Maisonneuve-Rosemont Hospital and Université de Montréal, Intensive Care Unit, Montréal, Quebec, Canada.
Crit Care Med. 2013 Apr;41(4):999-1008. doi: 10.1097/CCM.0b013e318275d014.
BACKGROUND: Delirium and sedative-induced coma are described as incremental manifestations of cerebral dysfunction. Both may be associated with sedative or opiate doses and pharmacokinetic or pharmacogenetic variables, such as drug plasma levels (exposure), drug metabolism, and/or their transport across the blood-brain barrier. OBJECTIVES: To compare biological and drug treatment characteristics in patients with coma and/or delirium while in the ICU. PATIENTS AND MEASUREMENTS: In 99 patients receiving IV fentanyl, midazolam, or both, we evaluated drug doses, covariates likely to influence drug effects (age, body mass index, and renal and hepatic dysfunction); delirium risk factors; concomitant administration of CYP3A and P-glycoprotein substrates/inhibitors; ABCB1, ABCG2, and CYP3A5 genetic polymorphisms; and fentanyl and midazolam plasma levels. Delirium and coma were evaluated daily. In patients with only coma (n=15), only delirium (n=7), and neither ever (n=14), we measured plasma levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-1RA, IL-6, IL-8, IL-10, IL-17,macrophage inflammatory protein-1β, and monocyte chemotactic protein-1. RESULTS: Time to first coma was associated with fentanyl and midazolam doses (p=0.03 and p=0.01, respectively). The number of days in coma was associated with the number of days of coadministration of CYP3A inhibitors (r=0.30; p=0.006). Plasma levels of fentanyl were higher in patients with clinical coma (3.7±4.7 vs. 2.0±1.8 ng/mL, p=0.0001) as were midazolam plasma levels (1050±2232 vs. 168±249 ng/mL, p=0.0001). Delirium occurrence was unrelated to midazolam administration, cumulative doses, or serum levels. Days with delirium were associated with days of coadministration of P-glycoprotein inhibitor (r=0.35; p=0.0004). Delirious patients had higher levels of the inflammatory mediator IL-6 than comatose patients (129.3 vs. 35.0 pg/mL, p=0.05). CONCLUSIONS: Coma is associated with fentanyl and midazolam exposure; delirium is unrelated to midazolam and may be linked to inflammatory status. These data suggest that iatrogenic coma and delirium are not mechanistically linked.
背景：谵妄和镇静诱导昏迷被描述为脑功能障碍的渐进表现。两者都可能与镇静或阿片类药物剂量以及药代动力学或药物遗传学变量相关，例如药物血浆水平（暴露）、药物代谢和/或它们在血脑屏障中的转运。
目的：比较 ICU 中昏迷和/或谵妄患者的生物学和药物治疗特征。
患者和测量：在 99 名接受 IV 芬太尼、咪达唑仑或两者联合治疗的患者中，我们评估了药物剂量、可能影响药物作用的协变量（年龄、体重指数和肾功能、肝功能不全）；谵妄危险因素；同时给予 CYP3A 和 P-糖蛋白底物/抑制剂；ABCB1、ABCG2 和 CYP3A5 遗传多态性；芬太尼和咪达唑仑的血浆水平。每天评估谵妄和昏迷。在仅出现昏迷的患者（n=15）、仅出现谵妄的患者（n=7）和从未出现过的患者（n=14）中，我们测量了肿瘤坏死因子-α、白细胞介素（IL）-1β、IL-1RA、IL-6、IL-8、IL-10、IL-17、巨噬细胞炎症蛋白-1β 和单核细胞趋化蛋白-1 的血浆水平。
结果：首次昏迷的时间与芬太尼和咪达唑仑的剂量有关（p=0.03 和 p=0.01）。昏迷天数与 CYP3A 抑制剂合用天数有关（r=0.30；p=0.006）。有临床昏迷的患者芬太尼的血浆水平较高（3.7±4.7 与 2.0±1.8ng/mL，p=0.0001），咪达唑仑的血浆水平也较高（1050±2232 与 168±249ng/mL，p=0.0001）。谵妄的发生与咪达唑仑的给药、累积剂量或血清水平无关。谵妄天数与 P-糖蛋白抑制剂的合用天数有关（r=0.35；p=0.0004）。有谵妄的患者炎症介质 IL-6 的水平高于昏迷患者（129.3 与 35.0pg/mL，p=0.05）。
结论：昏迷与芬太尼和咪达唑仑的暴露有关；谵妄与咪达唑仑无关，可能与炎症状态有关。这些数据表明，医源性昏迷和谵妄在机制上没有联系。
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