Sevoflurane and propofol–based anesthetics are dosed according to vital signs, movement, and expired sevoflurane concentrations, which do not assess the anesthetic state of the brain and, therefore, risk underdose and overdose. Electroencephalography (EEG) measures cortical brain activity and can assess hypnotic depth, a key component of the anesthetic state. Application of sevoflurane and propofol pharmacology along with EEG parameters can more precisely guide dosing to achieve the desired anesthetic state for an individual pediatric patient. This article reviews the principles underlying EEG use for sevoflurane and propofol dosing in pediatric anesthesia and offers case examples to illustrate their use in individual patients.
Key points
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The dose of sevoflurane and propofol that produces unconsciousness varies by age group (neonates, infants, and children) as well as between patients within the same age group, potentially creating risk for underdose and overdose in pediatric patients.
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Intraoperative electroencephalography (EEG) can be used as a biomarker of hypnotic depth in neonates, infants, and children to guide the dose of propofol and sevoflurane to the individual patient.
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Numeric proprietary indices on intraoperative EEG monitors do not reliably correlate with anesthetic dose in neonates and young infants. EEG waveforms and other nonproprietary EEG parameters, however, change reliably with increased doses of sevoflurane and propofol across all ages and can be utilized in pediatric anesthesia.
Introduction
Inhaled sevoflurane and intravenous (IV) propofol are 2 of the primary drugs used to anesthetize children. Dosing for these agents is guided by monitoring expired concentration for sevoflurane or infusion pump rate for propofol total IV anesthetic (TIVA); additional considerations include changes in heart rate, blood pressure, and movement in response to stimulation. None of these factors directly assesses the anesthetic state of the brain. EEG allows measurement of cortical electrical activity and can be used to assess hypnotic depth to adjust dosing of anesthetic agents to the individual patient. EEG monitoring recently has been recommended as one of the vital organ monitors used to guide anesthetic management. Potential benefits of intraoperative EEG monitoring include less incidence of hypotension and awareness under anesthesia, faster wakeup and recovery times, and less amount of drugs administered. , , Intraoperative EEG monitoring might be particularly beneficial in neonates and young infants undergoing major surgery and pediatric patients with cardiovascular disease, as they have greater risk of respiratory and cardiovascular events during anesthesia. , Intraoperative EEG monitoring might also be suited for propofol TIVA to assess propofol effect site concentration, which cannot be assessed otherwise, unlike sevoflurane anesthesia in which the expired concentration can be used to assess sevoflurane effect site concentration. ,
This article describes the rationale and application of EEG to guide sevoflurane and propofol TIVA dosing in children aged 0-12 years and specifically discusses the fundamentals necessary to interpret EEG, changes in EEG with age and anesthetic state, the interaction between anesthetic state and pharmacology, and how EEG can be used to guide dosing of sevoflurane and propofol.
Eeg fundamentals
Intraoperative EEG Monitors
EEG measures the electrical activity in the neocortex, which is generated by the summation of excitatory and inhibitory postsynaptic activities from pyramidal neurons. Although it has been known for many years that EEG changes with increasing doses of volatile and IV anesthetics, intraoperative EEG monitoring was uncommon until recently. The increased use of intraoperative EEG monitoring has been driven by clinical and media reports of intraoperative awareness and advances in EEG technology that make it more accessible to anesthesiologists. These advances include creation of a numeric proprietary index that provides an overview of hypnotic depth and improvements in sensor and signal processing technology to enable rapid application and noise-filtering.
Smaller and more practical than EEG machines utilized by neurologists, intraoperative EEG monitors typically combine 4 to 8 electrodes into a disposable sensor placed on the forehead. Intraoperative EEG monitors approved for pediatric use include BIS (Medtronic, Minnesota, Minnesota), Narcotrend (MonitorTechnik, Bad Bramstedt, Germany), and SedLine (Masimo, Irvine, California). These monitors display both unprocessed (EEG waveforms) and processed EEG (numeric proprietary indices and nonproprietary parameters). Because many anesthesiologists have some experience using numeric proprietary indices (eg, BIS), the emphasis of this article is on using EEG waveforms and nonproprietary EEG parameters to guide anesthetic dosing, since numeric proprietary indices are not always reliable in the pediatric population.
