Silverstein and Hopper Chapter 39: Ventilator-Induced Lung Injury + Hess Chapter 3: Ventilator-Induced Lung Injury

Ventilator-Induced Lung Injury (VILI)

Injury to the lung caused by mechanical ventilation in experimental models

Ventilator-Associated Lung Injury

Worsening of pulmonary function, or presence of lesions similar to ARDS in a clinical patient that is thought to be associated with the use of mechanical ventilation, with or without underlying lung disease

Barotrauma Description

Extraalveolar air

• Pneumothorax

• Pneumomediastinum

• Subcutaneous emphysema

Barotrauma Preventative Strategies

Minimize plateau airway pressure

• Target <30 cm H2O

Volutrauma Description

Overdistension causing stretch injury

Volutrauma Preventative Strategies

Minimize TV

• Target TV <10 ml/kg

Atelectrauma Description

Cyclic recruitment - derecruitment injury

Atelectrauma Preventative Strategies

Application of PEEP

Mechanical Power Description

Total energy transferred to the lung - includes TV, driving pressure, respiratory rate, flow rate, and PEEP

Mechanical Power Preventative Strategies

Minimize all ventilator settings - all energy transferred to the lung has the potential to cause injury

Spontaneous Breathing while Receiving Mechanical Ventilation Description

Alveolar distension, shear stress, atelectrauma, etc., during spontaneous breathing is equally as injurious as mechanical ventilator breaths.

May promote edema formation more than positive pressure ventilation

Spontaneous Breathing while Receiving Mechanical Ventilation Preventative Strategies

Minimize spontaneous breathing including patient-ventilator asynchrony with appropriate sedation, optimization of ventilator settings ± neuromuscular blockade

Biotrauma Description

Release of inflammatory mediators from the injured lung leading to systemic inflammation, which may promote multiple organ dysfunction

Biotrauma Preventative Strategies

Lung-protective ventilation strategies to limit lung injury and implement strategies to reduce microaspiration of oropharyngeal fluid

Oxygen Toxicity Description

High oxygen concentrations may directly cause lung injury as well as contribute to absorption atelectasis

Oxygen Toxicity Preventative Strategies

Minimizing FiO2 within 24 hours

• Target FiO2 <0.60

Barotrauma

• Barotrauma implies pressure-related injury to the lung

• In terms of VILI, barotrauma is defined as extraalveolar air and is manifested clinically by pneumothorax, pneumomediatstinum, or subcutaneous emphysema

  • Disruption of the alveolar capillary membrane allows air to dissect along facial planes, accumulating within the pleural space or other compartments, or the development of subcutaneous emphysema

What was associated with a higher incidence of pneumothorax in human ARDS patients?

• In a study of human ARDS patients, the use of high airway pressures (peak inspiratory pressure >40 cm H2O) was associated with a higher incidence of pneumothorax than when lower airway pressures were used

• In another study, when plateau pressure was maintained at less than 35 cm H2O, no relationship was found between ventilator setting and the occurrence of pneumothorax

When does barotrauma occur?

In lungs ventilated with high alveolar pressures and large tidal volumes (VT)

Evaluation of what pressure is best to assess risk of VILI?

• Airway pressure may not accurately reflect the stress imposed on the lung parenchyma as it includes the pressure needed to expand the chest wall

  • The distending pressure of the lung is best reflected by the transpulmonary pressure and this would be a better measure to use when assessing the risk of VILI

Volutrauma

• Results in an increase in the permeability of the alveolar capillary membrane, the development of pulmonary edema, the accumulation of neutrophils and proteins, the disruption of surfactant production, the development of hyaline membranes, and a decrease in compliance of the respiratory system

• Stretch injury as a result of high volume is more injurious to the lung than high pressure, without a large increase in volume

• In a study, rats were ventilated with either high volume/high pressure, high volume/low pressure (negative pressure ventilation), or low volume/high pressure (chest wall was restricted)

  • Both high-volume strategies caused substantial lung injury while the low volume/high pressure strategy had far less evident injury

