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Many people are suggesting...

..."novel" therapies for COVID-19 ARDS.
What has been tried in the past and how did it go?


This piece is courtesy of Dr. Dan Okin.
The FLARE Four:
 
  1. The therapy for ARDS, including ARDS associated with COVID-19, is essentially supportive.
  2. To date, the only specific therapies that have been found to help in cases of ARDS are those that target the underlying process that led to ARDS, such as antibiotics for bacterial infection. 
  3. There are many suggestions for novel therapies targeting the pathologic cascade of ARDS and the host response to SARS-CoV-2. Many of these are being evaluated in trials. Some have been suggested for clinical use. 
  4. Proposed therapies must be evaluated in light of the long history of failed investigational therapies for ARDS.
In tonight's FLARE, and continuing with tomorrow’s, we will review the literature on investigational therapies for ARDS prior to COVID-19.
Introduction: the biologic underpinnings of ARDS
The pathogenesis of ARDS is complex and involves a poorly understood set of interactions between insult, host immune response, clotting cascades, and pulmonary mechanics. We will not give an in-depth review of each phase of pathophysiology here, but rather will briefly discuss the pathophysiology relevant to the four major categories of previously investigated therapies in ARDS: (1) immune effector functions, (2) reactive oxygen species generation, (3) alterations in the coagulation cascade, and (4) alterations in pulmonary mechanical function. A common theme that runs through the ARDS literature is the uncertainty surrounding which biological processes are adaptive and which are pathologic. The observation that essentially all targeted therapies in ARDS have failed indicates that our knowledge of the underlying pathophysiology is incomplete and necessitates further research.
The normal alveolus (left) and the injured alveolus (right) in the exudative phase of ARDS (Ware and Matthay, 2000).
Therapies targeting reactive oxygen species generation
What’s the scientific rationale? 
Reactive oxygen species (ROS) can promote DNA damage, lipid oxidation, disrupt proteostasis, and increase cytokine secretion, thus perpetuating inflammatory cascades (Nathan and Cunningham-Bussel, 2013). Elevated ROS are seen in ARDS secondary to generation by neutrophils and macrophages, depletion of antioxidants, and utilization of high FiO2 during therapy (Thompson et al., 2017). These findings led to the hypothesis that ROS might contribute to pathogenesis in ARDS. However, the mere observation of increased activity of any particular pathway during ARDS does not establish that the increased activity is inappropriate and certainly does not, in and of itself, suggest that inhibiting that pathway will improve outcome. Indeed, locally generated ROS play an important role in enabling kinase mediated signaling, transcription, antimicrobial function of phagocytes, cellular metabolism, and proteostasis. Thus, ROS elevation might actually promote the local cellular adaptation to stress. Amid this equipoise, multiple clinical trials have asked whether reduction of ROS levels might be therapeutically beneficial in ARDS. As discussed below, 2 major strategies have been attempted in patients: (1) augmenting antioxidant capabilities and (2) lowering local oxygen tension.  

What’s the evidence?
Six independent studies evaluated the use of IV N-acetylcysteine to regenerate cellular glutathione stores in ARDS (Bernard et al., 1997; Domenighetti et al., 1997; Jepsen et al., 1992; Moradi et al., 2009; Ortolani et al., 2000; Suter et al., 1975), five of which showed no improvement in mortality or other ICU proxy outcomes. Moradi and colleagues showed a significant improvement in the patients who received NAC, but this study had significant methodological concerns including small sample size, poor matching of control and experimental groups, and limited information on ventilation details.  
 
