Emerging therapies for treatment of acute lung injury and acute respiratory distress syndrome

Abstract

In 2007, Bosma et. al provided a comprehensive review of emerging therapies for the acute respiratory distress syndrome (ARDS), a condition which continues to carry a mortality rate of greater than 30%. Over the past several years, the development of novel and effective therapeutic agents for ARDS remains disappointing, and unfortunately, no recent therapeutic interventions have demonstrated a clear benefit. Herein, the results of several of these early and late phase clinical trials are reviewed, the majority of which address known maladaptive processes that have been deemed critical in ARDS pathophysiology. Based on the ongoing futility of current therapeutic models to yield effective therapies, it is speculated whether or not novel treatment paradigms, which address distinctly different aspects of this disease paradigm, may be warranted.

Keywords::

• acute lung injury
• acute respiratory distress syndrome
• inflammation
• mechanical ventilation

1. Background

For nearly two decades, the clinical definition and diagnosis of the acute respiratory distress syndrome (ARDS) has remained unchanged and includes the presence of severe hypoxemia and bilateral radiographic pulmonary infiltrates in the setting of normal left ventricular function [1]. These findings commonly occur in a cohort of critically ill patients in which the underlying clinical events leading to this severe form of lung dysfunction are well known. These include both direct (e.g., pneumonia, gastric aspiration) and indirect (e.g., sepsis, trauma) causes. Unfortunately, despite the ability to clearly identify these clinical features, outcomes related to ARDS remain poor and the mortality associated with this condition continues to exceed 25% [2].

In spite of the nonspecific aspects of the clinical definition, significant progress has been made in our understanding of ARDS pathophysiology, including the specific mechanisms by which the physiologic derangements develop in both the early and late stages of this disease. The apparent disconnect between the relatively stagnant diagnostic criteria and the rapid advancement of our knowledge of disease pathology may be one explanation for the lack of successful therapeutic approaches over the past several years.

In 2007, Bosma et al. provided a comprehensive review of emerging therapies for ARDS, which highlighted ongoing treatment strategies aimed at targeting various components of disease pathophysiology [3]. Herein, updated information regarding the development of some of these strategies will be reviewed. Subsequently, larger issues of whether current therapeutic approaches will continue to offer a rational pathway for drug development or whether an alternate treatment paradigm may be ultimately necessary to facilitate the emergence of effective treatment and/or prevention options will be discussed.

2. Current therapeutic approaches

Over the past 5 years, several notable Phase III and IV clinical trials have been completed, the majority of which have focused on the treatment of established ARDS as defined by conventional parameters. These current approaches attempt to capitalize on the insight gained into disease pathogenesis attributable to basic research, animal experiments and other (pre)clinical studies. Generally speaking, these approaches address the aspects of i) mechanical ventilator techniques, ii) the alteration of the inflammatory process associated with ARDS or iii) attempts to counteracting other specific maladaptive pathways felt to be critical in disease progression.

2.1 Mechanical ventilation

The landmark ARDS Network study demonstrating a mortality benefit in patients mechanically ventilated with lower tidal volumes compared with conventional (higher) tidal volumes remains the single most important advance in management of patients with ARDS [4]. Based on this finding, investigation remains active to determine whether greater gains can be achieved through further refinement of this potentially detrimental yet necessary supportive maneuver. Furthermore, a critical link between mechanical ventilation (MV) and the development of multiple organ failure, the most common cause of death in these patients, has been described thereby reinforcing the importance of defining the optimal use of this life-sustaining intervention.

The notion that cyclic (over)distention of alveoli occurs in spared nondependent regions of the lung relative to the fluid-filled diseased portions has led researchers to speculate whether ‘extreme' low-tidal volume MV achieved through high-frequency oscillation (HFO) in the presence of optimal lung recruitment would translate into further improvements in mortality. The Oscillation for ARDS Treated Early (OSCILLATE) Trial conducted under the auspices of the Canadian Institutes of Health Research/Canadian Critical Care Trials group is currently randomizing patients (target of 1200 patients) with severe, persistent ARDS to receive continued low-tidal volume MV or HFO using predefined criteria and its impact on mortality has been defined as the primary outcome measure (http://www.oscillatetrial.com [5]). As of January 2012, patients are still being actively recruited.