• Concerns for volutrauma are supported by human clinical studies showing improved outcomes with use of low tidal volume ventilation

Chest Wall Effects on Volutrauma

• Alveolar distension is determined by the difference between alveolar and pleural pressure so the chest wall has a role in determining the extent of overdistension

  • When the chest wall is stiff (low compliance) or heavy, a high Pplat may be associated with less risk of overdistension

  • A stiff or heavy chest (e.g. obesity, abdominal distension, massive fluid resuscitation, chest wall deformity, chest wall burns) protects the lungs from VILI

Effect of Active Breathing Efforts on Volutrauma

• The alveolar distending pressure can change markedly on a breath-by-breath basis in a spontaneous breathing patient

• When the airway pressure is constant and the patient forcefully inhales, the alveolar distending pressure may exceed what is expected by the airway pressure setting

  • During pressure-targeted ventilation, the contribution of patient's effort to alveolar distending pressure must be appreciated

• Dependent pleural pressure changes can exceed the average measured pleural pressure due to in pendelluft, movement of gas from one part of the lungs into another during inspiration but without increasing overall tidal volume

  • Causes local distension and an increased risk of VILI

  • Avoid excessive patient effort regardless of mode of ventilation

Effect of Preexisting Injury of Development of VILI

• Increases the likelihood of VILI

• Two-hit process of lung injury

  • Previous injury predisposes the lungs to a greater likelihood of ventilator induced injury

Atelectrauma

• Atelectrauma or cycle recruitment-derecruitment injury - trauma to epithelial cells and injury to adjacent alveoli via shear stress from repetitive opening and closing of collapsed alveoli

• In healthy lungs, there are relatively few collapsed alveoli, but in injured lungs, alveoli become progressively unstable, changing shape during inflation and completely collapsing at the end of expiration

  • The junction between an open and a closed alveolus serves as a stress raiser

• When rats are ventilated with high pressures and no PEEP, the rapidly develop severe, diffuse pulmonary edema

  • If they are ventilated at the same pressure with the addition of PEEP, it is far less injurious

• PEEP can reduce the cyclic collapse and reexpansion of alveoli and minimize atelectrauma

Mechanical Power

• The total mechanical power or energy transferred to the lung during ventilation may correlate with the likelihood for VILI

• It is recommended that the mechanical power is normalized to the area of ventilated lung available

  • This normalized value for mechanical power has been described as intensity

• In lungs with smaller areas participating in ventilation, the value for intensity for a given degree of mechanical power would be higher

• A novel aspect of this approach is the inclusion of respiratory rate and PEEP as potential contributors to VILI

  • PEEP can be protective of lung injury, but does increase the energy load transmitted to the lung and may contribute to VILI in some circumstances

What does mechanical power include?

• Mechanical power includes all components of a ventilator breath that can contribute to VILI

  • Tidal volume

  • Driving pressure

  • Respiratory rate

  • Flow rate

  • PEEP

What are the primary determinants of lung injury?

Stress and strain

Stress

The internal counterforce per unit area that balances an extern load on a structure, or the pressure gradient across a structure (e.g. alveolar capillary membrane)

Strain

Deformation of the system as a result of the external load or the change in size or shape of the structure (alveolar distension)

What are stress and strain from a pulmonary perspective?

Stress is the alveolar distending pressure (alveolar pressure minus pleural pressure) and strain is the ratio of volume change (V_T plus volume increase caused by PEEP) to functional residual capacity (FRC) during the application of the stress

What lung strain is considered injurious to the lungs?

Lung strain of more than 2 (i.e. double the resting lung volume)

How are lung stress and strain related?

