The terms ventilator-associated lung injury (VALI) and ventilator-induced lung injury (VILI) have been used frequently in the literature with some inconsistency regarding their meaning. The term VALI is generally used when referring to lung injury occurring in humans that has been identified as a consequence of mechanical ventilation.2 The most common forms of VALI include ventilator-associated pneumonia (VAP), air trapping, patient-ventilator asynchrony, and extra-alveolar gas (barotrauma) such as pneumothorax and pneumomediastinum. (See Chapter 14 for a discussion of ventilator-associated pneumonia.)

VILI is lung injury that occurs at the level of the acinus. It is the microscopic level of injury that includes biotrauma, shear stress, and surfactant depletion (atelectrauma). VILI can be specifically studied only in animal models because ventilator strategies that will potentially harm the lung cannot be performed on human subjects during research investigations.

VILI is a form of lung injury that resembles ARDS. It has been studied using animal models and apparently occurs in patients receiving inappropriate mechanical ventilation. VILI is difficult to identify in humans because its appearance is based on radiologic and clinical findings, which overlap with the findings that occur with the underlying pulmonary pathology, such as ARDS. In fact, it is reasonable to assume that acute lung injury (ALI) and ARDS may be partially the result of ventilator management rather than the progression of the disease.³ This supports the idea that mechanical ventilation not only saves lives but has the potential to worsen preexistent lung injury.¹

The following section defines and describes the various forms of VALI and VILI (Key Point 17-1).

The risk of rupture to the lung is greater for patients with lung bullae or chest wall injury. A number of conditions can predispose a patient to barotrauma (extra-alveolar air). Some of these include the following4,5:

Barotrauma occurs when gas under pressure causes alveolar rupture. Air is forced into the interstitium of an adjacent bronchovascular (perivascular) sheath in the area of the distal noncartilaginous airways.4,6 The “escaped” air moves along the sheath toward the hilum and mediastinum, causing a pneumomediastinum (Fig. 17-1).^4,7 Air can then break through the pleural surface of the mediastinum into the intrapleural space, resulting in a pneumothorax. Pneumothorax may be unilateral or bilateral. Air in the mediastinum also may dissect along tissue planes, producing subcutaneous emphysema. Pneumoperitoneum may follow pneumomediastinum and occurs when air dissects initially into the retroperitoneum. Air that is trapped under the diaphragm in the peritoneum may interfere with effective ventilation.

From its location in the mediastinum, air can also dissect along tissue planes near the heart and form a pneumopericardium.2 The escaped air can be reabsorbed into adjacent tissues and resolve itself. If it is not reabsorbed by the body, evacuation by a drainage system may be required. Failure to remove this extra-alveolar air can lead to life-threatening problems, such as tension pneumothorax or pneumopericardium.

In early studies, researchers tried to determine whether lung injury was caused by high pressures (barotrauma) or high volumes (volutrauma). Dreyfuss and colleagues coined the term volutrauma to describe the injurious effects of mechanical ventilation they observed in laboratory studies using an animal model.12 These investigators found that it was not high pressure but the relatively large regional volumes that overstretched compliant areas of the lung that resulted in alveolar stretch and edema formation in these areas.^12,13

It is now generally accepted that using inordinately high tidal volume can lead to lung overdistention and iatrogenic lung injury. Overdistention occurs in those areas of the lungs where high distending pressures—in other words, high transpulmonary pressures (alveolar pressure-pleural pressure [P_alv−P_pl])—are present. Indeed, pressures as low as 30 to 35 cm H₂O have been shown to cause lung injury in animals.^4,12

Because regional differences in lung compliance and transpulmonary pressures (P_L) occur in most pulmonary disorders, positive pressure applied to the lung tends to produce larger volumes in more compliant lung areas (Box 17-1). The resulting overdistention to these areas causes acute alveolar injury and the formation of pulmonary edema by both increased permeability and filtration mechanisms. Tidal volumes of 10 to 12 mL/kg can cause overdistention of these areas of greater compliance.