Beyond the use of HFO, alternate forms of MV such as airway pressure release ventilation, which permit spontaneous respiration while minimizing cyclic damage of alveolar structures, are also being evaluated in small-scale randomized trials (Airway Pressure Release Ventilation Compared to ARDSNet Ventilation, PRESSURE Trial, http://www.clinicaltrials.gov [6]; NCT00793013). Although preliminary studies have reported benefit in terms of improvement in physiologic parameters, definitive clinical trials demonstrating a reduction in mortality compared with the current low-tidal volume techniques have not been demonstrated. Additionally, an extreme form of ‘lung rest' using extracorporeal membrane oxygenation has been employed for refractory hypoxemia; however, the use of either of these techniques for patients with ARDS remains limited to the context of clinical research trials (http://www.clinicaltrials.gov [6]; NCT0140703).

2.2 Anti-inflammatory agents

The recognition of ARDS as a maladaptive proinflammatory state has garnered significant attention, although previous attempts to dampen the host inflammatory response through the use of systemic corticosteroids, for example, have not proven beneficial. Over the past number of years, there has been significant interest in mitigating specific components of either the pulmonary and/or systemic inflammatory response associated with ARDS. Unfortunately, selective blockade of isolated aspects of the inflammatory state has, to this point in time, resulted in uniform inefficacy.

Currently, clinical trials are underway attempting to capitalize on the anti-inflammatory properties of various therapeutic agents that have been studied in other non-pulmonary, inflammatory conditions. For example, previous work has demonstrated beneficial pleiotropic, non-lipid-lowering effects of HMG-CoA reductase inhibitors (commonly known as ‘statins') used in the management of patients with hypercholesterolemia. The effects of ‘statins' on the regulation of cellular cytokine release and apoptosis, in addition to potent antioxidant properties, appears attractive given the fundamental dysregulation of these processes in the setting of ARDS. Recently, Craig et al. conducted a randomized control trial (The HARP Study) comparing simvastatin with placebo in mechanically ventilated patients within 48 h of meeting criteria for ARDS [7]. Although no difference in overall mortality was detected, patients receiving simvastatin demonstrated a significant improvement in systemic organ dysfunction at day 14 accompanied by a reduction in airspace inflammation. Currently, the ARDS Network is conducting a large-scale randomized trial (Statins for Acutely Injured Lungs from Sepsis (SAILS study)) examining the effects of 20 mg of rosuvastatin compared with placebo in a cohort of patients with ARDS with mortality identified as the primary outcome measure (http://www.clinicaltrials.gov [6]; NCT00979121). Enrollment for this trial commenced in March 2010, and further information from this study will be forthcoming.

In addition to this class of medication, other smaller Phase I and Phase II clinical trials are currently underway examining the safety and efficacy of other agents designed to interrupt specific proinflammatory pathways including, but not limited to p38α (MAP kinase) (http://www.clinicaltrials.gov [6]; NCT00996840), interferon-β (http://www.clinicaltrials.gov [6]; NCT00789685) and coagulation factor III (http://www.clinicaltrials.gov [6]; NCT01438853). Although complete details of these studies are currently unavailable, preliminary enrollment criteria for some of these agents, in particular dilmapimod (an orally active P38 MAP kinase inhibitor), will be utilized in patients deemed ‘at risk' of acute lung injury. It is important to note that in distinction from traditional studies employing intervention strategies subsequent to the diagnosis of ARDS (e.g., within 48 h of diagnosis), the latter study represent a potentially important shift in the treatment paradigm of this disease toward a more proximal point within the disease history. Such an approach may address a primary impediment in both previous and current treatment strategies and the validity of this approach will be subsequently discussed.

2.3 Non-pharmacologic approaches

Over the past year, the results of a number of clinical trials addressing alternate approaches to patient care have been reported that deserve mention. For example, the benefits of maintaining adequate nutritional supplementation in critically ill patients have been previously supported in the literature, now referred to as ‘pharmaconutrition.' Based on the principle that specific antioxidant supplementation in addition to basal enteral feeding would modulate systemic inflammatory responses, the ARDS Network Clinical Trials group randomized more than 100 patients to this antioxidant-enhanced diet or a basal enteral diet [8]. This study was recently discontinued early due to treatment ‘futility' as the authors concluded that antioxidant supplementation failed to improve the primary outcome endpoint of ventilator-free days or other outcomes in patients with ALI.

