Elsevier

Vascular Pharmacology

Volume 39, Issues 4–5, November 2002, Pages 247-256
Vascular Pharmacology

Review
Vascular pharmacology of acute lung injury and acute respiratory distress syndrome

https://doi.org/10.1016/S1537-1891(03)00013-2Get rights and content

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) following sepsis, major trauma and surgery are leading causes of respiratory insufficiency, warranting artificial ventilation in the intensive care unit. It is caused by an inflammatory reaction in the lung upon exogenous or endogenous etiologies eliciting proinflammatory factors, and results in increased alveolocapillary permeability and protein-rich alveolar edema. The interstitial and alveolar inflammation and edema alter ventilation perfusion matching, gas exchange and mechanical properties of the lung. The current therapy of the condition is supportive, paying careful attention to fluid balance, relieving the increased work of breathing and improving gas exchange by mechanical ventilation, but in vitro, animal and some clinical research is done to evaluate the value of anti-inflammatory therapies on morbidity and outcome, including inflammatory cell-stabilizing corticosteroids, xanthine derivates, prostanoids and inhibitors, O2 radical scavenging factors such as N-acetylcysteine, surfactant replacement, vasodilators including inhaled nitric oxide, vasoconstrictors such as almitrine, and others. None of these compounds has been proven to benefit survival in patients, however, even though carrying a physiologic benefit, except perhaps for steroids that may improve outcome in the later stage of ARDS. This partly relates to the difficulty to assess the lung injury at the bedside, to the multifactorial pathogenesis and the severity of comorbidity, adversely affecting survival.

Introduction

Trauma, sepsis, aspiration, pneumonia, ischemia/reperfusion and other clinical catastrophes may be complicated by acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), which form a continuum from mild to severe lung damage. ARDS is associated with severe gas exchange and mechanical abnormalities of the lungs, often necessitating mechanical ventilation with positive (end-expiratory) airway pressure, and carries a mortality rate of about 50%, depending on the underlying disease. Conversely, ALI/ARDS may contribute to morbidity and mortality in the critically ill patient in the intensive care unit. The basic underlying abnormality, either when attributed to exogenous or to endogenous causes, is an increase in alveolocapillary permeability and resultant increased permeability edema, which is more severe in ARDS than in ALI, as detected with the help of radionuclide-labeled protein fluxes in the lung at the bedside Groeneveld, 1997, Arif et al., 2002. In the absence or unavailability of the latter method, the diagnosis of ARDS is based on clinical characteristics that point to increased permeability and disfavor increased pressure edema Groeneveld, 1997, Arif et al., 2002.

The increase in permeability results from the inflammatory response at the endothelial side of the alveolus in endogenous ARDS and beginning at the alveolar side in exogenous ARDS, in the course of the clinical catastrophes mentioned, as documented in numerous animal and clinical studies. Increased endothelial permeability is the result of cytokine release, neutrophil–endothelial interactions and cytoskeleton changes Essler et al., 2000, Boer et al., submitted, Dudek and Garcia, 2001, whereby between but also within endothelial cells gaps and “pores” are created that facilitate transvascular transport of both neutrophils and plasma proteins and water. ARDS in man can be mimicked in animals by infusion of bacterial products such as endotoxin, repeated saline lavage of the lungs, oleic acid infusion or acid aspiration, among others.

Section snippets

Inflammation

During ALI and ARDS, the brochoalveolar lavage fluid contains numerous proinflammatory and procoagulant substances, in addition to proteins and neutrophils, underscoring the importance of inflammation in the pathogenesis of increased permeability edema. Inflammatory mediators that may contribute to lung vascular injury include complement activation products, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, platelet-activating factor (PAF), endothelin, thromboxane A2 and leukotrienes Hales et

Fluids

The theoretical framework elaborated above may help to explain the results of older and newer studies on the crystalloid–colloid and the colloid–colloid controversies, and may help to predict the development of pulmonary edema at the bedside, when fluid loading is carried out in treating hypovolemia (Groeneveld, 2000). Obviously, fluid therapy will increase hydrostatic pressures in the lungs and promote fluid filtration and edema formation, particularly in lungs with increased protein and thus

Conclusion

There is no universally accepted clinical drug treatment for permeability edema of the lungs associated with ALI/ARDS. New tools to evaluate the disease severity and course may help to monitor effects of potentially effective and new drugs in future trials. Promising agents for treatment have been developed in animal models, which should be evaluated clinically. Direct measurement of permeability could help to evaluate effects of drugs at the bedside (Groeneveld, 1997).

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