Additional animal studies found that when the chest wall movement was restricted by binding the thorax and pressure was applied to the lungs, less lung injury occurred.^12–14 Thoracic binding prevented severe transpulmonary (alveolar-distending) pressure. Furthermore, alveolar stretch and edema formation did not occur under these conditions. In the clinical setting, restriction to chest wall movement is present when patients are in the prone position, in severely obese patients, or when heavy dressings are used to manage surgical sites of chest or chest wall injuries (Box 17-2).¹⁵

To understand the importance of pressure in this setting and its distribution, several circumstances that affect lung pressures must be examined. Pressure at the upper airway is not equal to alveolar pressure (P_alv) except when flow is zero and the airway is open. (This is usually termed plateau pressure, or P_plateau.) To interpret P_alv, or P_plateau, the circumstances in which it is measured should be known. The following are seven of these circumstances¹⁵:

Figure 17-2 shows a pressure-volume curve that indicates the presence of overdistention. The shape of this curve is sometimes said to have a “duck-billed” appearance. Most clinicians now believe that this portion of the curve occurs with overdistention of more compliant areas of the lung, resulting in volutrauma. For the sake of simplicity, the term barotrauma will be used in this text to imply the leaking of air into body tissues (extra-alveolar air leak) and the term volutrauma to describe damage from overdistention that occurs at the alveolar level and involves alveolar and interstitial edema formation, alveolar stretch, and biotrauma.

The term atelectrauma is used to describe the injuries to the lungs that occur because of repeated opening and closing of lung units at lower lung volumes. Atelectrauma can occur in the management of ALI/ARDS when low tidal volumes are used and inadequate levels of PEEP are applied (see Chapter 13). Under these circumstances, alveoli tend to open on inspiration and close on expiration. (This most often occurs in the dependent areas of the lung. In supine patients this would be the dorsal area near the spine.) The repeated opening and closing of lung units in ALI/ARDS produces three primary types of lung injury: shear stress, alteration and washout of surfactant, and microvascular injury.^16–18

Research studies involving animal models showed that ventilating pressures of 30 to 80 cm H₂O produce atelectrauma with resulting reduced compliance and severe hypoxemia. Atelectrauma may be described as alveolar rupture, interstitial emphysema, or perivascular and alveolar hemorrhage, which can eventually lead to death.^12,19–26 Death occurred in experimental animal models in some cases within an hour.

Shear Stress

Shear stress occurs when an alveolus that is normally expanded is adjacent to one that is collapsed (atelectasis) and unstable. As airway pressure increases during inspiration, the normal alveolus inflates, but the collapsed unit does not. In the interstitial space between the two, force is exerted as these two units move or slide against each other. There is a potential zone of risk at the interface of open and closed lung units. This is similar to what occurs when a paper clip is repeatedly twisted; eventually the paper clip breaks. In the lung, the stress pulls normal tissues apart, resulting in physical damage to the alveolar cells, particularly epithelial and endothelial cells (pulmonary microvasculature). The term shear stress has been applied to this type of situation. The amount of stress across the entire lung can be estimated by using transpulmonary pressure (P_plateau−P_pl), where P_plateau represents P_alv and P_pl is the intrapleural pressure (Fig. 17-3, Key Point 17-2).^5,27

 Key Point 17-2

Shear stress causes intense strain and rupture of lung tissue, which may lead to an inflammatory response and edema formation.

The importance of shear stress has been known for a number of years. In fact, more than 30 years ago, Mead and colleagues28 calculated from a model that a transpulmonary pressure of only 30 cm H₂O could result in a stress of 140 cm H₂O being exerted between two adjacent alveoli as one expands and the other unstable unit remains collapsed. Not surprisingly, this force acting on the delicate tissues of the acinus can result in tearing of alveolar epithelium and capillary endothelium along with other structural injury.

