Background

Mechanical ventilation
Mechanical ventilation is a frequently applied intervention in medicine. Critically ill patients may need mechanical ventilation for airway protection or to improve gas exchange. Patients undergoing major surgery frequently need mechanical ventilation because of general anesthesia. A such, millions of critically ill patients receive mechanical ventilation in emergency rooms (ERs) or intensive care units (ICUs), and hundreds ofmillions surgery patients require mechanical ventilation in the operating room (OR) worldwide each year. For a long time critical care physicians and anesthesiologists assumed that mechanical ventilation was a relatively safe intervention. However, it is increasingly recognized that mechanical ventilation itself has the potential to harm.

Mechanical ventilation has strong potential to harm diseased lungs
Preclinical studies of mechanical ventilation in lung–injured animals and randomized controlled trials in patients with the ‘acute respiratory distress syndrome’ (ARDS) compellingly demonstrate mechanical ventilation to have a strong potential to harm lungs. So–called ‘ventilator–associated lung injury’ (VALI) is suggested to result, at least in part from hyperinflation of non–collapsed lung tissue (volutrauma) and tidal recruitment of collapsed lung tissue (atelectotrauma).
Lower tidal volumes – prevention of hyperinflation
The benefits of ventilation with lower tidal volumes (typically 6 ml/kg predicted body weight, PBW) in lung–injured animals are confirmed by results from randomized controlled trials in patients with ARDS comparing protective ventilation with lower tidal volumes with ‘conventional ventilation’ using traditionally–sized or higher tidal volumes. Randomized controlled trials show use of lower tidal volumes to improve survival, to shorten duration of ventilation and to reduce length of stay in ICU.
Higher levels of positive end–expiratory pressure – prevention of tidal recruitment
The benefits of higher levels of positive end–expiratory pressure (PEEP), with or without recruitment maneuvers, are less well defined. While animal studies showed higher levels of PEEP to prevent injury caused by repetitive opening and closing of collapsed lung tissue, randomized controlled trials comparing higher PEEP strategies with lower PEEP strategies suggest only benefit in patients with severe ARDS. Use of higher levels of PEEP in those patients reduces the need for rescue interventions.

Mechanical ventilation can also harm uninjured lungs
More recent preclinical studies in healthy animals and studies in patients without ARDS demonstrate that ventilation also has the potential to cause damage in uninjured lungs. And alike in patients with ARDS, in patients with uninjured lungs VALI is suggested to be the result of hyperinflation and tidal recruitment.
Lower tidal volumes – also protective in critically ill patients without ARDS?
Preclinical studies in animals with uninjured lungs show VALI to depend on tidal volume size, similar to studies in animals with diseased lungs. Randomized controlled trial–evidence for the beneficial effects of lower tidal volumes is scarce. One meta–analysis corroborates the results of numerous smaller clinical studies and one randomized controlled trial in critically ill patients without ARDS, and demonstrates that use of lower tidal volumes is associated with improved survival, and a lower incidence of new ARDS.
If mechanical ventilation with lower tidal volumes protects against VALI in critically ill patients, then one may wonder whether lower tidal volumes also protect the lungs of ventilated patients under general anesthesia. Notably, ICU patients usually receive mechanical ventilation for a long time (i.e., days), while patients under general anesthesia require mechanical ventilation only for a relatively short period of time (i.e., hours). The above–mentioned meta–analysis, however, not only shows an association between use of lower tidal volumes and development of lung injury in critically ill patients, but also in surgery patients.
Higher levels of positive end–expiratory pressure – beneficial for patients without ARDS?
While randomized controlled trials of PEEP in critically ill patients without ARDS are lacking, several trials compared a lower PEEP strategy with a higher PEEP strategy in patients undergoing mechanical ventilation for general anesthesia. These suggest beneficial effects of higher levels of PEEP in these patients, but it should be noted that all trials combined a higher PEEP strategy with use of lower tidal volumes. Thus, it is not clear whether higher PEEP or lower tidal volumes are responsible for the found beneficial effects.

Harmful effects of mechanical ventilation – distal organ failure
Emerging clinical and experimental evidence supports the hypothesis of a multidirectional organ crosstalk between lungs and distal organs. Together with volutrauma and atelectrauma, the two conditions responsible for VALI, mechanical ventilation can lead to even more subtle injury manifested by the release of various inflammatory mediators, a condition called biotrauma. Biotrauma provides a putative mechanism to explain the high incidence of multiorgan failure in patients with ARDS, once if the mediators released by the lung enter the circulation it could lead to distal organ dysfunction. As an example, animals ventilated with higher tidal volumes showed higher levels of chemokines putatively involved in renal and small intestinal apoptosis.

