The pharmacokinetics and pharmacodynamics of cisatracurium in critically ill patients with severe sepsis

• Published in: British journal of clinical pharmacology Vol. 73; no. 5; pp. 741 - 749
• Main Authors: Liu, Xin, Kruger, Peter S., Weiss, Michael, Roberts, Michael S.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.05.2012; Blackwell; Blackwell Science Inc
• Subjects: Adult; Aged; Anesthesia; Atracurium - analogs & derivatives; Atracurium - pharmacokinetics; Atracurium - pharmacology; Biological and medical sciences; cisatracurium; Critical Illness; Data processing; Delayed response; Dose-Response Relationship, Drug; Drug Resistance; Female; Humans; intensive care; Male; Medical sciences; Middle Aged; Models, Biological; Movement disorders; Neurodegenerative diseases; Neuromuscular Blocking Agents - pharmacokinetics; Neuromuscular Blocking Agents - pharmacology; Parkinson's disease; Peripheral nerves; pH effects; Pharmacodynamics; Pharmacokinetic Dynamic Relationships; Pharmacokinetics; Pharmacology. Drug treatments; Sepsis; Sepsis - drug therapy; Sepsis - metabolism; Severity of Illness Index; Time Factors; Infection; Human; Sepsis syndrome; Pharmacokinetic pharmacodynamic relationship; Intensive care; Pharmacodynamics; cisatracurium; Critically ill; Pharmacokinetics; Biological activity
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/j.1365-2125.2011.04149.x

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Cisatracurium is a non‐depolarizing neuromuscular blocking drug used in anaesthesia and intensive care. • Cisatracurium degrades at physiological pH via Hofmann elimination. Therefore, the elimination of cisatracurium may be from both plasma and tissues. • Critically ill patients may have or develop resistance to non‐depolarizing neuromuscular blocking drugs. • Pathophysiological changes in critically ill patients with sepsis can cause changes in both pharmacokinetics (PK) and pharmacodynamics (PD). WHAT THIS STUDY ADDS • This is the first study to characterize PK and PD of cisatracurium in intensive care patients with severe sepsis following a single bolus dose. • This study suggests that standard dosing of cisatracurium in patients with severe sepsis results in a slower patient response with a reduced effect. • The resistance to cisatracurium in these patients is more attributed to altered PD as pharmacokinetic parameters were similar to those described in other patient populations. AIM To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of cisatracurium in critically ill patients with severe sepsis. METHODS Blood samples were collected before and over 8 h after a single bolus dose of cisatracurium 0.1 mg kg−1. Neuromuscular block was assessed by accelerometric peripheral nerve stimulation (TOF Watch). Plasma concentration and neuromuscular block data were fitted using population analysis. RESULTS Steady‐state volume of distribution was determined to be 111 ± 71 ml kg−1 and plasma clearance was 5.2 ± 1.8 ml min−1 kg−1 in these patients with greater inter‐patient variability compared with other populations. The time to maximum block (8.3 ± 2.9 min) and delay time of transferring from central to effect compartment (17.2 min) was much longer, while the maximum block (95.0 ± 6.3%) was less compared with those in other patient populations. The effect compartment concentration resulting in 50% of maximum effect (128 ± 58 ng ml−1) was larger than previously described. CONCLUSIONS This study suggests that standard dosing of cisatracurium in patients with severe sepsis results in a slower patient response with a reduced effect. Use of a larger dose may overcome this reduced delayed response.