POINT OF VIEW
Year : 2014 | Volume
: 4 | Issue : 2 | Page : 98--100
Bench-to-bedside: The use of local anesthetics to attenuate inflammation in acute respiratory distress syndrome
Vijay Krishnamoorthy1, Linda Chung2,
1 Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA
2 Department of Anesthesiology, University of Illinois, Chicago, USA
Department of Anesthesiology and Pain Medicine, University of Washington, 1959 NE Pacific Ave, BB 1469, Seattle, WA 98195
The acute respiratory distress syndrome (ARDS) remains a world-wide treatment challenge, with high morbidity and mortality. The central pathophysiology of ARDS centers around inflammation in the lung and increased microvascular permeability. Local anesthetics have been shown to have anti-inflammatory effects at the basic science level and the advent of local anesthetics with improved cardiovascular safety profiles has made use of local anesthetics in attenuating the inflammation in ARDS a recent research interest. In this review, we will provide a brief summary of some of the basic science work in local anesthetics and lung inflammation and provide a case for the bench to bedside research in this potential therapy.
|How to cite this article:|
Krishnamoorthy V, Chung L. Bench-to-bedside: The use of local anesthetics to attenuate inflammation in acute respiratory distress syndrome.Int J Crit Illn Inj Sci 2014;4:98-100
|How to cite this URL:|
Krishnamoorthy V, Chung L. Bench-to-bedside: The use of local anesthetics to attenuate inflammation in acute respiratory distress syndrome. Int J Crit Illn Inj Sci [serial online] 2014 [cited 2020 Jul 11 ];4:98-100
Available from: http://www.ijciis.org/text.asp?2014/4/2/98/134143
The acute respiratory distress syndrome (ARDS) is a major cause of morbidity and mortality in critically ill-patients, with an estimated 190,000 new cases in the United States every year.  A variety of systemic insults can lead to ARDS including sepsis, trauma, pneumonia and neurologic hemorrhage. The pathophysiology centers around disruption of the alveolar capillary membrane, causing excess fluid accumulation in both the interstitium and alveoli; consequences include impaired gas exchange and decreased lung compliance. Despite advances in knowledge of the pathophysiology of this complex disease, remarkably few pharmacologic therapies have proven effective, with proper mechanical ventilation remaining the hallmark of management of the lung injury. 
Local anesthetics have a well-established niche in modern day medicine. Because of their ability to block sodium channels, they have been widely used in local and regional anesthesia, as well as in the treatment of cardiac arrhythmias. Recently, studies have shown a greater spectrum of use at lower concentrations, with beneficial effects on post-operative ileus, prevention of metastatic disease, microvascular permeability and neuroprotection.  However, these same anti-inflammatory principles have made use of local anesthetic to attenuate inflammatory reactions in the lung a recent research interest.  The microscopic pathophysiology of the ARDS is a continuing topic of research. Literature to date suggests that there are specific inflammatory steps leading to hypoxemia, high-permeability pulmonary edema and neutrophil accumulation in the lungs.  Thus, local anesthetics may have a potential role in attenuating the inflammatory cascade in ARDS.
Evidence from The Bench
The distal airway consists of alveolar macrophages (AM) and epithelial cells at the alveolar-capillary membrane. With an initial insult, it is hypothesized that AM and alveolar epithelial cells are activated and produce tumor necrosis factor (TNF)-alpha, muscle precursor cells-1, interleukinil (IL)-1B and other cytokines,  which in turn up-regulate intercellular adhesion molecules (ICAM-1).  Once ICAM-1 is up regulated, neutrophils release proteolytic enzymes and oxygen free radicals, which damage the delicate alveolar/endothelial barrier. Neutrophils gain access to the alveoli and lung parenchyma causing further inflammatory changes and hypoxia.  Beck-Schimmer et al. described the increase in ICAM-1 release in a lipopolysaccharide LPS-induced rat lung injury model in conjunction with an increase in TNF-alpha and IL-1; when the same model was treated with anti-TNF-alpha antibodies and anti-IL antibodies, ICAM-1 expression was decreased by 81% and 37% respectively.  Neff et al. demonstrated that when a LPS-induced lung injury model was treated with ICAM-1 antibodies, neutrophil induced necrosis of epithelial cells decreased from 53%-34%. 
The work of Blumenthal et al. has tried to expand on these known ideas with the use of local anesthetics. Using a very similar laboratory model of LPS-induced lung injury both in-vivo (rat lung) and in-vitro (alveolar epithelial cells and endothelial cells), Blumenthal et al., was able to show a decrease in ICAM-1 expression in alveolar epithelial and vascular endothelial cells with ropivacaine, a commonly used local anesthetic.  Ropivacaine was also shown to decrease neutrophil accumulation in-vivo when applied intravenously (IV) and intratracheally (IT) by 81% and 56% respectively. Cytokine accumulation was also decreased in both IV and IT applications. Finally, the alveolar-capillary permeability measured by albumin content in the respiratory compartment diminished with ropivacaine use. 
Ropivacaine has many benefits over older local anesthetics, such as lidocaine that have been studied in clinical trials. Lidocaine has been shown to attenuate lung injury in-vivo as well as aspiration, reperfusion injury and hyperoxia-induced lung injury.  Another study showed that lidocaine inhibits cellular adhesion molecules and superoxide formation.  Nevertheless, lidocaine has a known side effect profile including cardiotoxicity and neurotoxicity,  which has limited its study in ARDS patients. In addition, in the setting of ARDS and lidocaine administration, cardiovascular collapse has occurred.  Ropivacaine, with its improved safety profile when compared with other local anesthetics,  may prove to be a safer option in critically ill-patients, especially with its in-vivo benefits when administered IT,  further limiting systemic toxicity.
