Authors: Absalom A R et al.
Source: Anesthesia & Analgesia. December 2025. Volume 141(6):1226–1229. DOI: 10.1213/ANE.0000000000007599
Summary:
In this thought-provoking editorial, Absalom and Sneyd critically examine the increasingly common practice of administering total intravenous anesthesia (TIVA) using a single-syringe mixture of propofol and remifentanil. Prompted by a report from Bennion et al describing uneventful anesthesia in 109 young, healthy orthopedic patients using a fixed propofol–remifentanil mixture, the authors ask whether apparent convenience and short-term safety justify broader adoption of this technique.
The editorial systematically explores several domains of concern. From a physicochemical standpoint, propofol is a lipid emulsion whose stability depends on the zeta potential; adding other drugs, particularly electrolytes, risks emulsion destabilization. Existing laboratory data suggest that propofol–remifentanil mixtures are generally stable under defined conditions, but some changes in droplet size, zeta potential, and drug concentration uniformity—especially at low remifentanil concentrations—have been observed. Importantly, most stability studies dissolve remifentanil in water or saline before mixing with propofol, whereas Bennion et al directly reconstituted remifentanil powder in propofol, a method for which robust stability data are lacking.
Microbiological risk is another major concern. Propofol’s association with infection outbreaks led to the addition of preservatives in U.S. formulations, underscoring the vulnerability of lipid emulsions to contamination. Mixing drugs creates an additional opportunity for aseptic failure, and the authors emphasize that strict technique is essential whenever clinicians compound medications, especially lipid-based ones.
Pharmacokinetically and pharmacodynamically, the drugs differ markedly. Remifentanil’s rapid clearance means that boluses and infusion changes produce fast, pronounced opioid effects relative to propofol. Using a fixed mixture eliminates the ability to independently titrate hypnosis and analgesia, forcing clinicians to choose compromise concentrations—often “remifentanil-rich”—that may work in young, healthy patients but pose risks such as severe bradycardia or asystole, particularly in older or comorbid populations.
The authors also review broader clinical experience. While mixture-based TIVA has reportedly been used in large pediatric cohorts without obvious catastrophic harm, observational data remain limited, and professional societies in the UK have advised against routine mixing. Small studies and service evaluations suggest acceptable outcomes in expert hands, but accuracy of anesthetic depth control and true complication rates are difficult to determine without large datasets.
Ultimately, Absalom and Sneyd conclude that the absence of widespread reported harm does not equate to proof of safety. Key unanswered questions remain regarding drug distribution, emulsion stability, microbiology, and applicability to higher-risk patients. They commend investigators for studying the practice but urge caution, emphasizing that demonstrating a technique is “not obviously harmful” does not necessarily make it a good idea.
What You Should Know:
• Single-syringe propofol–remifentanil mixtures are increasingly used but remain incompletely studied.
• Physicochemical and microbiologic risks exist whenever drugs are mixed into a lipid emulsion.
• Fixed mixtures prevent independent titration of hypnosis and analgesia, which may be problematic in higher-risk patients.
• Limited observational data suggest feasibility, but robust safety evidence is lacking.
Key Points:
• Existing stability data may not apply to direct reconstitution of remifentanil powder in propofol.
• Remifentanil-rich mixtures carry risks of profound bradycardia and hemodynamic instability.
• Regulatory guidance permits limited mixing but does not endorse routine compounding.
• Caution is warranted until further laboratory and observational evidence clarifies safety.
Thank you to Anesthesia & Analgesia for publishing this nuanced editorial that challenges convenience-driven practice and reinforces the importance of physiology, pharmacology, and humility in anesthetic decision-making.