Mechanical stress disrupts normal cell function, strains normal cell configuration, and can also lead to an inflammatory response in the lungs.13 Current theory suggest that pulmonary cells, particularly epithelial cells, become distorted during mechanical ventilation when they are overstretched (overdistention). This overdistention causes the release of chemical mediators (i.e., cytokines). In addition to epithelial cells, the alveolar macrophages are another important source of inflammatory mediators, which are produced in response to a stretching strain and result in a potential molecular and cellular basis for VILI (Box 17-3).^30–35

It is important to understand that ALI/ARDS does not have to be present for this inflammatory response to occur. However, when the inflammatory mediators are released, the lung begins to resemble that of a lung with ALI/ARDS. Indeed, the damage that can be caused by ventilator mismanagement may actually be indistinguishable from the underlying disease process of ARDS.³

Chemical mediators produced in the lung can leak into the pulmonary blood vessels. The circulation then carries these substances to other areas of the body and sets up an inflammatory reaction in other organs, such as the kidneys, gut, and liver.31,36 The release of mediators may therefore lead to multiple organ failure, also called multisystem organ failure and multiple-organ dysfunction syndrome.^2,37,38

Treating patients with ARDS with lung-protective strategies, such as low VT and therapeutic PEEP, can significantly reduce morbidity and mortality rates in these patients (see Chapter 13).^35,39–41 It also has been suggested that hypercapnia may be beneficial in patients with ARDS who are difficult to ventilate because it has an antioxidant effect and may actually reduce inflammation. Therapeutic hypercapnia may actually be a more appropriate name, but additional studies are needed (see Chapter 13).^13,42–44

A third problem that can occur with repeated alveolar collapse and reopening involves the pulmonary microvasculature. Recall that during a positive-pressure breath, alveolar capillaries flatten out, but corner microalveolar vessels open wider (see Fig. 13-16). The interstitial areas adjacent to the corner vessels develop negative pressure relative to the inside of the vessels. This negative-pressure gradient tends to pull fluid and blood products out of the vessels and into the space. Thus the alveoli and perivascular areas become edematous.

If the vascular pressure of the lung is further increased, at a certain point the vessel can rupture and release red blood cells and other blood components into the alveoli and interstitial space (Fig. 17-4). In Mead’s model, a stress of 140 cm H₂O was proposed as occurring between two alveoli as one expanded and the other unit remained collapsed.²⁸ This pressure could also be transmitted to the pulmonary vessels, which could represent a second cause of vessel rupture. The increased fluid leaking into the lung would create a dramatic increase in lung weight, which may be one of the mechanisms associated with the hemorrhagic appearance of lungs on autopsy in animal models subjected to low VT ventilation without PEEP (Fig. 17-5).⁴⁵ Studies using a canine model have shown that it takes 90 to 100 mm Hg to produce this phenomenon. Perhaps leaving areas of the lung collapsed or at least ventilating them at low pressures might not damage the lung or the vasculature. Whether resting parts of the lung is better than trying to recruit the majority of the lung will require additional studies.

One of the original studies conducted by Webb and Tierney22 in the early 1970s showed that using inspiratory pressures of 45 cm of H₂O without PEEP resulted in the rapid death of normal rats. Their study is frequently cited as evidence of the benefits of using protective ventilatory strategies. Interestingly, their discovery took nearly two decades to be recognized. In a 2003 editorial, Tierney²⁹ wrote, “… we could hardly believe the results. It was as if we violated a thermodynamic law and got more out of it than we put into it. … Within minutes the rats were cyanotic and appeared moribund. … It took a decade or two for others to conclude that human lungs could be injured by such ventilation. … Our final paragraph 30 years ago suggested management … using protective ventilation and low tidal volumes.”

In ALI, PEEP appears to provide some protection from tissue damage when high pressures are used. This is especially true if PEEP levels are greater than the opening pressure for recruitable alveoli. PEEP helps restore functional residual capacity (FRC) by recruiting previously collapsed alveoli. Adequate levels of PEEP prevent repeated collapse and reopening of alveoli and help maintain lung recruitment.14,27 However, if PEEP overinflates already patent alveoli, then increasing PEEP for a given VT may maximally stretch alveoli. This situation also may reduce cardiac output. Safely establishing an optimum PEEP level is not an exact science and can be challenging in critically ill patients. (Case Study 17-2; see Chapter 13 for additional information on setting PEEP.)⁴⁶

