Date Published: March 30, 2017
Publisher: Public Library of Science
Author(s): Minhua Cheng, Tao Gao, Fengchan Xi, Chun Cao, Yan Chen, Chenyan Zhao, Qiurong Li, Wenkui Yu, Keiko Abe.
Dexmedetomidine is generally used for sedaton in critically ill, it could shorten duration of mechanical ventilation, ICU stay and lower basic metabolism. However, the exact mechanism of these positive effects remains unkown. Here we investigated the hypothesis that dexmedetomidine could ameliorate muscle wasting in endotoxemic rats and whether it was related to hypothalamic neuropeptides alteration and inflammation. Fourty-eight adult male Sprague–Dawley rats were intraperitoneally injected with lipopolysaccharide (LPS) (5 mg/kg) or saline, followed by 50 μg/kg dexmedetomidine or saline administration via the femoral vein catheter (infusion at 5 μg·kg-1·hr-1). Twenty-four hours after injection, hypothalamus tissues and skeletal muscle were obtained. Muscle wasting was measured by the mRNA expression of two E3 ubiquitin ligases, muscle atrophy F-box (MAFbx) and muscle ring finger 1 (MuRF-1) as well as 3-methylhistidine (3-MH) and tyrosine release. Hypothalamic inflammatory markers and neuropeptides expression were also detected in all four groups. Results showed that LPS administration led to significant increase in hypothalamic inflammation together with muscle wasting. Increased hypothalamic neuropeptides, proopiomelanocortin (POMC), cocaine and amphetamine-related transcript (CART) and neuropeptides Y (NPY) and decreased agouti-related protein (AgRP) were also observed. Meanwhile dexmedetomidine administration ameliorated muscle wasting, hypothalamic inflammation and modulated the alteration of neuropeptides, POMC, CART and AgRP, in endotoxemic rats. In conclusion, dexmedetomidine could alleviate muscle wasting in endotoxemic rats, and it could also attenuate the alteration of hypothalamic neuropeptides and reduce hypothalamic inflammation.
Pain and anxiety are common in critically ill due to intubation, infection, trauma and long-term bedridden. When inappropriately treated, pain and anxiety can cause tachycardia, immunosuppression, increased oxygen consumption, elevated catecholamine production and metabolism. So it is neccessary and beneficial to keep critically ill sedated. Traditional sedative agents may generate unpredictable and prolonged duration of action in critically ill, due to the redistribution and accumulation of active metabolites. Benzodiazepines have also been reported to be associated with increased risk of delirium, coma and respiratory depression. Nowadays many guidelines recommend using non-benzodiazepines, like dexmedetomidine. Dexmedetomidine, a new sedative, can cause analgesia and induce a sedative state similar to physiologic sleep without causing respiratory depression, by acting on α-2 receptors in the locus caeruleus. Besides the benefits of shortening duration of mechanical ventilation and length of ICU stay, dexmedetomidine has also been demonstrated to reduce risk of delirium and hypertension[7,8]. Moreover in our previous study, we found that the addition of dexmedetomidine to analgesia for patients after abdominal operations could enhance recovery of gastrointestinal function, alleviate postoperative pain and lower metabolism. However, the exact mechanism of these positive effecets on critically ill is still unkown.
It is well konwn that many factors could influence metabolism. For example, metabolism would elevate under the circumstances of pain or anxious. Due to intubation, infenction, trauma and long-term bedridden, pain and anxiety exist in most critically ill patients. When inappropriately treated, pain and anxiety can cause many negative effects, so it is neccessary and beneficial to keep critically ill patients sedated. Compared with tradional benzodiazepine sedatives, non-benzodiazepines, like midazolam and dexmedetomidine, may be more applicable and safer. Dexmedetomidine is a highly selective α-2 adrenoreceptor agonist providing sedative and anxiolytic activity via receptors within the locus ceruleus, analgesia via receptors in the spinal cord, and attenuation of the stress response with no significant respiratory depression. It proved to be safer by causing fewer adverse effects and could reduce cardiac output and hepatic blood flow, potentially increasing its action duration in critically ill patients. Although dexmedetomidine was generally used for sedation in critically ill patients, our previous clinical study found that applying dexmedetomidine to postoperative patients could accelerate the recovery of gastrointestinal function and lower metabolism. However, the exact mechanism of dexmedetomidine’s positive effecets on critically ill patients remains unkown. Here we first demonstrated that dexmedetomidine treatment could reduce endoxemia-induced muscle wasting and is associated with the alteration of hypothalamic peptides and inflammation.
In conclusion, dexmedetomidine could reversing muscle wasting, and it could also attenuate the alteration of hypothalamic neuropeptides and reduce hypothalamic inflammation. This expanded the usage of dexmedetomidine in critically ill besides sedation. The exact mechanism for dexmedetomidine’s central effect on endotoxemia-induced muscle wasting requires further exploration. These results may provide a new perspective for the research and management of muscle wasting in critically ill patients and the study of dexmedetomidine effect.