Attempts to limit oxygen delivery in an attempt to minimize generation of ROS showed early promise, but this strategy too has met with limited success. The single center Oxygen-ICU trial (Girardis et al., 2016) suggested a mortality benefit to conservative oxygen therapy in critically ill patients. This conclusion was further supported by a meta-analysis of critically ill non-ARDS patients in which it was suggested that targeting an SpO2 < 96% was associated with small reduction in mortality (Chu et al., 2018). These strategies were subsequently evaluated in two large multicenter ARDS-specific RCTs (ICU-ROX and LOCO2) and targeted SpO2 targets < 95% in the experimental arms. Despite excellent separation between the achieved oxygen saturation in the groups in both trials, neither trial demonstrated improved mortality and, concerningly, LOCO2 was stopped early for potential mortality increase and futility in the experimental group (Barrot et al., 2020; ICU-ROX Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group et al., 2020; Panwar et al., 2016).  

What’s the main point?
Based upon these studies, the evidence does not support targeting lower oxygen saturation in ARDS, but such a strategy may still be beneficial in other critically ill patients.
Therapies targeting the coagulation cascade
What’s the scientific rationale? 
Inflammation-dependent coagulation has been proposed to contribute to the pathogenesis of ARDS through enhanced local fibrin deposition and small vessel thrombosis (Beasley, 2010). The coagulopathy in ARDS is thought to be driven by exposure of tissue factor, reduction of natural anticoagulants such as protein C, and impairment in fibrinolysis due to lack of plasminogen activator. Given these biochemical and pathological abnormalities, there has been decades of interest in modulating or blocking coagulation in the setting of ARDS.
Activation protein C acts at multiple steps throughout the coagulation cascade (Bernard et al., 2001).
What’s the evidence? 
Activated protein c (aPC) is an inhibitor of coagulation which acts on multiple steps in the cascade and had previously been tested in septic shock, where it did not improve mortality and increased bleeding risk. Two small RCTs evaluated whether supplementation with aPC might be beneficial in ARDS, with neither demonstrating a significant difference in mortality or ventilator free days (Cornet et al., 2014; Liu et al., 2008). As aPC was withdrawn from the market based upon its lack of benefit in severe sepsis, further trials have not been conducted.
 
The hyperactivation of tissue factor in ARDS has increased interest in anticoagulants such as heparin. Multiple in vitro studies have suggested that heparin reduces pulmonary inflammation, but animal model data have been more mixed (Camprubí-Rimblas et al., 2018). A meta-analysis of 5 studies demonstrated no mortality benefit, but did show a slight trend toward fewer ICU days in patients receiving nebulized heparin (Glas et al., 2016). However, the group treated with heparin were also ventilated on lower tidal volumes than the control group, 3 of the 5 studies comprising this analysis were in burn patients, and many patients also received inhaled NAC. And, if you’re wondering if this failure is related to the route of delivery, a retrospective propensity matched cohort study also failed to show benefit associated with intravenous heparin administration (Hofstra et al., 2012).
 
Finally, there has been some recent interest in using tissue plasminogen activator (tPA) in COVID-19 patients. Please refer to the March 31st FLARE for an in-depth discussion. 

What’s the main point?
While activation of the coagulation cascade is a hallmark of ARDS, therapies aimed at restoring the “normal balance” of coagulation have not shown any benefit in patients. Looked at through the lens of the underlying biology, the activation of the coagulation cascade in response to inflammation is an evolutionarily conserved process that plays an important role in promoting local tissue repair and restoring homeostasis after exposure to noxious stimuli. A fuller understanding of the ways in which these processes are adaptive versus maladaptive will be required before therapeutic manipulation of coagulation in ARDS is likely to be beneficial.
More to come...
Tomorrow night, we will discuss the history of trials dealing with the pulmonary parenchyma and therapies targeting immune effector function.
FLARE is a collaborative effort within the Pulmonary and Critical Care Division and the Department of Medicine at Massachusetts General Hospital. Its mission is to appraise the rapidly evolving literature on SARS-CoV-2 with a focus on critical care issues.

Prior FLAREs can be found here, under "Fast Literature Updates".
Thank you for everything you are doing!
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References:
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  • Bernard, G.R., Vincent, J.-L., Laterre, P.-F., and Fisher, C.J. (2001). Figure 1. Proposed Actions of Activated Protein C in Modulating the.
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