Harmful effects of mechanical ventilation – diaphragm
Longer periods of controlled mechanical ventilation increase oxidative stress and proteolysis in the diaphragm, a muscle responsible for the ability to successfully wean patients from the ventilator. Only 18 hours of mechanical ventilation is sufficient to produce reduction of diaphragmatic force-generating capacity due to atrophy and injury of diaphragm muscle fibers, a condition termed ventilator-induced diaphragmatic dysfunction (VIDD). Several animal studies and few human trials suggest that maintaining spontaneous respiratory efforts during mechanical ventilation alleviates VIDD at either a functional or cellular structure level.

Harmful effects of mechanical ventilation – circulation
The heart and lungs work closely to meet the tissues’ oxygen demand and are highly integrated, a condition called heart-lung interaction. Mechanical ventilation induce changes in intrapleural and intrathoracic pressure and lung volumes, which can independently affect the atrial filling (preload), the impedance to ventricular emptying (afterload), heart rate and myocardial contractility. Mainly in healthy subjects and in patients with pulmonary pathology, particularly in the presence of preload-dependent left ventricle dysfunction or afterload-induced right ventricle dysfunction, mechanical ventilation can produce profound hemodynamic instability, manifested as hypotension and signs of hypoperfusion.

Has practice of mechanical ventilation changed?
Currently, ventilation with lower tidal volumes is considered standard of care in patients with ARDS. Mechanical ventilation with higher levels of PEEP remains controversial in patients with ARDS.
The ICU community is quite reluctant in using lower tidal volumes in patients without ARDS. It is argued that the beneficial effects of lower tidal volume ventilation could be offset by an increased need for sedation and maybe even muscle paralysis with this strategy. Increased use of sedatives and muscle relaxants could increase the incidence of ICU delirium and ICU acquired weakness, and both conditions could lengthen duration of ventilation and stay in ICU. Furthermore, it is argued that use of lower tidal volumes is not always possible with spontaneous modes of ventilation, which are most frequently used in ICU patients without ARDS. Consequently, the ICU community calls for more evidence for the alleged beneficial effects and feasibility of lower tidal volume ventilation, before extending this strategy to ICU patients without ARDS.
Anesthesiologists are also quite reluctant to use lower tidal volumes during surgery. It is argued that the time span of mechanical ventilation is too short to cause lung injury, despite the results of the abovementioned meta–analysis. Also, it is argued that surgery patients might benefit more from higher levels of PEEP than lower tidal volumes.

Is protective mechanical ventilation always possible?
If hyperinflation plays a role in the pathogenesis of VALI, then one may wonder whether lower tidal volumes of 6 ml/kg IBW is low enough. Experimental studies of lung injury in rats report that 3 ml/kg tidal volume is superior to 6 ml/kg in reducing alveolar epithelial injury and the degree of pulmonary edema as well as enhancing the rate of alveolar edema fluid clearance. Clinically, investigators show that tidal hyperinflation still occurs in one-third of patients with ARDS who are ventilated with tidal volumes of 6 ml/kg PBW. Thus, very low tidal volumes may be superior to the standard lower tidal volumes. With very low tidal volumes the plateau airway pressure will be lower, and lower plateau airway pressures are associated with a further reduction in ventilator associated lung injury. Use of very low tidal volumes may be difficult since such low tidal volumes could result in potentially dangerously elevated PaCO2 levels and a markedly decreased pH.

Alternatives for mechanical ventilation, and prevention of the need for injurious ventilation settings
With ARDS, aeration of lung can be very inhomogeneous potentially causing heterogeneous distribution of airway pressure and tidal volume, which could lead to hyperinflation and cyclic opening and closing of relatively healthy or moderately injured areas, and no ventilation in completed collapsed areas. This could make difficult to adopt a single tidal volume and plateau pressure to limit global stress and strain injury, and even a tidal volume as low as 6 ml/kg PBW might aggravate VALI.
Studies suggest that the lower the plateau pressure and the tidal volume better is the outcome of patients with ARDS, even for plateau pressure substantially below 30 cm H2O. However, the use of even lower tidal volumes in this group of patients is challenging and may be limited by an increased likelihood of severe hypercapnia, acidosis and dyssynchrony. The use of extracorporeal approaches to remove carbon dioxide using artificial membrane lung enables the decrease of tidal volume to value as low as 3 ml/kg PBW. Successful ventilation with ultra-protective strategy and ultra-lower tidal volume combined with extracorporeal CO2 removal has the potential to further reduce VALI compared with standard lung-protective strategy.
In more severe conditions, when the oxygenation is impossible in all situations or without the use of harmful ventilation strategies, lung support with a pump-driven extracorporeal membrane oxygenation (ECMO) is necessary. ECMO provides full support to the lungs, allowing a better oxygenation and carbon dioxide removal in patients under mechanical ventilation. Since oxygenation and ventilation is fully guaranteed by the ECMO machine, physician can rest the lung with the use of very low tidal volume, respiratory frequency, inspired oxygen fraction and positive end-expiratory pressure during the acute period of injury. In some case reports the use of ECMO avoided the need of mechanical ventilation for respiratory failure.
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