Tsao Amy C, Parker Michael J, Lovich Mark A, Suja Vineeth Chandran, Deng Hao, Houle Timothy, Peterfreund Robert A
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA.
HMX Office of Online Learning Harvard Medical School, Boston, MA 02115, USA, Division of Pulmonary, Critical Care, and Sleep Medicine Beth Israel Deaconess Medical Center Boston, MA 02215 Harvard Medical School, Telephone: +1 415-745-4931, Telephone: 617-432-0680.
Eur J Pharm Sci. 2022 May 1;172:106154. doi: 10.1016/j.ejps.2022.106154. Epub 2022 Feb 26.
Critically ill and anesthetized patients commonly receive life-sustaining medications by pump-driven continuous intravenous infusion. Microinfusion refers to delivering concentrated drugs with low flow carriers to conserve fluid administration. Most infused medications are water-soluble. Delivery onset lag times have been identified for microinfusions of water-soluble drugs or experimental surrogates. Drugs may be formulated as emulsions. Initiation of emulsion microinfusions has not been described. We tested in vitro the hypothesis that an emulsion's physical characteristics would influence its microinfusion delivery onset. We adapted an established in vitro model of pump-driven continuous intravenous microinfusion to compare the delivery of methylene blue as a surrogate for water-soluble drugs and a 10% lipid emulsion as a surrogate for a drug formulated as an emulsion. The drug surrogates joined the carrier with carrier flow vertically upwards, vertically downwards or horizontally. We measured the times to 5%, 50% and 95% of plateau delivery. Emulsion entry into a vertical (upwards) carrier flow resulted in a rapid initial emulsion delivery exceeding predictions of delivery models. Emulsion entry into both horizontal and vertical (downwards) carrier flows resulted in long lag times to steady state. Methylene blue delivery was unaffected by carrier flow orientation. Initiating microinfusion emulsion delivery with upward flow can result in a relative bolus, whereas long delivery lags would be expected with horizontal or downwards flow. An emulsion might carry a high potency drug having significant physiologic effects, e. g. clevidipine. Unrecognized, differences in initial emulsion delivery kinetics depending on carrier flow orientation may have clinical implications for both efficacy and safety.
重症和麻醉患者通常通过泵驱动的持续静脉输注接受维持生命的药物治疗。微量输注是指用低流量载体输送浓缩药物以节省液体给药量。大多数输注的药物是水溶性的。对于水溶性药物或实验替代物的微量输注，已确定了给药起始延迟时间。药物可制成乳剂。乳剂微量输注的起始尚未见描述。我们在体外测试了这样一个假设，即乳剂的物理特性会影响其微量输注给药起始。我们采用了一个已建立的泵驱动持续静脉微量输注体外模型，以比较亚甲蓝作为水溶性药物替代物和10%脂质乳剂作为乳剂形式药物替代物的给药情况。药物替代物以载体流垂直向上、垂直向下或水平的方式与载体混合。我们测量了达到平台期给药量的5%、50%和95%所需的时间。乳剂进入垂直（向上）载体流导致初始乳剂给药迅速，超过了给药模型的预测。乳剂进入水平和垂直（向下）载体流均导致达到稳态的延迟时间较长。亚甲蓝给药不受载体流方向的影响。以向上流开始微量输注乳剂给药可导致相对推注，而水平或向下流预计会有较长的给药延迟。乳剂可能携带具有显著生理效应的高效能药物，例如克levidipine。未被认识到的是，取决于载体流方向的初始乳剂给药动力学差异可能对疗效和安全性都有临床意义。
