Page 624 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

444 PART 4: Pulmonary Disorders

to be extended to include an EELV that will minimize lung injury and resident neutrophils was demonstrated to attenuate VILI. Of further
67
optimize cardiac performance. Finally as ARDS is not a static process, interest, there is growing body of evidence for a synergistic interaction
the optimum level of PEEP will vary over time, demanding that the level between mechanical stress and whole bacteria or bacterial products,
of PEEP be regularly reviewed in a given patient. which may exacerbate lung injury. Moderate-tidal-volume mechani-
82
cal ventilation was able to increase lung injury only when applied to
■ BIOTRAUMA lungs previously challenged with LPS. Macrophages under high-stress
83
mechanical ventilation may amplify the endotoxin recognition pathway.
• The release of various mediators by mechanical ventilation is termed Alveolar macrophages collected after large V ventilation revealed a
t
“biotrauma” and may contribute to both lung and distal organ injury. 20-fold increase in LPS-induced TNF-release and increasing expres-
• VILI induces a selective activation of genes, mainly inflammatory sion of CD14 on its surface compared with those collected after small
and related transcription factors. V ventilation, whereas TNF was undetectable without LPS stimula-
t
84
• Vascular permeability increases and alveolar fluid clearance impair- tion. Altemeier et al expanded upon these results and demonstrated
that mechanical ventilation further increased the expression of genes
ment are associated with VILI edema formation. induced by LPS. Moreover, mechanical ventilation acts synergistically
85
• A synergistic interaction contributing to lung injury exists between with whole bacteria such as Staphylococcus aureus and appears capable
mechanical stress and biological process such as the innate immune of increasing not only the severity of lung injury but also adversely
response to infections and coagulation. affecting distal organ function such as the liver and kidneys. 86
Mechanical ventilation is able to cause the release of numerous medi- In ALI/ARDS patients, activation of coagulation and attenuation of
ators and to stimulate the innate immune response, a process that has fibrinolysis have been described and support the notion of an interac-
87
been termed biotrauma. The notion of biotrauma initially stemmed tion between inflammation and coagulation. Recently in a rat model of
61
from in vivo and ex vivo studies in animal models and more recently pneumonia Haitsma et al demonstrated that injurious mechanical venti-
has been confirmed in humans. However, as emphasized in a recent lation significantly increased the pulmonary and systemic procoagulant
review, it is important to differentiate the effects of cellular stretch or response as demonstrated by an increase of the levels of thrombin-
shear stress induced necrosis from true mechanotransduction, in which antithrombin complexes and impairment of fibrinolysis as evidenced
intracellular signaling occurs. Potentially all the structural cells of the by an increase in the concentration of plasminogen activator inhibitor-1
62
lung can participate and are capable of initiating and perpetuating (a key inhibitor of fibrinolysis). 88
the lung injury induced by mechanical ventilation. The first step of this
interplay is the sensing of the mechanical stimulus by the cells. Several ■ DECOMPARTMENTALIZATION
studies have focused on the role of cellular mechanosensors in the con- • The decompartmentalization of local inflammatory response induced
version of a mechanical stimulus into intracellular activation pathways, by injurious mechanical ventilation may play an important role in
which in turn modulate regional cellular responses involved in inflam- initiating and propagating a systemic inflammatory response leading
mation, cell survival, and repair. Several studies focused on the role of to multiple organ dysfunction syndrome (MODS).
integrins, stretch-activated ion channels, and the cytoskeleton itself as
“mechanosensors.” In an isolated not injured rat model, Tremblay et Damage to the alveolar-capillary barrier from mechanical ventilation
al demonstrated that an injurious ventilation strategy (zero PEEP, high may be central to several important pathophysiologic mechanisms in the
tidal volume, or both) had a dramatic influence on lung inflammatory development of VILI. First, loss of membrane integrity is key to the devel-
mediators release (TNF-α, IL-1 β, IL-6, and MIP-2). Moreover, this opment of the pulmonary edema and hyaline membrane formation—the
63
injurious ventilatory strategy was associated with increased expression hallmarks of ARDS. The loss of barrier function may also allow for entry
of transcription nuclear factor such as c-fos. 63 of inflammatory cells into the lung, in turn promoting the perturbation
Parker et al, in an isolated perfused rat lung model, prevented the of lung structure and function. The loss of the integrity of the alveolar-
increase in vascular permeability, induced by high-stress mechanical capillary membrane has been proposed to be central to the spread of lung
ventilation, by using gadolinium, an inhibitor of endothelial stretch- inflammation (partially produced by mechanical injury) to nonpulmo-
activated cation channels. Since these studies, mechanical ventilation nary organs, and thus may lead to their subsequent dysfunction. 89
64
causing both overdistention (volutrauma) and underdistention (atelec- Although there is no definitive evidence demonstrating that media-
trauma) 65,66 have been shown to cause the regional production of a vari- tors generated in the lung can cause MODS in humans, injurious
ety of proinflammatory mediators including several chemokines capable ventilatory strategies can lead to release of a number of factors that
of recruiting leukocytes—further increasing lung damage. 65,67-73 Active could theoretically could impact MODS, including bacteria, bacterial
endothelial response to mechanical strain and shear stress has also been products, or circulating proapoptotic factors. 90-92 Although by defini-
demonstrated. 74,75 Rapid onset of increased capillary permeability result- tion severe hypoxemia is a clinical hallmark of ARDS, MOF and sepsis
ing from tensile failure and signal transduction events in endothelial are the leading causes of death in ARDS patients receiving mechanical
cells such as calcium entry and phosphorylation of junctional proteins ventilation. Moreover, MOF is the terminal irreversible condition pro-
is known to precede the acute effects of proinflammatory cytokines. 75-78 ceeded by a sustained overwhelming systemic inflammatory response.
The resultant protein leak and edema may aid in augmenting the Several studies have demonstrated an increase in filtration coefficient
inflammatory response and subsequent injury. VILI seems to impair during mechanical ventilation. 93,94 This effect is thought to be due to
cAMP-dependent alveolar fluid clearance by impairing nitric oxide a reduction in the integrity of the alveolar-capillary barrier. During
production. In this regard, augmenting signaling pathways aimed at mechanical ventilation, injury has been demonstrated to occur to both
79
increasing the intracellular levels of cAMP and Na-K pump activity may the epithelial and endothelial membranes. Both edema and injury to the
be useful in attenuating lung edema and inflammation. 80 alveolar-capillary barrier can develop rapidly, with transient alterations in
Resident alveolar macrophages (the front line cells of the innate immune filtration coefficient occurring in animals ventilated for only 2 minutes. 95
system) are activated by mechanical stress and contribute to the produc- Recent evidence suggests that translocation of proteins may occur
tion of IL-8, metalloproteinase-9, and the translocation of nuclear factor from lung to the circulation. Using a rat model of VILI, Chiumello
kB (NF-kB). Depletion of alveolar macrophages in rats with liposomal et al demonstrated that high-tidal-volume ventilation and low levels of
96
73
clodronate significantly decreased permeability and pulmonary edema PEEP were associated with release of cytokines into the systemic circula-
following high-stress mechanical ventilation. Moreover, neutrophil acti- tion, whereas Haitsma et al demonstrated that increased lung vascular
81
vation plays a role in lung vascular permeability changes. Interestingly the permeability was associated with an increase of cytokines into the lung
blockade of the PMN chemokine receptor 2 (CXCR2) with its ligand on deriving from systemic circulation. Imai and associates demonstrated
92

section04.indd 444 1/23/2015 2:19:30 PM