To summarize, lung injury may occur as a result of either overdistention of the lungs or from repeated opening and closing of lung units throughout the respiratory cycle during mechanical ventilation.⁴⁶ These two phenomena can result in shear stress and alveolar injury, edema formation, surfactant washout or alteration, microvascular injury, stretch injury, and biotrauma. Stretch injury and the associated biotrauma produces inflammatory mediators by lung tissue and leaking of these mediators into the circulation, where they have the potential of affecting distal organs and ultimately causing multiple-organ dysfunction syndrome.³⁷ Research findings strongly support the concept of maintaining P_plateau at less than 30 cm H₂O, setting low V_T, and using enough PEEP to adequately maintain open alveoli in patients with ARDS to avoid lung injury from mechanical ventilation.⁴⁷

It is clear that delivering high airway pressures and volumes during mechanical ventilation can lead to damage to the lung parenchyma. Recent studies have shown that mechanical ventilation may also cause damage to the respiratory muscles.45 Specifically, imposing too little stress on the diaphragm during mechanical ventilation by lowering the demands on a patient’s respiratory muscles can induce respiratory muscle weakness.⁴⁶

Laboratory studies using animal models have shown that prolonged controlled mechanical ventilation in which complete diaphragmatic inactivity occurs (i.e., no respiratory efforts are made and the mechanical ventilator performs all of the WOB) can lead to a significant decrease in the cross-sectional area of diaphragmatic fibers.⁴⁷ More recent studies by Levine and colleagues involving human subjects support these findings.⁴⁸ In their studies, Levine and colleagues obtained diaphragmatic muscle biopsies from mechanically ventilated patients who exhibited complete diaphragmatic inactivity for 18 to 69 hours. Histologic measurements of these muscle samples from the costal diaphragm revealed marked diaphragmatic atrophy. Biochemical analysis of the muscle samples suggested that the atrophy occurred as a result of increased oxidative stress and activation of protein-degradation pathways.⁴⁸

The implications of these findings on clinical management of mechanically ventilated patients are unclear at this time. Additional clinical studies will be required to identify more completely the presence of ventilator-induced respiratory muscle weakness and its effect on weaning and ventilator discontinuation. Although respiratory muscle weakness can result from ventilator injury, it is important for clinicians to recognize that it can be associated with other medical conditions and interventions, such as sepsis and pharmacologic therapy (e.g., antibiotics, corticosteroids, sedatives, and neuromuscular blocking agents.⁴⁶

Early studies of the effects of positive-pressure breathing on the gas distribution in the normal lungs were conducted more than 30 years ago. Froese and Bryan49 evaluated the movement of the diaphragm in spontaneously breathing, anesthetized adult volunteers. During spontaneous ventilation in the supine position, the greatest displacement of the diaphragm occurs in the dependent region, near the back (Fig. 17-6, A).⁴⁹ The dependent lung areas receive a higher portion of ventilation and perfusion (i.e.,  is best matched). When anesthesia is administered but spontaneous ventilation is still present, the diaphragm shifts its movement cephalad, toward the head. The effect of this shift is most pronounced in the dependent (dorsal) regions of the lung, the reverse of normal (Fig. 17-6, B). With anesthesia and the administration of paralytic agents, the contraction of the diaphragm is blocked. When PPV is provided, the diaphragm is most displaced in the nondependent regions of the lung (Fig. 17-6, C). The diaphragm becomes less compliant than the chest wall adjacent to the anterior part of the lungs in the supine patient. This alters the ratios by directing the greatest amount of gas flow to the nondependent lung regions, taking the path of least resistance. Unfortunately, this is also the area with the least blood flow.

During PPV, alveolar collapse is suspected to most likely occur in the dependent areas with absence of spontaneous diaphragmatic movement. These are also the areas that receive the most blood flow, resulting in increased mismatching of ventilation and perfusion and increased dead space ventilation.49

Experimental studies have shown that during spontaneous ventilation, the distribution of gas favors the dependent lung areas and also appears to favor the periphery of the lung closest to the moving pleural surfaces. The peripheral areas receive more ventilation than the central areas.51,52 However, during a positive-pressure breath with passive inflation of the lung (paralysis), the central, upper airway, or peribronchial portions of the lung are preferentially filled with air.⁵¹ This may be another mechanism by which mismatching occurs during PPV. If spontaneous breathing can be preserved when possible, these changes in associated with mechanical ventilation may be reduced. Thus ventilator modes that preserve spontaneous breathing may be beneficial (e.g., pressure support ventilation [PSV]).

