Altered Pharmacokinetics in Prolonged Infusions of Sedatives and Analgesics Among Adult Critically Ill Patients: A Systematic Review
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The pharmacokinetic (PK) parameters of many drugs are altered as a consequence of the pathophysiological changes associated with critical illness. The critically ill population presents challenges when titrating infusions of sedatives and analgesics to maintain optimal sedation and pain levels. This systematic review examined the PK data in critically ill adult patients with prolonged infusions (>24 hours) of commonly used sedatives and analgesics to highlight possible altered PK parameters compared with noncritically ill patients.
A literature search of PK studies was performed by using MEDLINE (1946–December 2017) and EMBASE (1910–December 2017); we identified further studies by citation tracking (Web of Science) and checked references of retrieved studies and review articles. All studies were included that were published in English, Chinese, or German; conducted in critically ill adult patients receiving lorazepam, midazolam, propofol, dexmedetomidine, sufentanil, alfentanil, remifentanil, morphine, or fentanyl infusion for ≥24 hours; and reported PK parameters. When appropriate, we conducted a meta-analysis on volume of distribution at steady state (Vdss) (liters), clearance (Cl) (liters per hour), and elimination t1/2 (hours) by using a DerSimonian-Laird random effects model to estimate the summary mean and 95% CIs. Results were compared with commonly reported PK ranges in 70-kg noncritically ill patients.
Thirty-three randomized controlled trials and prospective cohort studies were identified involving 1803 adult critically ill patients with 35 drug treatment arms: fifteen midazolam (n = 906) studies, three dexmedetomidine (n = 561), nine propofol (n = 165), four lorazepam (n = 86), one morphine (n = 20), two remifentanil (n = 55), and one sufentanil (n = 10). Each study showed large variations in Vdss, Cl, and elimination t1/2 within and between individual participants. High clinical and methodical heterogeneity between the dexmedetomidine studies prevented the direct comparison of PK parameters between critically ill and noncritically ill patients. Use of midazolam, propofol, and lorazepam in critically ill patients was associated with at least a 2- to 4-fold increase in Vdss compared with noncritically ill patients; Cl decreased ∼2-fold for midazolam and 10-fold for morphine. Critically ill patients receiving prolonged infusions of midazolam, propofol, remifentanil, and sufentanil had at least 2-fold longer elimination or terminal t1/2 than noncritically ill patients.
These findings show a marked difference in many PK parameters from those reported for noncritically ill patients. Initiatives to improve the delivery of prolonged sedatives and analgesic infusions should be informed by PK parameters (Vdss, context-sensitive t1/2, and elimination t1/2) and data derived from critically ill patients.
Acceptance Date30/07/2018
All Author(s) ListTse AHW, Ling L, Lee A, Joynt GM
Journal nameClinical Therapeutics
Volume Number40
Issue Number9
Pages1598 - 1615.e2
LanguagesEnglish-United Kingdom
Keywordsanalgesics, critical care, pharmacokinetics, sedatives, systematic review

Last updated on 2021-21-09 at 00:00