Department of Neurobiology, Pharmacology and Physiology, The University of Chicago, Chicago, Illinois, United States of America.
Department of Anesthesia and Critical Care, The University of Chicago, Chicago, Illinois, United States of America.
PLoS One. 2020 Nov 5;15(11):e0241818. doi: 10.1371/journal.pone.0241818. eCollection 2020.
Currently no drugs are employed clinically to reverse the unconsciousness induced by general anesthetics. Our previous studies showed that caffeine, when given near the end of an anesthesia session, accelerated emergence from isoflurane anesthesia, likely caused by caffeine's ability to elevate intracellular cAMP levels and to block adenosine receptors. These earlier studies showed that caffeine did not rouse either rats or humans from deep anesthesia (≥ 1 minimum alveolar concentration, MAC). In this current crossover study, we examined whether caffeine reversed the unconsciousness produced by light anesthesia (< 1 MAC) in the continued presence of isoflurane. The primary endpoint of this study was to measure isoflurane levels at the time of recovery of righting reflex, which was a proxy for consciousness. Rats were deeply anesthetized with 2% isoflurane (~1.5 MAC) for 20 minutes. Subsequently, isoflurane was reduced to 1.2% for 10 minutes, then by 0.2% every 10 min; animals were monitored until the recovery of righting reflex occurred, in the continued presence of isoflurane. Respiration rate, heart rate and electroencephalogram (EEG) were monitored. Our results show that caffeine-treated rats recovered their righting reflex at a significantly higher inspired isoflurane concentration, corresponding to light anesthesia, than the same rats treated with saline (control). Respiration rate and heart rate increased initially after caffeine injection but were then unchanged for the rest of the anesthesia session. Deep anesthesia is correlated with burst suppression in EEG recordings. Our data showed that caffeine transiently reduced the burst suppression time produced by deep anesthesia, suggesting that caffeine altered neuronal circuit function but not to a point where it caused arousal. In contrast, under light anesthesia, caffeine shifted the EEG power to high frequency beta and gamma bands. These data suggest that caffeine may represent a clinically viable drug to reverse the unconsciousness produced by light anesthesia.
目前临床上尚无药物可逆转全身麻醉引起的意识丧失。我们之前的研究表明，在麻醉结束时给予咖啡因可以加速异氟醚麻醉的苏醒，这可能是由于咖啡因能够提高细胞内环腺苷酸水平并阻断腺苷受体。这些早期的研究表明，咖啡因既不能使大鼠也不能使人类从深度麻醉（≥1 最低肺泡有效浓度，MAC）中苏醒。在这项当前的交叉研究中，我们研究了咖啡因是否能逆转异氟醚持续存在时轻度麻醉（<1 MAC）引起的意识丧失。本研究的主要终点是测量恢复翻正反射时异氟醚的水平，这是意识的替代指标。大鼠用 2%异氟醚（~1.5 MAC）深度麻醉 20 分钟。随后，异氟醚浓度降低至 1.2%持续 10 分钟，然后每 10 分钟降低 0.2%；在异氟醚持续存在的情况下，监测动物直到恢复翻正反射。监测呼吸频率、心率和脑电图（EEG）。我们的结果表明，与生理盐水（对照）治疗的相同大鼠相比，咖啡因治疗的大鼠在恢复翻正反射时需要吸入更高浓度的异氟醚，这表明处于轻度麻醉状态。咖啡因注射后，呼吸率和心率最初增加，但在麻醉过程的其余时间内保持不变。深度麻醉与脑电图记录中的爆发抑制有关。我们的数据表明，咖啡因短暂地降低了深度麻醉引起的爆发抑制时间，这表明咖啡因改变了神经元回路功能，但并未达到引起觉醒的程度。相比之下，在轻度麻醉下，咖啡因将脑电图功率转移到高频β和γ频段。这些数据表明，咖啡因可能代表一种有临床应用前景的药物，可逆转轻度麻醉引起的意识丧失。
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