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Mechanical ventilation in patients with acute ischemic stroke: from pathophysiology to clinical practice
Critical Care volume 24, Article number: 139 (2020)
- The original article was published in Critical Care 2019 23:388
Robba and colleagues are to be commended for exploring the pathophysiology of brain-lung interactions after acute ischemic stroke and the management of mechanical ventilation in these patients via a narrative review . Pulmonary complications are common in patients with acute ischemic stroke and are associated with a high risk of mortality. The mechanism of lung damage after brain injury is described as a “double-hit model,” which appears adequate to explain some pathophysiological phenomena in the lung secondary to stroke . However, pulmonary complications after acute ischemic stroke may occur with more complex mechanism.
Acute respiratory infection usually of bacterial origin, particularly in the week preceding stroke, is a significant risk factor for cerebral infarction; acute infection acts as a trigger for acute stroke . In this regard, the possibility cannot be excluded that some of the infections reported early poststroke actually developed prior to stroke onset but worsened thereafter .
We agree that mechanisms other than dysphagia or compromised level of consciousness are involved in stroke-associated pneumonia . However, both immune activation and immune immunodepression occur after acute ischemic stroke. Normally well-balanced brain-immune interactions may become dysregulated . Experimental and clinical data support that stroke may impair immunity or induce immunodepression . Factually, the PREDICT study confirmed that stroke-induced immunodepression syndrome is an independent risk factor for stroke-associated pneumonia, instead of aspiration pneumonia .
Acute ischemic brain injury swiftly activates the sympathetic, parasympathetic, and HPA axis pathways, leading to the release of norepinephrine (NE), acetylcholine, and glucocorticoids (GCs). Adrenergic and the HPA axis pathways act synergistically to induce splenic atrophy and natural killer (NK) cell deficiency in the periphery via coordinated effects of NE and GCs . Moreover, ischemic stroke may cause a significant increase in bronchoalveolar lavage fluid macrophages and neutrophils and whole lung tissue pro-inflammatory IL-1β mRNA expression in experimental mice . IL-1β is known to be involved in the development of acute lung injury (ALI) and/or acute respiratory distress syndrome and has been shown to be one of the most biologically active cytokines in ALI .
In summary, pulmonary complications are associated with a high risk of mortality in patients with acute ischemic stroke. The mechanism of lung damage after brain injury merits further investigation.
Denise Battaglini, Giulia Bonatti, Chiara Robba, Patricia RM Rocco, Paolo Pelosi
We would like to thank Zhang and collaborators for reading with interest our recent review  concerning the role of mechanical ventilation in patients with acute ischemic stroke. The authors highlighted the role of acute ischemic stroke on pulmonary complications and their association with clinical outcome and death. Indeed, the mechanisms associated with pulmonary complications after acute ischemic stroke are complex and further studies are required. In Fig. 1, we highlighted the main mechanisms of acute ischemic stroke-induced lung inflammation.
After vessel occlusion, oxygen and glucose deprivation induces neuronal and glial cell death, followed by the release of damage-associated molecular patterns (DAMPs) that include adenosine triphosphate (ATP), glutamate, and reactive oxygen species (ROS). These molecules bind to toll-like receptors (TLRs)-2, TLR-4, and receptor for advanced glycation end products (RAGE), activating resident microglial cells and stimulating the release of pro-inflammatory cytokines (such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6). Glutamate binds N-methyl-d-aspartate receptors (NMDA) increasing calcium influx and producing ROS .
Sympathetic nervous system, efferent vagus nerve, and hypothalamic-pituitary-adrenal (HPA) axis are overactivated by acute ischemic stroke and may induce immunosuppression. Particularly, the efferent vagus acts through the release of acetylcholine (Ach) that binds nicotinic acetylcholine receptor (nAchRα7) both on lung alveolar macrophages and epithelial cells reducing inflammation and neuronal cells protecting against oxidative stress . Catecholamines (on β2, α2, and D2 receptors) are released by sympathetic nervous system and activate T regulator lymphocytes with the liberation of interferon (IFN)-γ and IL-10. Moreover, HPA axis induces glucocorticoid secretion, thus activating apoptosis of lymphocytes, releasing IL-10, and reducing IFN-γ liberation by T cells .
Blood-brain barrier permeability is increased, and inflammatory cells are released into the systemic circulation. Microglia (M) are polarized into M1 (classically activated) or M2 (alternatively activated) phenotypes. Activation of these phenotypes affects the prognosis of stroke . The M2 phenotype plays a protective role in the brain by releasing transforming growth factor-β, whereas inflammatory cytokines induced by M1 phenotype aggravate brain injury after stroke .
Therefore, systemic inflammation is activated. Diffuse alveolar damage with lung edema and inflammation have been observed after acute ischemic stroke in mice associated with enhanced pro-inflammatory cytokines and reduced phagocytic capability of lung macrophages .
Although significant progress has been made in the pathogenesis of stroke and its interaction with peripheral organs, further investigations are needed to elucidate stroke-induced immunosuppression and its potential therapeutic strategies.
Availability of data and materials
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Gao, J., Zhou, C. & Zhang, H. Mechanical ventilation in patients with acute ischemic stroke: from pathophysiology to clinical practice. Crit Care 24, 139 (2020). https://doi.org/10.1186/s13054-020-2806-x