What's new in critical illness and injury science? State of the art in management of ARDS.

In this issue of the International Journal of Critical Illness and Injury Science, Krishnamoorthy and Chung[1] put forth a call to arms for a renewed investigative push in search of a clinical solution for the grave clinical problem of the acute respiratory distress syndrome (ARDS).[23] On a spectrum of inflammatory-mediated acute pulmonary disease, ARDS represents the most severe form of acute lung injury (ALI).[34]

The development of ARDS has been associated with a number of heterogeneous medical and surgical conditions, including aspiration,[56] sepsis,[7] pancreatitis,[8] bacterial or viral pneumonia,[9] and trauma.[410] The syndrome itself can be characterized by a phasic nature, beginning with an acute presentation, a subacute stage, and finally the chronic or “burnout” phase.[11] Survivors of ARDS may face significant functional disability following recovery from this syndrome.[1213]

A number of therapeutic strategies have been tested for ARDS, without delivery of consistent or reliable results.[1415161718] Among the most prominent efforts to improve patient outcomes in ARDS are the use of exogenous surfactant,[19] prone positioning,[20] corticosteroids,[21] adjunctive inhaled agents,[1922] paralytics,[23] advanced mechanical ventilation strategies,[224] perfluorocarbon-based liquid ventilation,[2526] and extracorporeal membrane oxygenation (ECMO) support for the refractory cases.[27] The advent and implementation of these therapies has allowed improved oxygenation of patients and guided more accurate discussions with families regarding prognosis. However, for patients suffering from ARDS, the attenuation of the inflammatory response, the ability to limit the associated tissue injury, and the improvement of subsequent functional disability, seem to be among the most urgent issues that need our immediate attention.[28] Prior research by Meduri et al.,[28] and Crandall et al.,[29] demonstrates the potential benefits of an attenuated inflammatory response in the setting of ARDS. However, the complications of glucocorticoid usage as described by Meduri[28] and the infeasibility of splenectomy as presented by Crandall[29] limit both the applicability and generalizability of these approaches across the inherently heterogeneous ARDS population.

The concept of intratracheal administration of ropivacaine, lidocaine, or possibly another local anesthetic and the need for further translational research, as put forth by Krishnamoorthy and Chung, is timely and intriguing.[130] An increasing number of publications seem to support some degree of physiologic or clinical benefit associated with intravenous and/or intratracheal lidocaine administration.[31323334] Ropivacaine administration has also been linked to attenuation of ALI in the experimental setting.[30] However, most of this preliminary evidence comes from studies involving animal models. Notably, as with any pharmacologic intervention, there is at least one reported case of local administration of lidocaine associated with ARDS[35] and one instance of seizures following aspiration of viscous lidocaine.[36]

Krishnamoorthy and Chung[1] present a very timely request for further scientific evaluation, and their position is well-supported by the evidence accumulated over the past 15 years. In 2000, Hollmann et al. raised the question of local anesthetics being used for new therapeutic indications, stressing the anti-inflammatory properties of these pharmacologic agents.[37] Their exhaustive review highlighted the evidence of in vitro and in vivo anti-inflammatory effects of local anesthetics through the modulation of the release of polymorphonuclear cell (PMN) mediators, as well as the apparent facilitation of PMNs concentrating at the site of needed action.[37] Hollmann et al., also called for further clinical studies, in addition to the need to specifically identify the associated mechanisms of action. Several years later, Cassuto et al., in another review further extolled the potential virtue of local anesthetics through their effects on the cells of the immune system.[38] In this review, the authors admitted that there were relatively limited numbers of diseases that could be treated with local anesthetics but local anesthetics could be a platform to pursue future therapeutic interventions in regard to inflammation.[38] This is indeed coming to pass.

In this decade, the non-anesthetic lidocaine analogue JMF2-1 was tested on mice and guinea pigs.[3940] The first study demonstrated that JMF2-1 prevented asthma symptoms by reduction of TH2 cytokine generation and pulmonary eosinophilia by inhibition of T-cell function and survival. Here, the modification of the lidocaine aromatic ring led to this therapeutic novelty. This evidence supports the abovementioned postulate by Cassuto.[38] This same research team, in a second study, suggested that JMF2-1 inhibits the contraction of respiratory smooth muscle and affects T-cell proliferation and survival through a cyclic adenosine monophosphate (cAMP) intracellular pathway[40]. This evidence, in turn, further highlights the possibilities of a modified local anesthetic platform from the pharmacological perspective.

Research on the mechanism(s) of action of local anesthetics and their role as anti-inflammatory modulators has also progressed nicely. Wang et al., enhanced our understanding of the mechanism of action of lidocaine by presenting evidence that lidocaine's anti-inflammatory effect occurred by inhibiting the expression of high mobility box group 1 (HMGB1) mRNA and translocating both HMGB1 and nuclear factor-κB (NF-κB) to the cytoplasm from the nucleus.[41] Sera et al., added to the evidence of lidocaine as an anti-inflammatory in asthma by nebulizing it in a murine model and demonstrating that: (a) it prevented eosinophilic inflammation, (b) prevented overproduction of mucous, (c) decreased peribronchial fibrosis, and (d) decreased hyperreactivity of the bronchial tree by the inhibition of allergen-evoked GATA3 expression.[42] A more recent work by Yuan et al., shows that use of lidocaine prophylactically inhibits lipopolysaccharide (LPS)-induced release of mediators of inflammation from microglia, and these effects are enforced by blockade of the p38 mitogen-activated protein kinase (MAPK) and NF-κB pathways.[43] Additional recent work by Picardi et al., introduced the concept of local anesthetic inhibition of neutrophil priming. This occurred through the Gαq-protein-mediated priming that was facilitated by ester compounds.[44]

In addition to Blumenthal's work with ropivacaine,[30] Piegler et al., have produced several works of interest that involve ropivacaine (actually both ropivacaine and lidocaine).[4546] In the former, Piegeler et al., studied the addition of ropivacaine, lidocaine, and chloroprocaine to NCI-H838 lung cancer cells incubated with tumor necrosis factor-α (TNFα). Ropivacaine and lidocaine significantly decreased Src-activation and intercellular adhesion molecule-1 phosphorylation. Chloroprocaine had no effect. Thus, amide-linked but not ester-linked local anesthetics may present anti-metastatic effects. In the latter study, Piegeler et al., presented the ability of ropivacaine and lidocaine to stop TNF-α signals in epithelial cells by lessening the p85 recruitment to TNF-receptor-1, causing a decrease in endothelial nitric oxide synthetase and Akt (also known as Protein Kinase B). In addition, Src phosphorylation is known to decrease neutrophil adhesion. Thus, both these local anesthetics, again, may have value in management of inflammatory disease.

This cumulative evidence provides a strong impetus of the investigational use of ropivacaine and lidocaine in the treatment of ARDS and further supports the push for bench-to-bedside multi-institutional trials. Thoughtful and safe protocols need to be considered and acted upon by the critical care community. Krishnamoorthy and Chung are to be commended for this timely call to arms. Without innovation and some risk-taking, true progress in our quest to tame ARDS will only remain a dream. Galileo and Copernicus claimed the Earth orbited the Sun and now we have modern astronomy;[47] Fleming followed up on an unusual fungal metabolite, and now we have penicillin;[48] and if not for Warren and Marshal considering a bacterium as the causative agent of peptic ulcer, we would continue to perform invasive procedures for this medically treatable condition.[49] Therefore, we are now faced with the distinct and increasingly credible possibility, if not probability, that local anesthetics may indeed be helpful in the treatment of ARDS.