ventilation is delivered may strongly influence the risk of lung injury. This research has raised questions about the pathophysiology and incidence of ventilator-associated lung injury (VALI) in patients with--or at high risk for--ARDS.

Recently, the American Thoracic Society, the European Society of Intensive Care Medicine, and the Societé de Réanimation de Langue Française, published a consensus report to address five key questions about VALI in patients with ARDS[1]:

• What are the factors responsible for VALI?
• What is the evidence that VALI occurs in ARDS patients?
• What are the risk factors and incidence of VALI, and how does it alter outcome?
• How can VALI be detected and monitored?
• Can nonpharmacologic methods prevent VALI?

The consensus report defines VALI as "lung injury that resembles ARDS and that occurs in patients receiving mechanical ventilation." Among the report's key conclusions was that low tidal volumes decrease mortality risk in ventilated patients. In fact, according to Michael A. Matthay, MD, professor of medicine and anesthesia at the University of California, San Francisco, smaller ventilator breaths of oxygen-rich air may protect the lung from injury and can reduce the mortality rate in patients with ARDS by up to 20%. Dr. Matthay, a coauthor of the consensus report, was one of the principal investigators of a breakthrough study on lung injury in ARDS, which detected the survival advantage with low tidal volume ventilation.

CAUSES

Many recent studies have shown that it is possible to induce alveolar and airway damage with mechanical ventilation. Before these studies, investigators had assumed that ventilator-induced damage was confined to air leaks, such as pneumothoraces. Now it is known that more subtle morphologic, structural, and physiologic changes may develop in ventilated patients.

Alveolar overdistention rather than high proximal airway pressure--that is, volutrauma rather than barotrauma--is the primary determinant of the lung injury; the consensus committee members acknowledge that this represents a major shift in thinking about the pathogenesis of ventilator-induced complications. However, the distinction between volutrauma and barotrauma may not be as clear-cut as has been thought. The consensus committee members note that increased transpulmonary pressure is responsible for the alveolar distention; thus, VALI remains a form of barotrauma--albeit a somewhat different form than previously thought.

According to the consensus report, the most important factors responsible for VALI are:

• High lung volumes associated with elevated transpulmonary pressure.
• Alveolar overdistention and repeated alveolar collapse and reopening due to low end-expiratory volume.

Other factors include pre-existing lung damage or inflammation, a high inspired oxygen concentration, the level of blood flow, and local production and systemic release of inflammatory mediators.

EVIDENCE

As the consensus report notes, "Clinical observations can only infer that VALI occurs in humans"; it is impossible to conduct trials that prove that mechanical ventilation causes lung injury in humans. Nevertheless, the lungs of mechanically ventilated patients with ARDS have physiologic, radiologic, and histopathologic features that resemble the types of lung injury induced by ventilation in animal models, including interstitial and alveolar edema, hemorrhage, hyaline membranes, neutrophilic alveolitis, and diffuse alveolar damage. As injury worsens and the duration of ventilation progresses, the lung structure undergoes dramatic remodeling: fibroproliferation, regional loss of lobular and alveolar architecture, cyst formation, and local emphysema. But the committee members note that "these changes in lung structure could be due to either progression of adult respiratory distress syndrome, ventilator-associated lung injury, or both."

In contrast, barotrauma--which can result from a single overinflation of the lungs--occurs in mechanically ventilated patients with severe ARDS. This overdistention may also result in more subtle forms of injury, such as pulmonary edema. Furthermore, the mechanisms responsible for VALI are complex and may require repeated mechanical insults, the authors add.

RISK, INCIDENCE, OUTCOME

The consensus committee members note that "Because VALI may not be readily defined or detected, our ability to determine its independent risk factors, incidence, and effects on outcome is inherently hampered." As a result, there are currently no prospective clinical studies that have identified these variables.

Many researchers believe that ARDS increases the risk of VALI, because patients with neuromuscular disease who undergo prolonged ventilation do not appear to suffer lung injury. However, it remains unclear whether specific groups of patients with ARDS may be at increased risk.

Because it can be difficult to separate the effects of VALI from the effects of ARDS, barotrauma is often used as a surrogate marker for VALI. Estimates of the incidence of barotrauma in patients with ARDS vary widely (from 5% to 50%); but in most studies, the incidence ranges from 5% to 15%. However, there appears to be a threshold in airway pressure above which the incidence of barotrauma rises dramatically--35 cm H2O.

In patients who die of ARDS, histopathologic studies reveal a greater than 85% incidence of cysts, bronchiolar dilatation, or alveolar overdistention. As expected, more severe lesions are seen at high airway pressures, tidal volumes, and concentrations of oxygen. However, studies have not evaluated specific lesions as predictors of outcome.

DETECTION AND MONITORING

Detection and monitoring of VALI presents a challenge because "There are no clinical symptoms, signs, changes in physiological variables, or bedside investigations that are specific to detect VALI," according to the consensus report. Nevertheless, VALI should be considered as part of the differential diagnosis if respiratory function deteriorates in an ARDS patient who is undergoing mechanical ventilation. However, other potential causes of the patient's deterioration, such as progression of ARDS, pulmonary or extrapulmonary infection, fluid overload, and absorption atelectasis, should not be overlooked.

The consensus report notes that "trials to minimize the potential impact of VALI have used the PV [pressure-volume] curve of the respiratory system to assess mechanics and titrate ventilator settings." Strategies that have been investigated include setting positive end-expiratory pressure above the lower inflection point, which appears to maintain recruitment, and setting the plateau pressure lower than the upper inflection point of the PV curve, which seems to avoid overdistention. However, the report adds that the inflection points on the PV curve can be difficult to identify. Furthermore, they are affected by chest wall compliance (not just lung compliance), which suggests that in clinical practice these points may not indicate lung recruitment and overdistention.

The consensus report points out that "Increases in peak inspiratory and plateau pressures during volume-controlled ventilation, or a decrease in tidal volume during pressure-controlled ventilation, may indicate deterioration in lung mechanics potentially related to VALI." It also suggests that VALI may be associated with a decrease in the arterial oxygen tension (PaO2) or the ratio of PaO2 to the fraction of inspired oxygen, and/or an increase in the arterial carbon dioxide pressure. The report warns, however, that "Such changes … virtually always have other potential explanations."

NONPHARMACOLOGIC PREVENTION

Five randomized trials have evaluated ventilatory strategies to prevent or attenuate VALI in adults with or at risk for ARDS. From these trials, the committee members concluded that:

• Use of high tidal volumes (12 mL/kg), which can result in high transpulmonary pressures and plateau airway pressures above 30 to 35 cm H2O, is potentially hazardous in that it can increase the risk of barotrauma and death. However, the consensus report noted that not all studies support the use of lower tidal volumes. Furthermore, it suggests the clinical studies performed to date "may not have specified a lung protective strategy derived from low tidal volume ventilation so much as they have identified risks associated with high tidal volume ventilation."
• Simply reducing tidal volume to 6 mL/kg or less (with a plateau airway pressure below 30 cm H2O) appears to be safe and is associated with a better outcome.
• An increase in positive end-expiratory pressure titrated to the pressure volume curve may protect against VALI, but further testing is needed.

Prone positioning may also help to prevent VALI, according to the report. But safety concerns, such as accidental extubation and catheter removal, hemodynamic instability, and pressure necrosis, could limit use of the prone position. Randomized trials are needed to better understand the benefits and risks.

--Margaret A. Inman

Reference
1. International Consensus Conferences in Intensive Care Medicine: Ventilator-associated Lung Injury in ARDS. Am J Respir Crit Care Med. 1999;160:2118-2124.

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