The Clearance of Midazolam and Metabolites during Continuous Renal Replacement Therapy in Critically Ill Patients with COVID-19.

IF 2.2 3区医学 Q3 HEMATOLOGY Blood Purification Pub Date : 2024-01-01 Epub Date: 2023-11-03 DOI:10.1159/000534538

Tim J L Smeets, Hilde R H de Geus, Abraham J Valkenburg, Lauren Baidjoe, Diederik A M P J Gommers, Birgit C P Koch, Nicole G M Hunfeld, Henrik Endeman

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Abstract

Introduction: Midazolam-based continuous intravenous sedation in patients admitted to the intensive care unit (ICU) was a necessity during the COVID-19 pandemic. However, benzodiazepine-based sedation is associated with a high incidence of benzodiazepine-related delirium and additional days on mechanical ventilation. Due to the requirement of high midazolam doses in combination with the impaired renal clearance (CL) of the pharmacological active metabolite 1-OH-midazolam-glucuronide (10% compared to midazolam), ICU patients with COVID-19 and continuous renal replacement therapy (CRRT) were at risk of unintended prolonged sedation. Several CRRT-related factors may have influenced the delivered CL of midazolam and its metabolites. Therefore, the aim of the study was to identify and describe these CRRT-related factors.

Methods: Pre-filter blood samples and ultrafiltrate samples were collected simultaneously. Midazolam, 1-OH-midazolam, and 1-OH-midazolam-glucuronide plasma samples were analyzed using an UPLC-MS/MS method. The prescribed CRRT dose was corrected for downtime and filter integrity using the urea ratio (urea concentration in effluent/urea concentration plasma). CL of midazolam and its metabolites were calculated with the delivered CRRT dose (corrected for downtime and saturation coefficient [SD]).

Results: Three patients on continuous venovenous hemodialysis (CVVHD) and 2 patients on continuous venovenous hemodiafiltration (CVVHDF) were included. Midazolam, 1-OH-midazolam, and 1-OH-midazolam-glucuronide concentrations were 2,849 (0-6,700) μg/L, 153 (0-295) μg/L, and 27,297 (1,727-39,000) μg/L, respectively. The SD was 0.03 (0.02-0.03) for midazolam, 0.05 (0.05-0.06) for 1-OH-midazolam, and 0.33 (0.23-0.43) for 1-OH-midazolam-glucuronide. The delivered CRRT CL was 1.4 (0-1.7) mL/min for midazolam, 2.7 (0-3.5) mL/min for 1-OH-midazolam, and 15.7 (4.0-27.7) mL/min for 1-OH-midazolam-glucuronide.

Conclusions: Midazolam and 1-OH-midazolam were not removed during CVVHD and CVVHDF. However, 1-OH-midazolam-glucuronide was removed reasonably, approximately up to 43%. CRRT modality, filter integrity, and downtime affect this removal. These data imply a personalized titration of midazolam in critically ill patients with renal failure and awareness for the additional sedative effects of its active metabolites.

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新冠肺炎危重患者持续肾替代治疗期间咪唑安定和代谢产物的清除。

简介：在新冠肺炎大流行期间，入住重症监护室（ICU）的患者需要以咪唑安定为基础的持续静脉镇静。然而，以苯二氮卓类药物为基础的镇静与苯二氮卓类药物相关谵妄的高发病率和额外的机械通气天数有关。由于需要高剂量咪达唑仑并结合药理活性代谢产物1-OH-咪唑间-葡糖苷酸的肾清除率（CL）受损（与咪达唑胺相比为10%），新冠肺炎和连续肾替代治疗（CRRT）的ICU患者有意外延长镇静的风险。一些CRRT相关因素可能影响咪达唑仑及其代谢产物的递送CL。因此，本研究的目的是识别和描述这些CRRT相关因素。方法：同时采集预滤血样和超滤血样。使用UPLC-MS/MS方法分析咪唑仑、1-OH-咪唑仑和1-OH-唑仑-葡糖苷酸血浆样品。使用尿素比（流出物中的尿素浓度/尿素浓度血浆）对规定的CRRT剂量进行停机时间和过滤器完整性校正。咪达唑仑及其代谢物的CL用CRRT剂量计算（校正停机时间和饱和系数[SD]）。结果：纳入3例持续性静脉-静脉血液透析（CVVHD）患者和2例持续性血液透析滤过（CVVHDF）患者。咪达唑仑、1-OH-咪唑仑和1-OH-唑仑-葡萄糖醛酸浓度分别为2849（0-6700）μg/L、153（0-295）μg/L和27297（1727-39000）μg/L。咪唑安定的SD为0.03（0.02-0.03），1-OH-咪唑仑的SD为0.05（0.05-0.06），1-OH-咪唑仑-葡萄糖醛酸的SD为0.33（0.23-0.43）。咪达唑仑的CRRT CL为1.4（0-1.7）mL/min，1-OH-咪唑仑为2.7（0-3.5）mL/min，1-OH-咪唑间葡萄糖醛酸苷为15.7（4.0-27.7）mL/min。结论：咪达唑仑和1-OH-咪唑仑在CVVHD和CVVHDF期间未被去除。然而，1-OH-咪唑间葡糖苷酸的去除率是合理的，约高达43%。CRRT模式、过滤器完整性和停机时间会影响此删除。这些数据意味着咪达唑仑在肾功能衰竭的危重患者中的个性化滴定，以及对其活性代谢产物的额外镇静作用的认识。

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来源期刊

Blood Purification 医学-泌尿学与肾脏学

CiteScore

5.80

自引率

3.30%

发文量

审稿时长

6-12 weeks

期刊介绍： Practical information on hemodialysis, hemofiltration, peritoneal dialysis and apheresis is featured in this journal. Recognizing the critical importance of equipment and procedures, particular emphasis has been placed on reports, drawn from a wide range of fields, describing technical advances and improvements in methodology. Papers reflect the search for cost-effective solutions which increase not only patient survival but also patient comfort and disease improvement through prevention or correction of undesirable effects. Advances in vascular access and blood anticoagulation, problems associated with exposure of blood to foreign surfaces and acute-care nephrology, including continuous therapies, also receive attention. Nephrologists, internists, intensivists and hospital staff involved in dialysis, apheresis and immunoadsorption for acute and chronic solid organ failure will find this journal useful and informative. ''Blood Purification'' also serves as a platform for multidisciplinary experiences involving nephrologists, cardiologists and critical care physicians in order to expand the level of interaction between different disciplines and specialities.