Gorlaeus Laboratories, Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, PO Box 9502, 2300RA, Leiden, The Netherlands.
Department of Paediatrics, St Antonius Hospital, Nieuwegein, The Netherlands.
Pharm Res. 2021 Oct;38(10):1711-1720. doi: 10.1007/s11095-021-03113-w. Epub 2021 Oct 18.
In critically ill mechanically ventilated children, midazolam is used first line for sedation, however its exact sedative effects have been difficult to quantify. In this analysis, we use parametric time-to-event (PTTE) analysis to quantify the effects of midazolam in critically ill children.
In the PTTE analysis, data was analyzed from a published study in mechanically ventilated children in which blinded midazolam or placebo infusions were administered during a sedation interruption phase until, based on COMFORT-B and NISS scores, patients became undersedated and unblinded midazolam was restarted. Using NONMEM® v.7.4.3., restart of unblinded midazolam was analysed as event. Patients in the trial were divided into internal and external validation cohorts prior to analysis.
Data contained 138 events from 79 individuals (37 blinded midazolam; 42 blinded placebo). In the PTTE model, the baseline hazard was best described by a constant function. Midazolam reduced the hazard for restart of unblinded midazolam due to undersedation by 51%. In the blinded midazolam group, time to midazolam restart was 26 h versus 58 h in patients with low versus high disease severity upon admission (PRISM II < 10 versus > 21), respectively. For blinded placebo, these times were 14 h and 33 h, respectively. The model performed well in an external validation with 42 individuals.
The PTTE analysis effectively quantified the effect of midazolam in prolonging sedation and also the influence of disease severity on sedation in mechanically ventilated critically ill children, and provides a valuable tool to quantify the effect of sedatives. Clinical trial number and registry URL: Netherlands Trial Register, Trial NL1913 (NTR2030), date registered 28 September 2009 https://www.trialregister.nl/trial/1913 .
在机械通气的危重症患儿中，咪达唑仑是一线镇静药物，但确切的镇静效果难以量化。在本分析中，我们使用参数时变（PTTE）分析来量化咪达唑仑在危重症患儿中的作用。
在 PTTE 分析中，对一项发表的机械通气患儿研究中的数据进行了分析，在镇静中断阶段，对患儿进行盲注咪达唑仑或安慰剂输注，直至根据 COMFORT-B 和 NISS 评分，患儿出现镇静不足并重新开始盲注咪达唑仑。使用 NONMEM® v.7.4.3，重新开始盲注咪达唑仑被分析为事件。在分析之前，将试验中的患者分为内部和外部验证队列。
数据包含 79 名患者中的 138 个事件（37 名盲注咪达唑仑；42 名盲注安慰剂）。在 PTTE 模型中，基线风险最好用常数函数描述。咪达唑仑使因镇静不足而重新开始盲注咪达唑仑的风险降低了 51%。在盲注咪达唑仑组中，疾病严重程度低（PRISM II <10）和高（PRISM II >21）的患者，再次开始咪达唑仑治疗的时间分别为 26 小时和 58 小时。对于盲注安慰剂，这些时间分别为 14 小时和 33 小时。该模型在 42 名患者的外部验证中表现良好。
PTTE 分析有效地量化了咪达唑仑延长镇静作用的效果，以及疾病严重程度对机械通气危重症患儿镇静作用的影响，为量化镇静剂的效果提供了有价值的工具。临床试验编号和注册网址：荷兰临床试验注册中心，试验 NL1913（NTR2030），于 2009 年 9 月 28 日注册[https://www.trialregister.nl/trial/1913]。