In a different therapeutic approach, Papazian and colleagues demonstrated a significant difference in the adjusted hazard ratio for death (0.68, 95% confidence interval 0.48 – 0.98, p = 0.04) with the use of early neuromuscular blockade with cisatracurium in patients with ARDS [9]. Unfortunately, the crude 90-day mortality was not statistically significant (31.6% in the cisatracurium group compared with 40.7% in the placebo arm), although important beneficial outcomes including an increased number of ventilator-free days and a decrease in the incidence of barotrauma in patients randomized to cisatracurium were noted. The precise mechanism(s) of action by which this paralytic agent achieved these results remains speculative however. Nonetheless, further studies using a paralytic approach in patients with ARDS will be required before its widespread use can be recommended.

Over the past year, two separate trials have examined the effectiveness of β-2 agonist in patients with ALI, based on earlier studies indicating that β-2 stimulation of type I and type II alveolar epithelial cells could enhance the removal of alveolar edema fluid. Despite these initial findings however, both nebulized albuterol [10] and intravenous salbutamol [11] failed to demonstrate an improvement in ALI outcomes, and in fact the use of intravenous salbutamol was associated with an increase in 28-day mortality.

Finally, in an NHLBI-sponsored trial, Paine and colleagues recently reported on the use of intravenous recombinant human GM-CSF versus placebo in ALI patients receiving MV using a lung-protective protocol [12]. Again, no significant differences were observed in ventilator-free days, organ failure-free days or 28-day mortality.

3. Future directions

The advent of low-tidal volume MV for patients with ARDS represents the single evidence-based intervention that has unequivocally resulted in improved outcomes. Ironically, this ‘therapeutic' strategy for patients with ARDS confers benefit by minimizing harm rather than actively intervening in a maladaptive process, thereby suggesting that ‘less is more' maybe a more attractive treatment approach for these patients [13]. Such a strategy has been supported by other similar measures including less blood transfusion, less invasive hemodynamic monitoring, less sedation and potentially less intensive glucose monitoring.

With recent data suggesting that mortality attributable to ARDS remains greater than 25%, there is no question that our current traditional approaches to disease intervention require careful reexamination. Although, as indicated earlier, significant resources are being invested in the discovery of novel pathways that are believed to undermine the pathology of ARDS, it is difficult to remain optimistic that any of these approaches will yield a single ‘magic bullet' that will dramatically change the way in which these patients are currently managed. This is not to say, however, that these approaches will not be of any value or lead to improved care, but complimentary approaches and/or reconsideration of the clinical definitions or identification of disease may be ultimately required.

Thus, in order to address some of the aforementioned impediments to successful intervention, the emergence of a novel treatment paradigm that addresses earlier stages of this disease process, which may arrest disease progression during a time-sensitive phase, may be necessary [14]. For instance, it has been previously observed that chronic alcohol consumption leads to an increased susceptibility to ARDS, whereby distinct mechanisms have been implicated in adverse outcomes. Similarly, from a therapeutic standpoint, the pre-hospital use of aspirin has been recently demonstrated to reduce the incidence of acute lung injury [15], indirectly suggesting that adverse outcomes related to ARDS could be mitigated at an earlier phase of the disease process. In order to address this issue, an NHLBI/ARDSNet-sponsored clinical trial is currently underway to evaluate the effectiveness of low-dose aspirin versus placebo in early ALI (www.clinicaltrials.gov [6]; NCT01504867).

Ultimately, the ability to identify individuals who may be more susceptible to development of ARDS or at increased risk of adverse outcomes due to an inherent clinical or genetic risk factor may represent an ideal situation in which targeted pharmacologic intervention may advert the current therapeutic conundrum of ‘too little, too late.' Based on the aforementioned epidemiologic studies, and from a drug development standpoint, one wonders whether or not some of these therapeutic or pharmacologic interventions may already exist. However, until greater insight is achieved into this or other shifts in the therapeutic paradigm, it appears, at least for now, that yet another decade of unsuccessful intervention may lie ahead.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.