• Stress and strain are related by the specific lung elastance of 12 cm H2O

  • Lung stress is 12 cm H2O times lung strain

  • Surrogates for stress and strain are plateau pressure (Pplat) and V_T

Spontaneous Breathing and VILI

• Mechanisms of VILI are a product of the dynamic stress applied to the lung during breathing efforts and this stress can be equally injurious if breaths are generated by mechanical ventilation or spontaneous respiratory efforts

• The decrease in pleural pressure as a result of spontaneous breathing efforts increases transvascular pressure (the transmural pressure of pulmonary vessels)

  • Then there is distension of the vessels which can promote the formation of edema

• These concerns are relevant to spontaneous breathing modes, in addition to animals with patient-ventilator asynchrony

Biotrauma

• VILI causes cell damage and results in an inflammatory response

• The release of proinflammatory cytokines caused by VILI may promote multiple organ dysfunction and increased inflammatory cytokines can worsen VILI in a circular fashion

  • Pro-inflammatory and anti-inflammatory mediators increase edema formation, neutrophil migration, and relaxation of vascular smooth muscle

• The morbidity and mortality associated with VILI, from any mechanism, are largely the result of the subsequent systemic inflammation known as biotrauma

• Lung-protective ventilation strategies limit lung injury and have been shown to reduce multiple organ dysfunction and improve outcomes

Oxygen Toxicity

• Patients receiving PPV are invariably on supra-atmospheric levels of oxygen supplementation

  • This may have an additive effect to the injury caused by VILI, especially if a high oxygen concentration is delivered for an extended period

• Inspired oxygen concentration of 100% in the short term can cause absorption atelectasis and decreased oxygen diffusion capacity

• Beyond 24 hours, an FiO2 between 50-100% promotes the production of reactive oxygen and nitrogen species and causes pathologic changes similar to ARDS and VILI, including interstitial edema, hyaline membrane formation, damage to the alveolar membrane, altered mucociliary function, and fibroproliferation

  • The damage appears to be positively associated with the level of FiO2 and the length of time that oxygen was administered

• Laboratory data suggest that former exposure to bacterial endotoxin, inflammatory mediators, and sublethal levels of oxygen (less than or equal to 85%) protect the lungs from further injury when inspiring a high FiO2

• Combination of bleomycin and oxygen results in marked injury to the lungs

  • In this setting the lowest FiO2 should be used, tolerating a PaO2 as low as 50 mm Hg (SpO2 85-88%)

What FiO2 should be administered whenever there is uncertainty about the PaO2?

1

What should the target PaO2 when adjusting FiO2 be?

• FiO2 should be lowered to the level resulting in a PaO2 of 50-80 mmHg (SpO2 88-95%) as soon as possible

What is the target FiO2 in the mechanically ventilated patient?

Less than or equal to 0.50

Translocation of Cells and VILI

• Leakage of inflammatory mediators into the bloodstream increases systemic inflammation

• Bacteria instilled into the lungs of otherwise healthy animals produce bacteremia when inappropriate respiratory patterns are employed

Other Mechanisms of VILI

• Higher vascular infusion volumes, rapid respiratory rates and inspiratory flows, and high body temperature potentially cause greater injury

Histopathology Associated with VILI

• Histopathologic changes associated with VILI are hard to distinguish from changes associated with ARDS

• Include decreased integrity of small airway epithelial cells, destruction of type 1 alveolar epithelial cells, alveolar and airway flooding, hyaline, membrane formation, interstitial edema, and infiltration of inflammatory cells

• Lesions usually have an uneven distribution but tend to be worse in the dependent lung, likely because of worsened airway flooding and shear injury

VILI and MODS

• Disruption of the alveolar-capillary membrane allows leakage of pulmonary inflammatory mediators into the bloodstream, allowing downstream organ failures

Low Tidal Volume Ventilation

• Growing evidence that high-volume/low-PEEP ventilation can cause harm and worsen preexisting lung injury

• Volume limitation in patients with ALI and ARDS has shown the most dramatic results in outcome, with the landmark ARDSnet study showing a decrease in mortality when 6 ml/kg tidal volume was used vs 12 ml/kg

  • The group receiving lower tidal volumes also, incidentally, received slightly higher PEEP and inspired oxygen concentration

• Evidence that low tidal volume ventilation may be of benefit in people without ARDS or ALI

  • Meta-analysis of intraoperative ventilation concluded that low tidal volume (<10 ml/kg) ventilation decreased the frequency of pneumonia and the need for postoperative ventilatory support