EEG Waveforms
EEG waveforms can be described using frequency and amplitude/power. Frequency (hertz) is the number of times the EEG waveform crosses 0 within a second and is grouped into frequency bands, from lowest to highest frequencies: slow (<1 Hz), delta (1–4 Hz), theta (5–8 Hz), alpha (9–12 Hz), beta (13–25 Hz), and gamma (26–80 Hz). Amplitude (microvolts) is the height of the EEG waveform and indicates the synchrony of the underlying neuronal discharges; the larger the EEG amplitude, the more synchronized the neuronal discharges, indicating a deeper state of unconsciousness. Slow and delta waves with large amplitudes are seen in deep sleep or coma, whereas theta waves are present in light sleep. Alpha waves are seen in an awake state with eyes closed or when meditating, whereas beta waves are present in a state of active thinking. EEG power (decibels) is the quantity of EEG activity at a given frequency; with increased depth of unconsciousness, EEG power typically decreases in higher frequencies and increases in lower frequencies. Amplitude and power are related mathematically but in processed EEG, power is used instead of amplitude because it is easier to display graphically.
EEG Artifacts
EEG amplitude is 100 times less than electrocardiography and 10 times less than electromyography (EMG), thereby making intraoperative EEG highly susceptible to electrical interference (eg, electrocautery), motion artifact, and contamination from electrocardiography and EMG. Intraoperative EEG is able to overcome many of these limitations using filters and signal processing to remove or identify artifacts. Although the patient usually is immobile during anesthesia, motion artifact often is unavoidable in head and neck surgery, rendering EEG interpretation problematic. The sterile field in craniofacial surgery may also preclude EEG monitoring. The EEG module should not be located next to warming devices or the table controller as both can generate electrical noise.
Processed EEG Parameters
Using signal processing, a complex EEG waveform can be broken down into multiple waveforms of discrete frequencies; a mathematical process known as Fourier transformation. Fig. 1 shows an example of a complex waveform that contains three underlying waveforms of frequencies 4, 8, and 32 Hz which are decomposed into three simple waveforms of those three frequencies. The decomposition of an EEG waveform into discrete frequency bands (e.g. slow, delta, theta, alpha, beta, and gamma) over time allows creation of a spectrogram also known as a density spectral array (DSA), a type of processed non-proprietary EEG parameter.
The DSA displays the relationship between EEG power and frequency over time. In the DSA, the x-axis represents time and y-axis represents frequency. To display EEG power at a certain frequency and time, a colored or grey scale is used to represent power intensity, with dark-brilliant colors representing higher power and light-dull colors denoting lower power. Fig. 2 illustrates an example of DSA during 30 minutes of a propofol anesthetic. At minutes 0-5 (see Fig. 2 ), the majority of EEG power is concentrated in lower frequencies, denoted by the intense red color at frequencies < 3 Hz (lower left in Fig. 2 ), while a minority of EEG power exists in higher frequencies, denoted by blue color at frequencies > 15 Hz. At minutes 8-27 (see Fig. 2 ), there is an increase in power at frequencies 10-12 Hz as indicated by the appearance of yellow/orange colors, along with a decrease in power at frequencies < 5 Hz as indicated by the change from red to yellow. The DSA shows that the level of hypnosis was greater at minutes 0-5 than at 8-27, as indicated by the majority of power existing in lower frequencies in minutes 0-5. Because propofol and sevoflurane exert dose-dependent effects on frequency and power, the DSA can visually display hypnotic level during the course of the anesthetic. Purdon and colleagues provides an excellent tutorial on interpreting DSA for the clinical anesthesiologist.
Many intraoperative EEG monitors display their proprietary index along with EEG waveforms, DSA, and nonproprietary processed parameters ( Fig. 3 ). These nonproprietary processed EEG parameters include spectral edge frequency (SEF), burst suppression ratio (BSR), and relative beta ratio (RBR). SEF95 is the frequency below which 95% of EEG power is located. A lower SEF95 represents a deeper state of hypnosis. In the DSA in Fig. 2 , SEF95 is shown by the top white line and is less than 5 Hz at minute 0, steadily increasing to 12 Hz by minute 10, indicating decreased hypnotic depth over time. DSA and SEF95 often are used together to assess hypnotic depth: SEF95 provides a numeric index of EEG frequency and power at a moment in time, whereas DSA provides a graphical representation of EEG frequency and power over time. BSR shows the percentage of time that EEG is isoelectric, which indicates an electrically inactive cortex and very deep hypnosis. , RBR is the ratio of power in theta versus beta frequency bands; a higher ratio indicates more power in the slower frequencies and a deeper state of hypnosis. ,
A non-EEG parameter is EMG, which shows the amount of temporalis muscle activity. EMG represents an alert for artifact and potentially erroneous calculation of the EEG parameters; muscle relaxants can decrease EMG artifact. EMG activity also can indicate increased muscle tone consistent with light anesthesia.
