Time-course relationship between cerebrospinal fluid and serum concentrations of midazolam and albumin in patients with cardiac arrest undergoing targeted temperature management

Park, Jong-Il; Kang, Changshin; Jeong, Wonjoon; Park, Jung Soo; You, Yeonho; Ahn, Hong Joon; Cho, Yong Chul; Jeon, So Young; Min, Jin Hong; In, Yong

doi:10.1016/j.resuscitation.2023.109867

Cited by 2 publications

(1 citation statement)

References 28 publications

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“…Out of the 15 enrolled patients, seven were previously included in a published study for the purpose of comparing serum and cerebrospinal fluid concentrations (Fig. S2 ) 15 . Of the finally enrolled 15 patients, 7 (46.7%) awakened after the discontinuation of MDZ administration (Fig.…”

Section: Resultsmentioning

confidence: 99%

Distribution and elimination kinetics of midazolam and metabolites after post-resuscitation care: a prospective observational study

Jeong,

Sunwoo,

You

et al. 2024

Sci Rep

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Administration of sedatives for post-resuscitation care can complicate the determination of the optimal timing to avoid inappropriate, pessimistic prognostications. This prospective study aimed to investigate the distribution and elimination kinetics of midazolam (MDZ) and its metabolites, and their association with awakening time. The concentrations of MDZ and its seven metabolites were measured immediately and at 4, 8, 12, and 24 h after the discontinuation of MDZ infusion, using liquid chromatography-tandem mass spectrometry. The area under the time-plasma concentration curve from 0 to 24 h after MDZ discontinuation (AUClast) was calculated based on the trapezoidal rule. Of the 15 enrolled patients, seven awakened after the discontinuation of MDZ infusion. MDZ and three of its metabolites were major compounds and their elimination kinetics followed a first-order elimination profile. In the multivariable analysis, only MDZ was associated with awakening time (AUClast: R2 = 0.59, p = 0.03; AUCinf: R2 = 0.96, p < 0.001). Specifically, a 0.001% increase in MDZ AUC was associated with a 1% increase in awakening time. In the individual regression analysis between MDZ concentration and awakening time, the mean MDZ concentration at awakening time was 16.8 ng/mL. The AUC of MDZ is the only significant factor associated with the awakening time.

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Section: Resultsmentioning

confidence: 99%

Distribution and elimination kinetics of midazolam and metabolites after post-resuscitation care: a prospective observational study

Jeong,

Sunwoo,

You

et al. 2024

Sci Rep

Self Cite

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Correlation Between Serum and CSF Concentrations of Midazolam and 1-Hydroxy-Midazolam in Critically Ill Neurosurgical Patients

Farrar,

Stefanos,

Cava

et al. 2024

Ann Pharmacother

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Background: Midazolam (MZ) is commonly used in critically ill neurosurgical patients. Neuro-penetration of MZ and its metabolite, 1-hydroxy-midazolam (1-OH-MZ), is not well characterized. Objective: This study evaluated correlations between serum and cerebrospinal fluid (CSF) concentrations of MZ and 1-OH-MZ and assessed implications on patient sedation. Methods: Adults in the neurosurgical intensive care unit (ICU) with external ventricular drains receiving MZ via continuous infusion were prospectively studied. Serum and CSF samples were obtained 12-24 h and 72-96 h after initiation, and concentrations were determined in duplicate by high-performance liquid chromatography with tandem mass spectrometry. Bivariate correlation analyses used Pearson coefficient. Results: A total of 31 serum and CSF samples were obtained from 18 subjects. At sampling, mean MZ infusion rate was 3.9 ± 4.4 mg/h, and previous 12-h cumulative dose was 51.4 ± 78.2 mg. Mean concentrations of MZ and 1-OH-MZ in serum and CSF were similar between timepoints. Similarly, ratios of 1-OH-MZ to MZ in serum and CSF remained stable over time. Serum MZ (126.2 ± 89.3 ng/mL) showed moderate correlation (r2 = 0.68, P < 0.001) with serum 1-OH-MZ (17.7 ± 17.6 ng/mL) but not CSF MZ (3.9 ± 2.5 ng/mL; r2 = 0.24, P = 0.005) or CSF 1-OH-MZ (2.5 ± 0.6 ng/mL; r2 = 0.47, P = 0.30). CSF MZ did not correlate with CSF 1-OH-MZ (r2 = 0.003, P < 0.001). Mean serum ratio of 1-OH-MZ to MZ (0.14 ± 0.2 ng/mL) did not correlate with CSF ratio (1.06 ± 0.83 ng/mL; r2 = 0.06, P = 0.19). Concentrations and ratios were unrelated to MZ infusion rate or 12-h cumulative dose. Sedation was weakly correlated with CSF 1-OH-MZ, but not with serum MZ, serum 1-OH-MZ, or CSF MZ. Conclusion and Relevance: Continuous infusions of MZ result in measurable concentrations of MZ and 1-OH-MZ in CSF; however, CSF concentrations of MZ and 1-OH-MZ poorly represent serum concentrations or dosages. Accumulation of MZ and 1-OH-MZ in serum or CSF over time was not evident. Concentrations of MZ and 1-OH-MZ do not predict sedation levels, reinforcing that pharmacodynamic assessments are warranted.

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Time-course relationship between cerebrospinal fluid and serum concentrations of midazolam and albumin in patients with cardiac arrest undergoing targeted temperature management

Cited by 2 publications

References 28 publications

Distribution and elimination kinetics of midazolam and metabolites after post-resuscitation care: a prospective observational study

Distribution and elimination kinetics of midazolam and metabolites after post-resuscitation care: a prospective observational study

Correlation Between Serum and CSF Concentrations of Midazolam and 1-Hydroxy-Midazolam in Critically Ill Neurosurgical Patients

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