Normal pulmonary blood flow favors the gravity-dependent areas and the central, or core, areas of the lungs. However, during PPV, particularly when PEEP is administered, cardiac output may decrease and pulmonary perfusion redistributes to the lung periphery rather than to the center area (i.e., as if the lung had been exposed to a centrifugal force).53 The clinical significance of this is unknown, but it may influence matching.

The increased volume during a positive-pressure breath and PEEP squeezes the blood out of nondependent zones, particularly in areas of normal lung. This further contributes to mismatching and physiological dead space by sending more blood into dependent areas, where ventilation is now lower, or into disease-affected areas of the lung, where lung volumes are not substantially increased. This can lead to increased shunting and decreased PaO₂.⁵⁴

Conversely, improvement in matching occurs when PEEP is applied to patients who have refractory hypoxemia resulting from a decreased FRC and increased shunting (i.e., ALI/ARDS). PEEP reduces intrapulmonary shunting resulting in an increase in PaO₂. This increase in PaO₂ implies improvement in matching.^2,6,55,56 A classic and predictable response of gas distribution and pulmonary perfusion during PPV apparently does not exist.

As described previously, pulmonary perfusion may be compromised during PPV, especially when high levels of PEEP are also applied. Increased airway and alveolar pressures can lead to thinning and compression of pulmonary capillaries, decreased perfusion, and increased pulmonary vascular resistance (PVR) (Fig. 17-7). Fortunately, if expiration is prolonged and unimpeded (i.e., PEEP is not applied), the decreased pulmonary perfusion may be offset by normal flow back into the thorax during expiration with no net effect on PVR.

Rapidly rising PaCO₂ levels and falling pH values can lead to serious problems, including coma. Elevated plasma hydrogen ion levels can contribute to high plasma potassium levels (hyperkalemia), which can affect cardiac function and can lead to cardiac dysrhythmias (Box 17-4). Hypercapnia also increases cerebral perfusion and can lead to increased intracranial pressure, which can be detrimental to patients with cerebral trauma, cerebral hemorrhage, or similar disorders.

On the other hand, in patients with ARDS, ventilation may be difficult to maintain without causing VILI. In these situations, permissive hypercapnia may be appropriate. In addition, hypercapnia may reduce the release of inflammatory mediators (see Chapter 13).^42–44 Ultimately, the decision to allow respiratory acidosis to persist must be carefully evaluated on the basis of the patient’s condition.

The kidneys normally can compensate for respiratory acidosis within 18 to 36 hours. Obviously, it is desirable for problem to be corrected by increasing alveolar ventilation rather than waiting for renal compensation. Increasing ventilation can be accomplished by increasing the VT or mandatory rate.

When respiratory acidosis is present, patients receiving controlled mechanical ventilation may try to override the ventilator and take in a breath. They may not be able to trigger the machine or receive adequate flow and will appear to be fighting the ventilator. Increasing the sensitivity or flow will allow the patient to trigger the ventilator and receive an adequate breath. (See the discussion of ventilator asynchrony in this chapter.)

Hyperventilation results in a lower than normal PaCO₂ and a rise in pH. Patient-induced hyperventilation is often associated with hypoxemia, pain and anxiety syndromes, circulatory failure, and airway inflammation. Ventilator-induced hyperventilation is generally caused by inappropriate ventilator settings. Alkalosis causes a left shift in the oxygen dissociation curve, which enhances the ability of hemoglobin to pick up oxygen in the lungs but makes it less available at the tissue level (i.e., the Haldane effect). Reduced hydrogen ion concentrations in the blood (i.e., arterial pH) are often accompanied by hypokalemia (low potassium levels), which can lead to cardiac arrhythmias (Box 17-5).

Box 17-5

Clinical and ECG Changes Associated with Respiratory Alkalosis and Hypokalemia

Clinical Signs and Symptoms

• Cool skin (decreased PaCO₂)

• Twitching

• Tetany

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Related posts:

1. Ventilator-Associated Pneumonia
2. Basic Concepts of Noninvasive Positive-Pressure Ventilation
3. Weaning and Discontinuation from Mechanical Ventilation
4. Methods to Improve Ventilation in Patient-Ventilator Management

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