Inflammatory mechanisms of lung injury during mechanical ventilation
- Arthur S Slutsky, MD
Arthur S Slutsky, MD
- Professor of Medicine, Surgery and Biomedical Engineering
- University of Toronto School of Medicine
Mechanical ventilation is a life-saving therapy that is the mainstay for treating patients with acute respiratory failure. Since its widespread use was initiated in the early to mid-1950s for the treatment of paralytic poliomyelitis, our understanding of the impact of mechanical ventilation on gas exchange, pulmonary mechanics, and heart-lung interactions has increased tremendously. In addition, the complications of mechanical ventilation have also become more apparent [1,2].
The adverse consequences of mechanical ventilation (other than oxygen toxicity) were thought to be due largely to mechanical factors, such as hemodynamic compromise from decreased venous return and/or barotrauma due to pulmonary overdistention. Subsequent research revealed more subtle types of ventilator-induced lung injury, including diffuse alveolar damage and up-regulation of the inflammatory response; the latter is referred to as biotrauma [3-7]. The concept of biotrauma may help explain why most patients who die with the acute respiratory distress syndrome (ARDS) succumb not to lung failure but to the development of multiple organ dysfunction syndrome (MODS) involving both the lungs and other organs [4,8,9].
Mechanisms of ventilator-induced lung injury, particularly biotrauma, will be reviewed here. General issues related to mechanical ventilation and its use in ARDS are discussed separately. (See "Overview of mechanical ventilation" and "Physiologic and pathophysiologic consequences of mechanical ventilation" and "Mechanical ventilation of adults in acute respiratory distress syndrome".)
TYPES OF VENTILATOR-INDUCED LUNG INJURY (VILI)
Barotrauma refers to gross air leaks (including pneumothorax or pneumomediastinum) that are due to the development of an excessive pressure difference between an alveolus and its adjacent bronchovascular sheath [10-12]. Factors that impact the development of barotrauma include :
●The specific diagnosis (more common with acute respiratory distress syndrome [ARDS]) (see "Secondary spontaneous pneumothorax in adults")
- Tremblay LN, Slutsky AS. Ventilator-induced lung injury: from the bench to the bedside. Intensive Care Med 2006; 32:24.
- Slutsky AS, Ranieri VM. Ventilator-induced lung injury. N Engl J Med 2013; 369:2126.
- Tremblay LN, Slutsky AS. Ventilator-induced injury: from barotrauma to biotrauma. Proc Assoc Am Physicians 1998; 110:482.
- Plötz FB, Slutsky AS, van Vught AJ, Heijnen CJ. Ventilator-induced lung injury and multiple system organ failure: a critical review of facts and hypotheses. Intensive Care Med 2004; 30:1865.
- Lionetti V, Recchia FA, Ranieri VM. Overview of ventilator-induced lung injury mechanisms. Curr Opin Crit Care 2005; 11:82.
- dos Santos CC, Slutsky AS. The contribution of biophysical lung injury to the development of biotrauma. Annu Rev Physiol 2006; 68:585.
- Halbertsma FJ, Vaneker M, Scheffer GJ, van der Hoeven JG. Cytokines and biotrauma in ventilator-induced lung injury: a critical review of the literature. Neth J Med 2005; 63:382.
- Slutsky AS, Tremblay LN. Multiple system organ failure. Is mechanical ventilation a contributing factor? Am J Respir Crit Care Med 1998; 157:1721.
- Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA, et al. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; 342:1301.
- Macklin CC. Transport of air along sheaths of pulmonic blood vessels from alveoli to mediastinum. Arch Intern Med 1939; 64:913.
- Rouby JJ, Lherm T, Martin de Lassale E, et al. Histologic aspects of pulmonary barotrauma in critically ill patients with acute respiratory failure. Intensive Care Med 1993; 19:383.
- Pierson, DJ. Alveolar rupture during mechanical ventilation: role of PEEP, peak airway pressure, and distending volume. Respir Care 1988; 33:472.
- Gammon RB, Shin MS, Groves RH Jr, et al. Clinical risk factors for pulmonary barotrauma: a multivariate analysis. Am J Respir Crit Care Med 1995; 152:1235.
- Webb HH, Tierney DF. Experimental pulmonary edema due to intermittent positive pressure ventilation with high inflation pressures. Protection by positive end-expiratory pressure. Am Rev Respir Dis 1974; 110:556.
- Parker JC, Hernandez LA, Longenecker GL, et al. Lung edema caused by high peak inspiratory pressures in dogs. Role of increased microvascular filtration pressure and permeability. Am Rev Respir Dis 1990; 142:321.
- Parker JC, Hernandez LA, Peevy KJ. Mechanisms of ventilator-induced lung injury. Crit Care Med 1993; 21:131.
- Dreyfuss D, Saumon G. Barotrauma is volutrauma, but which volume is the one responsible? Intensive Care Med 1992; 18:139.
