Over the next few weeks, Drs. Ian Yuan, Dean Kurth and I will continue to present several articles on the use of EEG monitoring to guide anesthetic vapor and propofol administration in the operating rooms. Ian and Dean are real experts in this field and they’ve helped me pick several of their recent papers for review in the Pediatric Anesthesia Article of the Day. Like most of you, I know almost nothing about how to make sense of these complex squiggly lines. Hopefully my lack of knowledge will allow me to ask the stupid questions that will help you understand this new technology that I believe will become as common place in our practice as pulse oximetry. In some ways, figuring out what the squiggly lines mean is similar to how I felt when I was first learning how to use and make sense of ultrasound images. It really is all about pattern recognition. Myron Yaster MD
Original article
Xu T, Kurth CD, Yuan I, Vutskits L, Zhu T.
An approach to using pharmacokinetics and electroencephalography for propofol anesthesia for surgery in infants. Paediatr Anaesth. 2020 Dec;30(12):1299-1307. PMID: 32965066
Unlike sevoflurane, for which we have end-tidal monitoring and MAC, there is no practical way to monitor the target effect site concentration (Ce) of propofol. This can result in under- or over-dosing of propofol, particularly in infants and young children due to biological variations in pharmacokinetics and pharmacodynamics related to age, as well as differences in body water/fat composition, kidney and liver function, and brain maturity”.1-3 In much of the world, except the United States, target-controlled infusion pumps (TCI) based on population pharmacokinetics are used to guide propofol administration The United States Food and Drug Administration has not allowed TCI in America. So, how do we dose propofol infusions in clinical practice in the U.S.? We basically guess and rely on autonomic responses to surgical stimulation, which has more to do with pain than consciousness!
Today’s PAAD focuses on propofol and TIVA. However, much of the discussion is also applicable for sevoflurane and we will discuss this in an upcoming PAAD. First, let’s review some basic anesthesia pharmacology. Anesthesia consists of hypnosis, nociception, amnesia, and immobility that are mediated by different neurotransmitter neuroanatomic systems. Propofol is a strong hypnotic and weak analgesic and immobilizer. By comparison, sevoflurane is a strong hypnotic, analgesic, amnestic, and immobilizer. In thinking about TIVA vs inhaled anesthesia, the two techniques are not the same because propofol is not the same drug as inhaled agents.
How does propofol produce unconsciousness? Once it reaches the effect site (the brain), propofol binds to gamma amino-butyric acid (GABA) receptors in the neocortex and thalamus to produce graded levels of unconsciousness (hypnosis). “In adults and children, propofol Ce for clinical endpoints of unconsciousness, unconsciousness with minor nociception, and unconsciousness with major nociception range from approximately 1.5-2.5, 2-3.5, and 3-6 μg/mL, respectively.”3 Obviously, adding an opioid will reduce the propofol dose by 30-70% because opioids are more powerful analgesics than propofol. When nociception is key to the anesthetic, opioids are needed to bind to receptors in the brain and periphery to do their magic. The propofol dose to achieve the hypnotic state and targeted Ce decreases over time as a result of the pharmacokinetics of volume of distribution, organ blood flow, and clearance. If the propofol infusion dose rate is not decreased as a function of time, propofol Ce will continue to increase over time which may result in hypotension, prolonged emergence, delayed recovery, etc.
How can one titrate down the dose without over or underdosing the propofol infusion rate in an individual patient, particularly in the first year of life when volumes of distribution, organ blood flow and clearance, are changing rapidly? For most of us there is no way to do this at all. We are simply guessing. What about in Europe that have TCI for propofol ? Although TCI may be better than guessing, because it is based on population pharmacokinetics it will also over or under dose in many individuals because there is biological variability amongst patients. And TCI is not approved for infants in those countries in which it is approved because of greater variability in this age group. In other words, we are basically flying blind regardless of TCI. Enter EEG monitoring!
As discussed in last week’s PAAD, “The EEG detects synchronous electrical discharges from cortical pyramidal neurons and displays the summation of electrical activity as a complex waveform. It is possible to mathematically deconvolute a complex waveform into a series of waves of varying frequencies through a Fourier transformation. In EEG, the series of frequency bands are conventionally named: slow (<1 Hz), delta (1-5 Hz), theta (5-9 Hz), alpha (9-13 Hz), beta (13-25 Hz), and gamma (25-200 Hz).10 The relative amplitude or quantity of the frequency is known as the power”.3
The current monitors display raw EEG waveforms in real time and are used to identify isoelectricity, burst suppression, seizure spikes, and artifact. This is something we are trying to avoid and as you will see in next week’s PAAD this happens all of the time when we fly blind. Density spectral array (DSA) displays the frequencies and their power over time as a color “heat map” that identify trends and “anesthetic signatures” or frequency bands associated with targeted hypnotic state, such as alpha and delta bands. “The EEG parameters may be generic or proprietary. Common public parameters are spectral edge frequency (SEF); proprietary indices are Bispectral Index (BIS, Medtronic Inc), Patient State Index (PSI, Masimo Inc), and Narcotrend Index (Narcotrend Inc) and can be used like SEF95. The SEF95 represents the frequency containing 95% of the power and is useful to evaluate depth of hypnosis at a moment in time”.3 The proprietary EEG indices (BIS, PSI) are not reliable in younger children and infants.
Using DSA and SEF 95 as a guide to dose propofol, the authors target “Ce 2-3, Ce 3-4, and Ce 4-6 µg/mL corresponding to SEF95 of 15-20, 10-15, and <10 Hz, respectively, which are our targets for sedation, surgery, and intubation”.3 They provide specific examples of how to do this if using an IV induction, a sevoflurane induction followed by TIVA etc. Finally, they provide 2 case studies to show how the EEG was used to titrate propofol “in combat”.
A key take-away is the EEG is a depth of hypnosis monitor. It is not a depth of anesthesia monitor because anesthesia also consists of nociception and immobility. Hemodynamics are used as the monitor of nociception. There is no monitor of immobility unless a muscle relaxant is used. The value of EEG is high for TIVA because it serves as the biomarker for propofol Ce and depth of hypnosis. The value of EEG is less for inhaled agents because end expired concentration is the biomarker for inhaled agent Ce.
Over the next 2 weeks we’ll discuss how often isoelectric EEGs occur during pediatric anesthesia when you “fly blind” and how to implement EEG monitoring into your practice.
References
1. Yuan I, Xu T, Kurth CD. Using Electroencephalography (EEG) to Guide Propofol and Sevoflurane Dosing in Pediatric Anesthesia. Anesthesiology clinics. Sep 2020;38(3):709-725. doi:10.1016/j.anclin.2020.06.007
2. Yuan I, Missett RM, Jones-Oguh S, et al. Implementation of an electroencephalogram-guided propofol anesthesia education program in an academic pediatric anesthesia practice. Paediatric anaesthesia. Jul 6 2022;doi:10.1111/pan.14520
3. Xu T, Kurth CD, Yuan I, Vutskits L, Zhu T. An approach to using pharmacokinetics and electroencephalography for propofol anesthesia for surgery in infants. Paediatric anaesthesia. Dec 2020;30(12):1299-1307. doi:10.1111/pan.14021