Is Mechanical Ventilation a Contributing Factor?
ARTHUR S. SLUTSKY and LORRAINE N. TREMBLAY
Departments of Medicine and Surgery and the Samuel Lunenfeld Research Institute, University of Toronto, Toronto, Canada
Few problems facing the intensivist are as frustrating or as difficult to manage as multiple system organ failure (MSOF).
While the precise etiology remains unknown, an integral feature is the development of a rampant systemic inflammatory
response that persists unabated by host control mechanisms.
Either a single massive insult, or a series of less intense insults
(i.e., “two-hits”) appear to be necessary to overwhelm the individuals innate regulatory mechanisms. Often the lung is the
first organ to fail, leading to initiation (or continuation) of
ventilatory support. Although in some patients a precipitating
nidus of infection or inflammation is identifiable, and lung injury is simply the first clinically evident manifestation of a systemic process, there remain a large number of patients in
whom the explanation for progression from respiratory failure
to multiple system organ failure is unclear.
In this Perspective, we explore the hypothesis that mechanical ventilation may play a pivotal (and hereto unrecognized)
role in the initiation and/or propagation of a systemic inflammatory response leading to MSOF in certain patients. We address this issue by examining the following questions: Can
mechanical ventilation initiate or exacerbate lung injury/inflammation? Can lung injury/inflammation lead to systemic
inflammation? Is there evidence of MSOF secondary to mechanical ventilation?
CAN MECHANICAL VENTILATION INITIATE OR
EXACERBATE LUNG INJURY/INFLAMMATION?
Mechanical ventilation is an indispensable tool for providing
adequate gas exchange and resting respiratory muscles in
many disease states. However, in certain patients with the
acute respiratory distress syndrome (ARDS) or acute lung injury (ALI), the ventilatory strategy required to maintain adequate gas exchange may exacerbate, or even initiate, significant lung injury and inflammation (1, 2). Patients with ALI/
ARDS often have a number of risk factors (e.g., surfactant
dysfunction, underlying lung disease, malnutrition, oxygen
toxicity, infection, age) that not only increase the lungs’ susceptibility to injury by mechanical ventilation, but also impair
the lungs’ ability to repair the damage incurred (3). Furthermore, the atelectasis of dependent lung regions and alveolar
edema that is often present can markedly reduce their aerated
lung capacity (e.g., to as little as 25% of normal) (4). As a result, mechanical ventilation with even modest tidal volumes
(e.g., 10 to 12 ml/kg) may result in overdistention of the remaining aerated lung regions to a level equivalent to that observed if healthy lungs were ventilated with tidal volumes of
40 to 48 ml/kg.
Research in a number of species has shown that mechanical
ventilation can produce lung injury that is functionally and
histologically indistinguishable from that seen in ARDS (2, 5).
The mechanisms of injury include structural disruption due to
either lung overdistension, or to the shear forces generated
during repetitive opening and collapse of atelectatic regions
(1, 2). Mechanical ventilation has also been shown to have
profound effects on the function of both endogenous and exogenous surfactant (6–9) resulting in an increased tendency
for collapse of air spaces (distal airways and alveoli), a need
for higher airway pressures to reopen (and keep open) the
lung, and increased surface tension at the gas–liquid interface
in the alveoli resulting in increased transmural capillary pressure gradients (favoring movement of fluid into the lung).
More recently, mechanical ventilation has also been shown
to have significant effects on lung levels of inflammatory cells
and soluble mediators. In saline-lavaged rabbits, manifestations of lung injury (i.e., hyaline membranes, neutrophil infiltration, and impaired gas exchange) originally attributed to
mechanical disruption by conventional mechanical ventilation, were found to be almost completely abrogated in granulocyte-depleted rabbits (10). In normal rabbits subjected to
saline lavage, injurious mechanical ventilation was shown to
significantly increase lung neutrophil accumulation and chemiluminescence (an indicator of neutrophil priming) (11, 12), as
well as bronchoalveolar lavage (BAL) levels of inflammatory
mediators (platelet activating factor and thromboxane-B2 [13])
and expression of tumor necrosis factor-alpha (TNF-a) by alveolar macrophages (14). Similarly, in rat lungs ventilated ex
vivo increased BAL concentrations of a number of cytokines
(including TNF-a and interleukin-1b [IL-1b]) were found following injurious mechanical ventilation with low end-expiratory
lung volumes allowing tidal alveolar reopening and collapse
with each breath (15). The su