- Dreyfuss D, Saumon G. Role of tidal volume, FRC, and end-inspiratory volume in the development of pulmonary edema following mechanical ventilation. Am Rev Respir Dis 1993; 148:1194.
- Dreyfuss D, Saumon G. Ventilator-induced lung injury: lessons from experimental studies. Am J Respir Crit Care Med 1998; 157:294.
- Slutsky AS. Lung injury caused by mechanical ventilation. Chest 1999; 116:9S.
- Vlahakis NE, Hubmayr RD. Cellular stress failure in ventilator-injured lungs. Am J Respir Crit Care Med 2005; 171:1328.
- Chu EK, Whitehead T, Slutsky AS. Effects of cyclic opening and closing at low- and high-volume ventilation on bronchoalveolar lavage cytokines. Crit Care Med 2004; 32:168.
- Sandhar BK, Niblett DJ, Argiras EP, et al. Effects of positive end-expiratory pressure on hyaline membrane formation in a rabbit model of the neonatal respiratory distress syndrome. Intensive Care Med 1988; 14:538.
- Muscedere JG, Mullen JB, Gan K, Slutsky AS. Tidal ventilation at low airway pressures can augment lung injury. Am J Respir Crit Care Med 1994; 149:1327.
- Hamilton PP, Onayemi A, Smyth JA, et al. Comparison of conventional and high-frequency ventilation: oxygenation and lung pathology. J Appl Physiol Respir Environ Exerc Physiol 1983; 55:131.
- Lachmann B. Open up the lung and keep the lung open. Intensive Care Med 1992; 18:319.
- Imai Y, Kawano T, Miyasaka K, et al. Inflammatory chemical mediators during conventional ventilation and during high frequency oscillatory ventilation. Am J Respir Crit Care Med 1994; 150:1550.
- Kawano T, Mori S, Cybulsky M, et al. Effect of granulocyte depletion in a ventilated surfactant-depleted lung. J Appl Physiol (1985) 1987; 62:27.
- Tremblay L, Valenza F, Ribeiro SP, et al. Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model. J Clin Invest 1997; 99:944.
- von Bethmann AN, Brasch F, Nüsing R, et al. Hyperventilation induces release of cytokines from perfused mouse lung. Am J Respir Crit Care Med 1998; 157:263.
- Pugin J, Dunn I, Jolliet P, et al. Activation of human macrophages by mechanical ventilation in vitro. Am J Physiol 1998; 275:L1040.
- Held HD, Boettcher S, Hamann L, Uhlig S. Ventilation-induced chemokine and cytokine release is associated with activation of nuclear factor-kappaB and is blocked by steroids. Am J Respir Crit Care Med 2001; 163:711.
- Dahlem P, Bos AP, Haitsma JJ, et al. Alveolar fibrinolytic capacity suppressed by injurious mechanical ventilation. Intensive Care Med 2005; 31:724.
- Dahlem P, Bos AP, Haitsma JJ, et al. Mechanical ventilation affects alveolar fibrinolysis in LPS-induced lung injury. Eur Respir J 2006; 28:992.
- Choi G, Wolthuis EK, Bresser P, et al. Mechanical ventilation with lower tidal volumes and positive end-expiratory pressure prevents alveolar coagulation in patients without lung injury. Anesthesiology 2006; 105:689.
- Haitsma JJ, Schultz MJ, Hofstra JJ, et al. Ventilator-induced coagulopathy in experimental Streptococcus pneumoniae pneumonia. Eur Respir J 2008; 32:1599.
- Schultz MJ, Haitsma JJ, Zhang H, Slutsky AS. Pulmonary coagulopathy as a new target in therapeutic studies of acute lung injury or pneumonia--a review. Crit Care Med 2006; 34:871.
- Ware LB, Matthay MA, Parsons PE, et al. Pathogenetic and prognostic significance of altered coagulation and fibrinolysis in acute lung injury/acute respiratory distress syndrome. Crit Care Med 2007; 35:1821.
- Hofstra JJ, Haitsma JJ, Juffermans NP, et al. The role of bronchoalveolar hemostasis in the pathogenesis of acute lung injury. Semin Thromb Hemost 2008; 34:475.
- Liu KD, Levitt J, Zhuo H, et al. Randomized clinical trial of activated protein C for the treatment of acute lung injury. Am J Respir Crit Care Med 2008; 178:618.
- Cabrera-Benitez NE, Laffey JG, Parotto M, et al. Mechanical ventilation-associated lung fibrosis in acute respiratory distress syndrome: a significant contributor to poor outcome. Anesthesiology 2014; 121:189.
- Cabrera-Benítez NE, Parotto M, Post M, et al. Mechanical stress induces lung fibrosis by epithelial-mesenchymal transition. Crit Care Med 2012; 40:510.
