Targeted temperature management is standard of care for cardiac arrest and is in clinical trials for stroke. N6-cyclohexyladenosine (CHA), an A1 adenosine receptor (A1AR) agonist, inhibits thermogenesis and induces onset of hibernation in hibernating species. Despite promising thermolytic efficacy of CHA, prior work has failed to achieve and maintain a prescribed target core body temperature (Tb) between 32°C and 34°C for 24 hours. We instrumented Sprague-Dawley rats (n = 19) with indwelling arterial and venous cannulae and a transmitter for monitoring Tb and ECG, then administered CHA via continuous IV infusion or intraperitoneal (IP) injection. In the first experiment (n = 11), we modulated ambient temperature and increased the dose of CHA in an attempt to manage Tb. In the second experiment (n = 8), we administered CHA (0.25 mg/[kg·h]) via continuous IV infusion and modulated cage surface temperature to control Tb. We rewarmed animals by increasing surface temperature at 1°C h-1 and discontinued CHA after Tb reached 36.5°C. Tb, brain temperature (Tbrain), heart rate, blood gas, and electrolytes were also monitored. Results show that titrating dose to adjust for individual variation in response to CHA led to tolerance and failed to manage a prescribed Tb. Starting with a dose (0.25 mg/[kg·h]) and modulating surface temperature to prevent overcooling proved to be an effective means to achieve and maintain Tb between 32°C and 34°C for 24 hours. Increasing surface temperature to 37°C during CHA administration brought Tb back to normothermic levels. All animals treated in this way rewarmed without incident. During the initiation of cooling, we observed bradycardia within 30 minutes of the start of IV infusion, transient hyperglycemia, and a mild hypercapnia; the latter normalized via metabolic compensation. In conclusion, we describe an intravenous delivery protocol for CHA at 0.25 mg/(kg·h) that, when coupled with conductive cooling, achieves and maintains a prescribed and consistent target Tb between 32°C and 34°C for 24 hours.

中文翻译：

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使用N6-环己基腺苷精确控制目标温度并实时控制表面温度。

定向温度管理是心脏骤停的标准治疗方法，并且正在中风的临床试验中。N6-环己基腺苷（CHA）是一种A1腺苷受体（A1AR）激动剂，可抑制生热作用并诱导冬眠物种冬眠。尽管CHA具有良好的热分解功效，但先前的工作未能在32°C至34°C的温度范围内达到并维持规定的目标核心体温（Tb）24小时。我们为Sprague-Dawley大鼠（n = 19）留置了动脉和静脉插管，并配备了变送器来监测Tb和ECG，然后通过连续IV输注或腹膜内（IP）注射给予CHA。在第一个实验（n = 11）中，我们调节环境温度并增加CHA的剂量，以尝试控制Tb。在第二个实验（n = 8）中，我们使用了CHA（0。25 mg / [kg·h]）通过连续静脉输注和调节笼表面温度来控制Tb。我们通过在1°C h-1处升高表面温度来给动物重新加热，并在Tb达到36.5°C后停止CHA。还监测了Tb，脑温（Tbrain），心率，血气和电解质。结果表明，针对CHA的个体变化而调整剂量的滴定剂量会导致耐受，并且无法控制规定的Tb。从剂量（0.25 mg / [kg·h]）开始，调节表面温度以防止过冷，是将Tb维持在32°C至34°C之间并保持24小时的有效手段。在使用CHA的过程中，将表面温度提高到37°C，使Tb恢复到常温水平。以这种方式治疗的所有动物都可以恢复体温，而不会发生任何事故。在冷却开始期间，我们在静脉输注开始30分钟内观察到心动过缓，短暂性高血糖和轻度高碳酸血症；后者通过代谢补偿标准化。总之，我们描述了静脉注射CHA的剂量为0.25 mg /（kg·h），当与传导冷却相结合时，可在32°C至34°C之间达到并保持规定的目标Tb 24小时。