Total intravenous anesthesia (TIVA) uses continuous intravenous infusion to achieve hypnosis, analgesia, and immobility without the use of inhalational anesthetics. This is most often accomplished by using propofol as the hypnotic agent and an opioid, such as remifentanil or fentanyl, for analgesia. While this multimodal approach enhances anesthetic precision and recovery quality, the practice of physically mixing these agents in the same syringe or infusion system remains a continuing area of debate.
Although propofol–remifentanil and propofol–ketamine mixtures have been studied and used in some clinical settings, substantial evidence cautions against their routine use due to instability, unpredictable pharmacokinetics, and contamination risk. To access the benefits of TIVA in certain clinical scenarios, anesthesiologists must understand the relevant safety considerations when mixing drugs for TIVA.
The propofol–remifentanil mixture is the most extensively studied TIVA combination. Both agents have a rapid onset and offset, which, in theory, complement each other. Several clinicians have experimented with co-administering the two drugs in a single syringe to simplify anesthesia delivery, particularly in pediatric and ambulatory settings. Bagshaw et al. reported effective anesthesia and smooth recovery when mixing propofol–remifentanil for TIVA in children but also noted instability of the drug emulsion over time (1). Similarly, O’Connor et al. demonstrated that, when mixed, the two agents layer and separate within hours, which can lead to nonuniform distribution and variable drug delivery rates (2).
The underlying cause of this incompatibility is formulation differences. Propofol is a lipid emulsion and remifentanil is an aqueous peptide solution. When these two substances are mixed, the lipid and aqueous phases separate. This process destabilizes the emulsion and alters the drug concentration gradients. Additionally, propofol’s lipid matrix supports bacterial growth, so sterility and prompt disposal are critical. Guidelines from the Association of Anaesthetists explicitly warn against mixing these drugs, noting that separate, clearly labeled infusion lines in TIVA allow for safer, independent titration of the hypnotic and opioid components (3). This independence is particularly vital when adjusting for changes in surgical stimulation or patient physiology.
Other mixtures, such as propofol–ketamine, sometimes termed “ketofol,” have been explored as alternatives that can offer potential advantages. Ketamine provides analgesia and sympathetic stimulation that counteracts propofol-induced hypotension, allowing for more stable hemodynamics. Bajwa et al. compared propofol–ketamine and propofol–fentanyl regimens and found that the ketamine combination provided superior cardiovascular stability and faster recovery (4). This mixture exhibits greater chemical compatibility than propofol–remifentanil, though it may increase the risk of psychomimetic effects at higher doses. Nevertheless, most best-practice recommendations still advise separate administration to preserve dosing flexibility and prevent unintended synergistic effects.
The advent of multi-channel infusion pumps and target-controlled infusion systems has largely rendered mixing drugs for TIVA unnecessary in modern anesthesia practice. These technologies enable the simultaneous yet independent administration of multiple agents while preserving pharmacologic precision and safety. Although mixtures such as propofol–remifentanil or propofol–ketamine can be used in select short-duration cases under controlled, aseptic conditions, the current evidence and professional guidelines consistently favor separate infusions. The essential principle of safe TIVA practice remains clear: pharmacologic accuracy and sterility must always take precedence over convenience, and efficiency should never come at the expense of patient safety.
References
1. Bagshaw O, McCormack J, Brooks P, Marriott D, Baxter A. The safety profile and effectiveness of propofol-remifentanil mixtures for total intravenous anesthesia in children. Paediatr Anaesth. 2020;30(12):1331-1339. doi:10.1111/pan.14018
2. O’Connor S, Zhang YL, Christians U, Morrison JE Jr, Friesen RH. Remifentanil and propofol undergo separation and layering when mixed in the same syringe for total intravenous anesthesia. Paediatr Anaesth. 2016;26(7):703-709. doi:10.1111/pan.12917
3. Nimmo AF, Absalom AR, Bagshaw O, et al. Guidelines for the safe practice of total intravenous anaesthesia (TIVA): Joint Guidelines from the Association of Anaesthetists and the Society for Intravenous Anaesthesia. Anaesthesia. 2019;74(2):211-224. doi:10.1111/anae.14428
4. Singh Bajwa SJ, Bajwa SK, Kaur J. Comparison of two drug combinations in total intravenous anesthesia: Propofol-ketamine and propofol-fentanyl. Saudi J Anaesth. 2010;4(2):72-79. doi:10.4103/1658-354X.65132