Lung Protective Ventilation Strategy

• Limits tidal volume to 4-8 mL/kg

• Maintains plateau pressure less than 28 cm H2O

• Maintains driving pressure less than 15 cmH2O

• Sets PEEP based on the patient's pathophysiology and respiratory mechanics

• Provides a FiO2 that maintains the PaO2 between 55 and 80 mmHg and SpO2 between 88 and 95%

Low Tidal Volume Ventilation to Prevent VILI

• There is strong evidence for limiting tidal volume to less than normal in human studies, where values of 4-6 ml/kg have been recommended in ARDS patients

• Optimal target for tidal volume in dogs and cats is unknown and likely varies between breeds due to anatomical differences

  • Most clinical veterinary studies on mechanical ventilation have reported the use of tidal volumes of greater than 10 ml/kg

  • Recommended to target the lowest possible tidal volume needed to maintain adequate blood gases, likely to be in the range of 6-12 ml/kg in dogs and cats

• Healthy dogs have a higher normal tidal volume than other species, but the volume of functional units available for gas exchange in injured lungs may be much reduced

• Inflammation in the lung causes heterogenous changes throughout, with regions of poorer compliance and atelectasis, which causes more compliant regions to become overdistended

  • Limit tidal volume to prevent portions of the lung from being overdistended

• Low tidal volume increases the risk of perpetuating atelectasis and creating further shear injury so application of PEEP is vital

What is a common consequence of low tidal volume ventilation?

Hypercapnia

• Permissive hypercapnia - tolerating higher than normal PaCO2 levels rather than increasing ventilator settings

• This approach may reduce the likelihood of VILI, but there are physiological consequences of hypercapnia that may impact patient outcome

Positive End-Expiratory Pressure to Prevent VILI

• Well established that some PEEP is better than no PEEP or zero end-expiratory pressure

• Minimum amount of PEEP needed to reduce VILI has not been established

• Common levels of PEEP considered adequate in human medicine are in the range of 5-10 cm H2O

Limitation of Plateau Pressure to Prevent VILI

• Plateau pressure best represents the pressure applied to the lung as it is not impacted by resistance of the system

  • Measured during an inspiratory hold maneuver and the animal should not be making active respiratory efforts during measurement

• The combination of high PEEP, auto PEEP (PEEP created by increased outflow resistance during expiration, asynchrony, or incomplete expiration), and tidal volume can lead to high end-inspiratory volume, which may be indicated by high plateau pressure

• Protective lung ventilation strategies in human medicine recommend targeting a plateau pressure of less than 30 cm H2O

  • Peak inspiratory pressure may be used as a surrogate for plateau pressure unless there is increased resistance in the system

Respiratory Rate and Inspiratory Flow to Prevent VILI

• Some evidence that high respiratory rates and inspiratory flow rates can promote VILI

Subjective Analysis of the Pressure Volume Loop to Prevent VILI

• An optimal ventilator breath avoids both alveolar collapse on exhalation and overdistension on inhalation

  • The upper and lower inflection points of the pressure-volume loop theoretically show where these events occur and maintaining PEEP and peak inspiratory pressure between these points could be beneficial

• Subjective analysis of the pressure-volume loop may be of some benefit, in particular recognition of overdistension from the presence of "beaking"

Recommendations for Spontaneous Breathing to Prevent VILI

• In severe ARDS, spontaneous breathing effort has been associated with poorer outcomes, while in less severe pulmonary disease, spontaneous breathing may actually provide benefits such as better lung recruitment and improved diaphragmatic tone

• A recent human clinical practice guideline recommended against the routine use of NMBA in patients with moderate or severe ARDS that tolerate light sedation

  • In patients that require deep sedation or prone ventilation, the use of NMBA is reasonable

Advanced Pulmonary Support Techniques to Prevent VILI

• Advanced strategies such as partial liquid ventilation, high-frequency oscillatory ventilation, extracorporeal membrane oxygenation, and carbon dioxide removal are being researched to look for strategies with lower risk of VILI than conventional mechanical ventilation