Approved by the Food and Drug Administration (FDA) in 1989, propofol has become one of the most common induction agents for general anesthesia (1). Nicknamed the “milk of amnesia” due to the white liquid appearance of the intravenous formula and its memory impairment effects, propofol is commonly used in preoperative sedation for both inpatient and outpatient surgical procedures (2). Despite its higher cost compared to some other medications, the sedative-hypnotic anesthetic is preferred to other induction agents due to its rapid onset of action, short duration, and low prevalence of side effects (3). Furthermore, propofol exhibits anticonvulsant, anti-inflammatory, antiemetic, and neuroprotective properties (4, 5). The medication works by activating GABA receptors and inhibiting glutamate receptors in the central nervous system, resulting in sedation and cardiorespiratory depression (5). Propofol has a steep dose-response curve – it can cause a potentially lethal complication known as propofol-related infusion syndrome (PIRS) at high doses (5, 6). Therefore, calculating the correct induction dose of propofol is extremely important to avoid severe side effects.
In response to a rise in PIRS cases in the 1990s (4), many researchers sought to describe the pharmacokinetics of propofol and create dosage guidelines. Originally, propofol was administered at a standardized dose of 2 to 2.5 milligrams per kilogram of absolute body weight for anesthesia induction and sedation (3). However, studies demonstrated that propofol is lipophilic and causes different reactions in patients with similar weights but different levels of fat (7). Because of the non-linear relationship between propofol clearance and absolute body weight, current research suggests calculating propofol doses based on lean body mass (8, 9). Additionally, propofol metabolism can be affected by sex – males, who on average have less fat within which lipophilic medications like propofol can spread, exhibit higher sensitivity and thus require lower doses than females (10). Age is also a significant predictor of the necessary dose, as older patients typically require smaller amounts than younger patients to achieve the same effect (8). Finally, clinical factors such as shock, cardiac output, liver dysfunction, and concurrent medication administration can alter the pharmacokinetics of propofol (9, 11). To determine the propofol dose required for induction of anesthesia, all of these factors must be considered instead of solely absolute body weight.
To incorporate these elements in propofol administration, many anesthesiologists prefer target-controlled infusion (TCI), a novel alternative to traditional manually-controlled infusion (MCI) (12). Both methods utilize infusion devices, but the MCI technique requires the anesthesiologist to make manual changes to the infusion rate while TCI devices automatically calculate and alter the infusion rate based on the difference between the theoretical plasma concentration and the user-defined target concentration (13). The formulas programmed into TCI devices incorporate factors such as sex, body fat concentration, and age (14). Studies have indicated that both methods result in similar outcomes for most patients, although TCI may be associated with marginally higher doses of propofol (13). Regardless of the infusion method, care must be taken to monitor the concentration of propofol.
Since its discovery, propofol administration guidelines have undergone innumerable developments to maximize the medication’s effectiveness and safety. Notably, dosage calculations for both TCI and MCI methods must be interpreted as approximations, as clinical factors can adapt the body’s response to propofol. In particular, geriatric and pediatric patients remain at the highest risk for adverse effects (15, 16). Researchers recommend utilizing bispectral index readings in these patients to monitor the depth of anesthesia and titrate the infusion (15, 16). As the understanding of the pharmacokinetics of propofol continues to improve, thus will the administration guidelines, but anesthesiologists should make calculations and adjustments to the induction dose based on their patients’ experiences in the operating room.
References
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2: Mashour, G. (2012). Milk of amnesia. Science of Translational Medicine, vol. 4. DOI: 10.1126/scitranslmed.3005250.
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8: Absalom, A., Mani, V., de Smet, T. and Struys, M. (2009). Pharmacokinetic models for propofol—defining and illuminating the devil in the detail. British Journal of Anaesthesia, vol. 103. DOI: 10.1093/bja/aep143.
9: Sahinovic, M., Struys, M. and Absalom, A. (2018). Clinical pharmacokinetics and pharmacodynamics of propofol. Clinical Pharmacokinetics, vol. 57. DOI: 10.1007/s40262-018-0672-3.
10: Hoymork, S. and Raeder, J. (2005). Why do women wake up faster than men from propofol anaesthesia? British Journal of Anaesthesia, vol. 95. DOI: 10.1093/bja/aei245.
11: Johnson, K., Egan, T., Kern, S., White, J., McJames, S., Syroid, N., Whiddon, D. and Church, T. (2003). The influence of hemorrhagic shock on propofol: a pharmacokinetic and pharmacodynamic analysis. Anesthesiology, vol. 99. DOI: 10.1097/00000542-200308000-00023.
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13: Hunt-Smith J., Donaghy, A. and Warwick, N. (1999). Safety and efficacy of target controlled diffusion (Diprifusor) versus manually controlled infusion of propofol for anaesthesia. Anaesthesia and Intensive Care, vol. 27. DOI: 10.1177/0310057X9902700306.
14: Short, T., Campbell, D. and Egan, T. (2018). Increasing the utility of target-controlled infusions: one model to rule them all. British Journal of Anaesthesia, vol. 120. DOI: 10.1016/j.bja.2018.02.012.
15: Louvet, N., Rigouzzo, A., Sabourdin, N. and Constant, I. (2016). Bispectral index under propofol anesthesia in children: a comparative randomized study between TIVA and TCI. Paediatric Anaesthesia, vol. 26. DOI: 10.1111/pan.12957.
16: Gurses, E., Sungurtekin, H., Tomatir, E. and Dogan, H. (2004). Assessing propofol induction of anesthesia dose using bispectral index analysis. Anesthesia and Analgesia, vol. 98. DOI: 10.1213/01.ANE.0000090314.43496.1D.