- Tutor JD, Mason CM, Dobard E, et al. Loss of compartmentalization of alveolar tumor necrosis factor after lung injury. Am J Respir Crit Care Med 1994; 149:1107.
- Chiumello D, Pristine G, Slutsky AS. Mechanical ventilation affects local and systemic cytokines in an animal model of acute respiratory distress syndrome. Am J Respir Crit Care Med 1999; 160:109.
- Borrelli E, Roux-Lombard P, Grau GE, et al. Plasma concentrations of cytokines, their soluble receptors, and antioxidant vitamins can predict the development of multiple organ failure in patients at risk. Crit Care Med 1996; 24:392.
- Law MM, Cryer HG, Abraham E. Elevated levels of soluble ICAM-1 correlate with the development of multiple organ failure in severely injured trauma patients. J Trauma 1994; 37:100.
- Imai Y, Parodo J, Kajikawa O, et al. Injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome. JAMA 2003; 289:2104.
- Nahum A, Hoyt J, Schmitz L, et al. Effect of mechanical ventilation strategy on dissemination of intratracheally instilled Escherichia coli in dogs. Crit Care Med 1997; 25:1733.
- Verbrugge SJ, Sorm V, van 't Veen A, et al. Lung overinflation without positive end-expiratory pressure promotes bacteremia after experimental Klebsiella pneumoniae inoculation. Intensive Care Med 1998; 24:172.
- Murphy DB, Cregg N, Tremblay L, et al. Adverse ventilatory strategy causes pulmonary-to-systemic translocation of endotoxin. Am J Respir Crit Care Med 2000; 162:27.
- Hoegl S, Bachmann M, Scheiermann P, et al. Protective properties of inhaled IL-22 in a model of ventilator-induced lung injury. Am J Respir Cell Mol Biol 2011; 44:369.
- Jaecklin T, Otulakowski G, Kavanagh BP. Do soluble mediators cause ventilator-induced lung injury and multi-organ failure? Intensive Care Med 2010; 36:750.
- Hoegl S, Boost KA, Czerwonka H, et al. Inhaled IL-10 reduces biotrauma and mortality in a model of ventilator-induced lung injury. Respir Med 2009; 103:463.
- Jaecklin T, Engelberts D, Otulakowski G, et al. Lung-derived soluble mediators are pathogenic in ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol 2011; 300:L648.
- Ranieri VM, Suter PM, Tortorella C, et al. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA 1999; 282:54.
- Stüber F, Wrigge H, Schroeder S, et al. Kinetic and reversibility of mechanical ventilation-associated pulmonary and systemic inflammatory response in patients with acute lung injury. Intensive Care Med 2002; 28:834.
- Parsons PE, Eisner MD, Thompson BT, et al. Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury. Crit Care Med 2005; 33:1.
- Parsons PE, Matthay MA, Ware LB, et al. Elevated plasma levels of soluble TNF receptors are associated with morbidity and mortality in patients with acute lung injury. Am J Physiol Lung Cell Mol Physiol 2005; 288:L426.
- Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010; 363:1107.
- Slutsky AS. Neuromuscular blocking agents in ARDS. N Engl J Med 2010; 363:1176.
- Forel JM, Roch A, Marin V, et al. Neuromuscular blocking agents decrease inflammatory response in patients presenting with acute respiratory distress syndrome. Crit Care Med 2006; 34:2749.
- Victorino JA, Borges JB, Okamoto VN, et al. Imbalances in regional lung ventilation: a validation study on electrical impedance tomography. Am J Respir Crit Care Med 2004; 169:791.
- Gattinoni L, D'Andrea L, Pelosi P, et al. Regional effects and mechanism of positive end-expiratory pressure in early adult respiratory distress syndrome. JAMA 1993; 269:2122.
- Amato MB, Meade MO, Slutsky AS, et al. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med 2015; 372:747.
- Narimanbekov IO, Rozycki HJ. Effect of IL-1 blockade on inflammatory manifestations of acute ventilator-induced lung injury in a rabbit model. Exp Lung Res 1995; 21:239.
- Imai Y, Kawano T, Iwamoto S, et al. Intratracheal anti-tumor necrosis factor-alpha antibody attenuates ventilator-induced lung injury in rabbits. J Appl Physiol (1985) 1999; 87:510.
- Terragni PP, Del Sorbo L, Mascia L, et al. Tidal volume lower than 6 ml/kg enhances lung protection: role of extracorporeal carbon dioxide removal. Anesthesiology 2009; 111:826.
- Bein T, Weber-Carstens S, Goldmann A, et al. Lower tidal volume strategy (≈3 ml/kg) combined with extracorporeal CO2 removal versus 'conventional' protective ventilation (6 ml/kg) in severe ARDS: the prospective randomized Xtravent-study. Intensive Care Med 2013; 39:847.