DOI: 10.1097/CCM.0000000000001173

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PMID: 26274720

Issn Print: 0090-3493

Publication Date: 2015/09/01


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Purposeful Repurposing: Unexpected but Not Necessarily Unwelcome Effects of Dexmedetomidine*

Melanie J. Scott

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Excerpt

Severe liver disease does not only affect the way the liver functions but also causes more systemic problems. Patients in liver failure, whether from alcohol-related, viral-related, or drug-induced liver damage, will often also present with multiple-organ damage and failure. This includes damage to the brain (encephalopathy), kidneys (hepatorenal syndrome), and lungs (hepatopulmonary syndrome [HPS]). Up to 47% of patients with severe chronic liver disease may have HPS, and these patients have a bad overall prognosis with few specific treatments available to help them (1). More acute liver injury also often goes hand-in-hand with signs of pulmonary damage, with patients having reduced lung function that can develop into full-blown respiratory distress syndrome. The clinical features of pulmonary failure are mirrored on a cellular level with damage to (and death of) alveolar epithelial cells, as well as signs of inflammation with increased numbers of infiltrating immune cells and damage to the endothelial lining of small blood vessels. What causes all these cellular changes and damage is not really clear, and this makes it hard to determine what might be a good treatment strategy to help lungs heal or prevent the damage from occurring in the first place.
In this issue of Critical Care Medicine, Cui et al (2) hypothesized that increased levels of bilirubin, which can be present in patients with either acute or chronic liver failure, damage alveolar epithelial cells, and that this damage can be ameliorated using a commonly used ICU drug, dexmedetomidine. Dexmedetomidine is an α-2 adrenergic agonist with a good safety profile that is used primarily for patient sedation in many ICUs. Recent studies have suggested that using dexmedetomidine can reduce the need to use other types of sedation (3) and may reduce the length of time that patients are on mechanical ventilation in the ICU (3). The mechanisms of dexmedetomidine action to reduce ventilation days are poorly identified or understood, but dexmedetomidine is thought to have antioxidant properties in addition to sedation although little research has been done to really examine whether this potentially beneficial characteristic plays a role in the function of the drug in patients.
In this current study, the authors tested the effects of dexmedetomidine in an in vitro model, using a cell line derived from alveolar epithelial cells, and also in vivo using a model of acute hyperbilirubinemia induced by common bile duct ligation (CBDL) in rats. In vitro, the investigators confirm that bilirubin increases alveolar epithelial cell death and reduces cell proliferation in a concentration-dependent manner. These effects are reduced in dexmedetomidine-treated cells, and dexmedetomidine-driven protection seems to be mediated partly through its α-adrenergic agonist properties. Dexmedetomidine also seems to directly affect cell survival by reducing the activation of certain apoptosis signaling pathways in bilirubin-treated alveolar epithelial cells. Apoptosis is a form of programmed cell death that can result from damage to mitochondria and release of reactive oxygen species that are detrimental to cells (4). Reducing apoptosis and reactive oxygen species formation may represent antioxidant actions of dexmedetomidine separate from its main α-adrenergic agonist functions. However, this would need to be confirmed experimentally and this was not investigated in this particular study.
More interestingly for clinicians, data in this current study also demonstrate protective effects of dexmedetomidine in vivo in the rat model of CBDL. This is an established experimental surgical model to induce hyperbilirubinemia (5), and the authors confirm what others have shown that bilirubin levels are highest at about 7 days after surgery and then start to decline although the levels are still comparatively high at 21 days.
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