Proprietary indices (eg, BIS, Narcotrend index, and Patient State Index [PSI]) are calculated from an algorithm that uses a combination of EEG and non-EEG parameters to construct the numeric index ranging from 0 to 100; a lower value represents a deeper state of hypnosis. In general, hypnotic states representing sedation, surgical anesthesia, and burst suppression/isoelectricity correspond to proprietary indices of 60-80, 40-60, and 0-20, respectively, which in turn correspond to SEF95 ranges of 15-20 Hz, 6-14 Hz, and <5 Hz. ,
Traditionally, pediatric anesthesiologists have relied primarily on the numeric proprietary index to determine anesthetic depth. This practice has several issues: (1) the index may be inaccurate for certain age groups and anesthetic drugs; (2) the index is subject to artifact and noise, which may not be properly accounted for; and (3) the index does not measure the nonhypnotic components of the anesthetic state (eg, muscle tone–immobility, awareness, and analgesia), which are important in assessing overall anesthetic depth. Therefore, proper use of EEG requires (1) knowledge of age and drug effects on EEG, which are discussed later; (2) basic understanding of the EEG waveform and commonly used nonproprietary EEG parameters (eg, DSA and SEF95) to aid interpretation of the index; and (3) understanding the limitations of EEG in assessing the overall anesthetic state. To understand these limitations, the components of the anesthetic state and involvement of the neocortex are described next.
Anesthetic state
The anesthetic state includes components of hypnosis (unconsciousness), analgesia, areflexia (immobility), and amnesia (awareness). The anesthetic state is induced by drugs interfering with synaptic transmission within or between several brain regions. γ-Aminobutyric acid (GABA) and α-adrenergic neurotransmitter-receptor systems in the neocortex, thalamus, and brainstem strongly influence the level of consciousness. , , Opioid and glutamate neurotransmitter-receptors in the amygdala, thalamus, brainstem, and spinal cord strongly affect analgesia. , Memory formation, which is key to awareness, involves several neurotransmitter-receptor systems in many areas of the neocortex as well as the hippocampus. As a monitor of neocortical activity, EEG is able to assess the level of hypnosis and, in theory, also can assess the risk of awareness. , , EEG does not assess the analgesia or areflexia components of the anesthetic state.
Pediatric EEG changes with age
For anesthesiologists taking care of young children, understanding normal EEG changes with age is important because it can affect the interpretation of intraoperative EEG. By ages 10 to 14 years, the EEG resembles that of an adult. In children older than age 3 years, all EEG frequency bands are present.
The neonatal and infant EEG is characterized by low frequency and power compared with older children. In preterm neonates 28 weeks to 34 weeks postmenstrual age, periods of isoelectric EEG are common, occurring during both awake and sleep. Thus, a normal EEG in a non-anesthetized neonate or infant could be similar to the EEG in an anesthetized child or adult. Accordingly, proprietary indices that were developed in adults are not reliable in neonates and infants. EEG waveform and some nonproprietary processed EEG parameters, however, can be used to assess the level of hypnosis for all ages, as described later.
EEG to guide anesthetic dose
Using EEG to guide sevoflurane and propofol TIVA dosing requires knowledge of each drug’s pharmacokinetics and pharmacodynamics. Therefore, each section starts with an introduction to the pharmacokinetics-pharmacodynamics of each drug, followed by a description of the EEG parameters that can be used to adjust dosing across all age groups; the sections end with sample cases demonstrating EEG-guided dosing.
Sevoflurane
Pharmacokinetics-pharmacodynamics
The effect of sevoflurane on synaptic neurotransmission is related to its partial pressure in the brain and spinal cord, represented at equilibrium by the alveolar concentration. The rate constant between brain and lung is 6 minutes, indicating rapid equilibration between brain and alveolar concentrations. Sevoflurane alveolar concentration is related directly to the inhaled concentration and minute ventilation, and indirectly to its solubility and cardiac output. Sevoflurane solubility is similar in neonates, infants, and children. Because the ratio of alveolar ventilation and cardiac output per body weight is similar from neonates through childhood, sevoflurane pharmacokinetics behaves similarly in the pediatric population regardless of age.
