Mechanisms of fenofibrate alone or combined with propranolol in burned patients

摘要 对严重烧伤的反应的特征是持续的高代谢和分解代谢状态，导致大量的 肌肉组织的损失，即使在进食状态下。在烧伤总体表面积> 30%的患者中，蛋白质分解 在烧伤创面愈合95%后持续约一年。内源性儿茶酚胺已经被 被认为是创伤或烧伤后高代谢反应的主要介质。慢性血浆升高 儿茶酚胺水平导致高动力循环的发展，增加的基础能量消耗， 外周胰岛素抵抗伴高血糖，外周脂解增加，免疫功能低下，骨骼肌 肌肉蛋白卡他赛和增生性瘢痕。烧伤后的高代谢反应也表现为 严重的心动过速和增加的心脏工作对心脏有害。持续的心动过速和 肌肉痉挛严重影响康复，导致恢复正常前的过度延迟 身体和功能活动。我们机构最近的研究表明高血糖症的负面影响 和胰岛素抵抗对存活率、伤口愈合和骨骼肌钙蛋白的影响。胰岛素抵抗可持续至少3 严重烧伤患者的平均寿命为10年，进一步延迟了患者恢复正常并降低了他们的生活质量。在 在上一个资助期，我们证明了单独使用强化胰岛素或与普萘洛尔联合使用 改善严重烧伤患者的预后。然而，胰岛素的使用与高水平的 低血糖因此，我们现在将采用一种无低血糖风险的降糖治疗。 我们已经证明，急性给药非诺贝特，贝特类，降低血糖水平，在严重烧伤， 患者我们现在将非诺贝特单独给药或与普萘洛尔联合给药，以确定临床疗效， 对胰岛素抵抗、伤口愈合、脓毒症和心脏功能的潜在作用机制。 我们假设血糖水平的降低，沿着儿茶酚胺的阻断，将导致 长期烧伤后分解代谢和高代谢反应，这些反应将得到改善， 非诺贝特单独或与普萘洛尔组合在烧伤后给药一年的治疗用途。共300 患者将随机接受非诺贝特单独或与普萘洛尔联合的每日给药。 将这些患者的数据与相同数量的安慰剂或普萘洛尔治疗患者的数据进行比较， 这是使用我们已经资助的P50烧伤中心试验的数据完成的，该试验将于2015年1月完成。

ABSTRACT The response to a severe burn is characterized by persistent hypermetabolic and catabolic state that result in the massive loss of muscle tissue, even in the fed state. In patients with > 30% of total body surface area burned, protein breakdown persists for approximately one year after the burn wound is 95% healed. Endogenous catecholamines have been implicated as primary mediators of the hypermetabolic response to trauma or burn. Chronic elevation of plasma catecholamine levels results in the development of hyperdynamic circulation, increased basal energy expenditure, peripheral insulin resistance with hyperglycemia, increased peripheral lipolysis, depressed immune function, skeletal muscle protein catabolism and hypertrophic scarring. The hypermetabolic response to burns is also characterized by a profound tachycardia and increased cardiac work that are detrimental to the heart. The persistence of tachycardia and muscle catabolism significantly compromises rehabilitation and results in an excessive delay before resuming normal physical and functional activities. Recent studies from our institution have shown the negative impact of hyperglycemia and insulin resistance on survival, wound healing, and skeletal muscle catabolism. Insulin resistance can last for at least 3 years in severely burned patients, further delaying a patient's return to normal and reducing their quality of life. In the previous funding period, we demonstrated that administration of intensive insulin alone or in combination with propranolol improves outcomes for severely burned patients. However, the use of insulin was associated with high levels of hypoglycemia. Therefore, we now will utilize an anti-hyperglycemic therapy that does not have the risk of hypoglycemia. We have shown that acute administration of fenofibrate, a fibrate, reduces blood glucose levels in severely burned patients. We will now administer fenofibrate alone or in combination with propranolol to determine the clinical efficacy and underlying mechanisms of action on insulin resistance, wound healing, sepsis, and cardiac function. We hypothesize that reduction of blood glucose levels, along with blockade of catecholamines, will result in attenuation of the long-term post-burn catabolic and hypermetabolic responses, and that these responses will be ameliorated by the therapeutic use of fenofibrate alone or in combination with propranolol, administered for one year post burn. A total of 300 patients will be randomized to receive daily administration of Fenofibrate alone or in combination with propranolol. Comparison of the data from these patients to an equal number of placebo- or propranolol-treated patients will be accomplished using data from our already funded P50 burn center trial which will be completed by January 2015.