Purpose: Critically ill patients have substantially altered pharmacokinetic (PK) and pharmacodynamic (PD) parameters as a result of the haemodynamic instability, fluid resuscitation, altered protein binding and organ dysfunction from severe systemic illness [1, 2]. Under-sedation or over-sedation occurs in up to 75% of critically ill patients requiring sedation for 24h or more . This systematic review examined the PK data in critically ill patients with prolonged infusions of sedatives and analgesics to highlight possible altered PK parameters compared to non-critically ill patients.
Methods: We performed a literature search of PK studies using MEDLINE (1946-Dec 2017), EMBASE (1974-Dec 2017), identified further studies by citation tracking (Web of Science), and checked references of retrieved studies and review articles. All studies published in English, Chinese and German, conducted in adult critically ill patients receiving midazolam, propofol, dexmedetomidine, sufentanil, alfentanil, morphine or fentanyl infusion for 24h or more, and reporting PK parameters were included. Three reviewers screened all titles, abstracts and full text independently and met to resolve any discrepancies. When appropriate, we conducted a meta-analysis on Volume of distribution at steady state (Vdss) (L), Clearance (Cl) (L/h) and elimination t1/2 (h) using a DerSimonian-Laird random-effects model to estimate the summary mean and 95% confidence interval (95% CI). Subgroup analysis by severity of illness using the Acute Physiology And Chronic Health Evaluation II score (APACHE II) and organ dysfunction were performed to explain high heterogeneity (I2 statistic >75%). Results were compared to commonly reported PK ranges in 70 kg non-critically ill patients .
Results: We included 31 (randomized controlled trials and prospective cohort) studies involving 1774 participants: 15 midazolam (n=906), 3 dexmedetomidine (n=561), 9 propofol (n=165), 3 lorazepam (n=72), 1 morphine (n=20), 1 remifentanil (n=40) and 1 sufentanil (n=10). Two studies (n=113) compared lorazepam versus midazolam. Each study demonstrated large variations in PK data within and between individual participants. High clinical heterogeneity between the dexmedetomidine studies did not allow us to make PK parameter comparisons between critically ill and non-critically ill patients. Table 1 shows the summary PK differences between critically ill and non-critically ill patients.
Midazolam: Critically ill patients given midazolam had a 2-fold higher Vdss, lower Cl and 4-fold longer elimination t1/2 than non-critically ill patients. Patients with APACHE II ≤ 20 had higher midazolam Cl (22, 12-32) than those with APACHE II > 20 (12, 11-14) (P<0.01). Organ dysfunction did not explain the high heterogeneity for elimnation t1/2 (P=0.23).
Propofol: Compared to non-critically ill patients, those receiving propofol demonstrated a 4-fold higer Vdss, similar Cl and longer elimination t1/2. The high level of heterogeneity for Vdss may be explained by differences in the number of compartment models used. Patients with APACHE II ≤ 20 had trend towards lower Cl (92, 81-104) than those with APACHE II > 20 (117, 89-144) (P=0.07). Patients with APACHE II ≤ 20 had lower terminal elimination t1/2 (24, 19-29) than those with APACHE II > 20 (50, 42-59) (P<0.01).
There was a 3-fold higher lorazepam Vdss and a 10-fold lower morphine Cl in critically ill patients compared to non-critically ill patients. Remifentanil PK parameters in critically ill patients seem to describe higher Vd, Cl and marginally longer elimination t1/2 in those with moderate to severe renal impairment, than in non-critically ill patients. Sufentanil Cl was similar, but elimination t1/2 in critically ill patients compared to non-critically ill patients was longer.
Conclusion: Many PK parameters were substantially different from those reported for non-criticallly 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.
 Smith BS, et a. Introduction to drug pharmacokinetics in the critically ill patient. Chest. 2012;141(5):1327-1336.
 Goncalves-Pereira J, et al. Antibiotics in critically ill patients: a systematic review of the pharmacokinetics of beta-lactams. Crit Care. 2011;15(5):R206.
 Jackson DL, et al. The incidence of sub-optimal sedation in the ICU: a systematic review. Critical Care. 2009;13(6):R204-R204.
 Miller RD. Miller's Anesthesia. New York: Churchill Livingstone; 2005.
Lowell Ling– Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong
Anna Lee– Professor, Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong
Gavin Joynt– Professor, Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong