De‐mystifying the “Mixifusor”

Abstract

Total intravenous anesthesia (TIVA) using a mixture of propofol and remifentanil in the same syringe has become an accepted technique in Pediatric Anesthesia. A survey by a group of respected UK anesthetists demonstrated a low incidence of serious complications, related to the pharmacology and dose of the drugs. However, a current guideline for the safe use of TIVA recommends against this practice. Pharmaceutical concerns include the physical stability of the emulsion when remifentanil is mixed with propofol; changes in drug concentration over time; nonuniform mixing of propofol and remifentanil; the risk of bacterial contamination; and the potential for drug administration errors. Propofol and remifentanil have markedly different pharmacokinetic profiles. When remifentanil is mixed with propofol and delivered as a target-controlled infusion (TCI) of propofol, remifentanil delivery is not target-controlled but passively follows the variable infusion rates calculated by the syringe driver to deliver predicted plasma or effect-site concentrations of propofol. The pharmacokinetic consequences can be illustrated using pharmacokinetic modeling similar to that used in TCI pumps. The clinical consequences reflect the dose-dependent pharmacodynamics of remifentanil. Increasing the target propofol concentration produces a rapid increase and peak in remifentanil concentration that risks apnea, bradycardia, and hypotension, especially with higher concentrations of remifentanil. The faster decline in remifentanil concentration with falling propofol concentrations risks inadequate narcosis and unwanted responses to surgical stimuli. Remifentanil delivery is inflexible and dosing cannot be adjusted to the clinical need and responses of individual patients. The medicolegal considerations are stark. In UK and EU Law, mixing propofol and remifentanil creates a new, unlicensed drug and the person mixing takes on the responsibilities of manufacturer. If a patient receiving anesthesia in the form of a mixed propofol-remifentanil infusion suffered a critical incident or actual harm, the clinician's practice may come under scrutiny and criticism, potentially involving a legal challenge and the Medical Regulator.

Consistency of remifentanil concentrations in propofol–Remifentanil infusions. A laboratory‐based study

“…The Cpt of 3.0 mcg.ml −1 is within the median ranges of PR5 plasma targets that have been reported in clinical use for anesthesia (2.9 to 4 mcg.ml −1 ) 10,13 . It was also consistent with the practice of minimizing high infusion start targets in those patients transferred to TIVA after inhalational induction, for whom the infusion is commonly started while the initial volatile agent is washing out.…”

“…Over the past several decades, TIVA has become an increasingly popular modality in adult and pediatric anesthesia 1,16,17 . The logistical demand to minimize the number of pumps required for TIVA administration has resulted in a body of work around the use of admixtures (including propofol–remifentanil) for a variety of clinical scenarios 8–10,13,18,19 . One key concern has been the dose accuracy and efficacy of any mixed preparations 1,10 .…”

“…While multi‐pump techniques are now well established, 2,5,7 there has been an increasing interest in single‐pump, multi‐agent techniques in a variety of settings 8,9 . This technique remains unapproved by both the US Food and Drug Administration and the UK Medicines and Healthcare products Regulatory Agency 10 and there are significant concerns about its use. Key pharmacological questions regarding medium and longer‐term stability, 11 miscibility and separation, 12 and subsequently the safety and reliability of the admixture have been raised 1,13 .…”

Mixing of propofol and remifentanil

“…We read with interest the study published by Bagshaw et al 1 and the accompanying editorial by Absalom et al 2 on the safety profile and effectiveness of propofol‐remifentanil mixtures. The authors of the research paper need to be congratulated on assessing the safety profile of propofol‐remifentanil mixtures in pediatric patients undergoing surgery, as well as quantifying the incidence of adverse events.…”

The use of propofol‐remifentanil mixture for TIVA in pediatric anesthesia—An opinion from a group of pediatric anesthetists

“…We write in response to the article by Bagshaw et al entitled “The safety profile and effectiveness of propofol‐remifentanil mixture for total intravenous anesthesia in children,” 1 and the subsequent editorial by Absalom et al 2 …”