Sevoflurane pharmacodynamics are described in terms of the minimum alveolar concentration (MAC) of sevoflurane required to suppress movement to a surgical incision in 50% of the patients. , MAC of sevoflurane varies by age, ranging from 2.4% in premature infants, 3.2% in infants, and 2.1% in young adults. Individual differences also exist within the same age group. , For example, even though the MAC of sevoflurane is 3.2% for age 0-6 months, the dose of sevoflurane for 95% of young infants in that age group to not move during surgical incision could range from 2.5% to 3.8%. , Because of these inherent variabilities in MAC, there is a potential risk of underdose/overdose in an individual pediatric patient when using population-based MAC and expired sevoflurane concentration as a dosing guide. EEG permits titration of hypnotic dose to the individual patient, often at a lower dose than that based on MAC and cardiovascular parameters. This is useful particularly for neonates and infants undergoing major surgery as well as neonates, infants, and children with cardiovascular disease, because these patients are at greater risk of hypotension during anesthesia. , , ,
EEG parameters for sevoflurane dosing
Proprietary EEG indices are unreliable in neonates and young infants ages less than 6 months but are generally reliable in children ages greater than 1 year. , Unreliability in infants is due to the proprietary EEG indices being developed in adults without consideration for the normal age-related EEG changes in infants. , , Even in older infants and children, proprietary EEG indices do not always correlate with sevoflurane concentration. , , For example, in children ages 6 months to 12 years, BIS index decreased from sevoflurane 1% to 3%, as expected, and then paradoxically increased from sevoflurane 3% to 5%. This is due to the proprietary index misinterpreting high frequency epileptiform EEG activity during high-dose sevoflurane as a lighter state of hypnosis. , ,
By comparison, nonproprietary EEG parameters have been shown to reflect sevoflurane concentration in infants ages greater than 3 months but not in infants ages less than 1 month. For example, in infants ages less than 1 month, SEF95, BSR, and RBR do not reliably indicate changes in sevoflurane concentration, whereas they do by ages 3 months to 5 months. In infants ages greater than 3 months, Koch and colleagues have identified SEF95 values (cutoffs) of less than 7 Hz (deep anesthesia), less than 13 Hz (surgical anesthesia), and greater than 20 Hz (sedation/consciousness) that can be utilized to indicate time to intubate, start surgery, and emerge/extubate, respectively. Accordingly, SEF95 at 15 Hz to 20 Hz, 10 Hz to 15 Hz, and 6 Hz to 14 Hz are targets for sedation, surgical maintenance, and laryngoscopy/surgical incision, respectively.
Given the unreliability of proprietary indices for infants ages less than 1 year and nonproprietary processed EEG parameters for infants ages less than 3 months, anesthesiologists can use the EEG waveform to identify isoelectricity as an indicator of cortical inactivity and excess sevoflurane dose. Isoelectricity is common during sevoflurane anesthesia in neonates and infants when the dose is guided by MAC and hemodynamic parameters, and is associated with low arterial pressure. , When an infant demonstrates isoelectricity on the EEG, sevoflurane dose should be decreased until activity returns on EEG waveform. Case 1 demonstrates how to use EEG waveform to titrate sevoflurane dose in a young infant.
Case 1
A 2-month-old term infant was scheduled for laparoscopic inguinal hernia repair. Sevoflurane anesthesia with endotracheal tube and local anesthetic infiltration were planned. During sevoflurane induction, SedLine EEG sensors were applied on the forehead. EEG waveform revealed EMG artifact (23%), consistent with patient movement during induction ( Fig. 4 A). After inserting an IV catheter, 1 mg/kg of propofol, was given for intubation. In Fig. 4 B, EEG waveform revealed isoelectricity and SEF95 was 3 Hz; DSA showed stronger power (green) in lower frequencies and weaker power (blue) in higher frequencies, all consistent with deep hypnosis. The numeric proprietary index, however, was inaccurately high (PSI 82). At incision, expired sevoflurane was 1.5% (0.47 MAC); EEG continued to display isoelectricity, indicating unnecessarily deep anesthesia, yet PSI still was inaccurately high (not shown in screenshot). Inspired sevoflurane was decreased to 1.2% (0.35 MAC) and shortly afterward, EEG activity resumed ( Fig. 4 C). SEF95 increased to 6.8 Hz, and DSA showed red in lower frequencies and green in higher frequencies (see Fig. 4 C), a preferred level of anesthetic depth. At the end of surgery, the patient was extubated after demonstration of purposeful, spontaneous movement, and expired sevoflurane was less than 0.2%. EEG waveforms after extubation ( Fig. 4 D) showed increased activity (increased EEG frequency and amplitude) compared with earlier (see Fig. 4 C); both PSI and SEF95 were similar between the 2 screenshots, suggesting that EEG waveforms can more reliably differentiate between anesthetic states than processed EEG parameters in this patient.