Future Directions at The Bedside
The findings of Blumenthal et al. (taken with the existing basic science literature) may now provide the impetus for translational trials at the bedside, to assess whether ropivacaine may in fact have a role in ARDS.
Treatment for ARDS has primarily consisted of lung protective ventilation. Lower tidal volumes, higher positive-end expiratory pressure and permissive hypercapnia are standards of care in ARDS literature.  Despite much research regarding pharmacologic therapies, there has been only one study that has shown improved mortality with a pharmacologic intervention. Papazian et al. showed reduction in barotrauma, days off ventilator, days out of the intensive care unit and adjusted 90 day survival rate with a continuous infusion of cisatracurium.  The mechanism of neuromuscular blocking agents to affect the pathology of acute lung injury (ALI) is speculative, although a reduction in proinflammatory cytokines, eventually leading to improved oxygenation may have played a role  this is a similar theory to ropivacaine's possible benefits.
It is time to start the process of clinical trials in this novel pharmacologic therapy to possibly attenuate inflammation in ARDS. Important questions that lie ahead include: The logistics and safety of IT administration of local anesthetics in critically ill-patients, the magnitude of reduction in inflammatory mediators and the measurement of patient-level outcomes, including lung function, quality-of-life, morbidity and mortality. This process will require collaboration with both basic science and clinical investigators, with an eye to critically evaluate a hopefully beneficial translational intervention.
The process of lung injury secondary to a primary insult, inflammation, hypoxia and worsening inflammation consist of a cyclical cascade, with each insult "fueling the fire" and leading to worsened lung function. Basic science and clinical research support both support the concept of potentially targeting the inflammatory pathway in helping to attenuate lung injury in ARDS. The next step is to perform well-designed studies at the clinical level to delineate the effects of local anesthetics, particularly ropivacaine via the IT route, in attenuating ALI. The time has come to translate what we have learned about inflammation and lung injury at the bench and start to evaluate it at the bedside.
|1||Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, et al. Incidence and outcomes of acute lung injury. N Engl J Med 2005;353:1685-93.|
|2||Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The acute respiratory distress syndrome network. N Engl J Med 2000;342:1301-8.|
|3||Hollmann MW, Durieux ME. Local anesthetics and the inflammatory response: A new therapeutic indication? Anesthesiology 2000;93:858-75.|
|4||Borgeat A, Aguirre J. Update on local anesthetics. Curr Opin Anaesthesiol 2010;23:466-71.|
|5||Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000;342:1334-49.|
|6||Beck-Schimmer B, Schwendener R, Pasch T, Reyes L, Booy C, Schimmer RC. Alveolar macrophages regulate neutrophil recruitment in endotoxin-induced lung injury. Respir Res 2005;6:61.|
|7||Ikeda U, Ikeda M, Seino Y, Takahashi M, Kasahara T, Kano S, et al. Expression of intercellular adhesion molecule-1 on rat vascular smooth muscle cells by pro-inflammatory cytokines. Atherosclerosis 1993;104:61-8.|
|8||Schmal H, Czermak BJ, Lentsch AB, Bless NM, Beck-Schimmer B, Friedl HP, et al. Soluble ICAM-1 activates lung macrophages and enhances lung injury. J Immunol 1998;161:3685-93.|
|9||Beck-Schimmer B, Schimmer RC, Warner RL, Schmal H, Nordblom G, Flory CM, et al. Expression of lung vascular and airway ICAM-1 after exposure to bacterial lipopolysaccharide. Am J Respir Cell Mol Biol 1997;17:344-52.|
|10||Neff SB, Z′graggen BR, Neff TA, Jamnicki-Abegg M, Suter D, Schimmer RC, et al. Inflammatory response of tracheobronchial epithelial cells to endotoxin. Am J Physiol Lung Cell Mol Physiol 2006;290: L86-96.|
|11||Blumenthal S, Borgeat A, Pasch T, Reyes L, Booy C, Lambert M, et al. Ropivacaine decreases inflammation in experimental endotoxin-induced lung injury. Anesthesiology 2006;104:961-9.|
|12||Takao Y, Mikawa K, Nishina K, Maekawa N, Obara H. Lidocaine attenuates hyperoxic lung injury in rabbits. Acta Anaesthesiol Scand 1996;40:318-25.|
|13||Ohsaka A, Saionji K, Sato N, Igari J. Local anesthetic lidocaine inhibits the effect of granulocyte colony-stimulating factor on human neutrophil functions. Exp Hematol 1994;22:460-6.|
|14||Radwan IA, Saito S, Goto F. The neurotoxicity of local anesthetics on growing neurons: A comparative study of lidocaine, bupivacaine, mepivacaine, and ropivacaine. Anesth Analg 2002;94:319-24.|
|15||Promisloff RA, DuPont DC. Death from ARDS and cardiovascular collapse following lidocaine administration. Chest 1983;83:585.|
|16||Graf BM. The cardiotoxicity of local anesthetics: The place of ropivacaine. Curr Top Med Chem 2001;1:207-14.|
|17||Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010;363:1107-16.|
|18||Forel JM, Roch A, Marin V, Michelet P, Demory D, Blache JL, et al. Neuromuscular blocking agents decrease inflammatory response in patients presenting with acute respiratory distress syndrome. Crit Care Med 2006;34:2749-57.|