Abstract
In this case, the electroencephalogram (EEG) was used to guide anesthesia care for a pediatric patient with Alexander’s Disease undergoing serial intrathecal injections. Previous procedures using a standard maintenance propofol dose of up to 225 µg/kg/min led to postanesthetic recovery times of over 6 hours, requiring a neurology consult for noncoherence. The EEG assisted in guiding maintenance propofol dosing to 75 µg/kg/min, decreasing postanesthetic wash-off and postanesthesia care unit (PACU) recovery time by 50%. This highlights the potential impact of astrocyte dysfunction on anesthetic sensitivity and robustness of EEG as a biomarker of anesthetic effect, including for pediatric patients with rare neurodevelopmental diseases.
Every year there are 3.9 million surgeries in the United States performed on pediatric patients, and a total of 6 million children undergoing general anesthesia for both surgical and nonsurgical procedures.1,2 Currently, dosing for anesthetic drugs is based on population-based pharmacokinetics and pharmacodynamics models.3,4 However, these models are often developed in patient populations that do not include children, whose bodies and physiology may differ significantly from a typical adult patient.3,4 The electroencephalogram (EEG) is a leading candidate for neural monitoring for pediatric anesthesia given that it is noninvasive and reliable, with stereotyped patterns of anesthesia-induced EEG activity that have been thoroughly described and related to underlying neural mechanisms of unconsciousness. Two of these stereotyped patterns are the propofol-induced frontal alpha (8–12 Hz) and delta (0.1–4 Hz) oscillations.5 It is interesting to consider how other neurological disorders might influence anesthesia-induced EEG patterns.
Alexander’s Disease is a rare neurological disease caused by a genetic mutation in glial fibrillary acidic protein (GFAP) that leads to astrocyte dysfunction and neurodegeneration.6 Patients with this disease present with macrocephaly, seizures, and developmental delays.6 While studies have shown how astrocytes are integral components of the neural circuits responsible for anesthetic-induced consciousness, amnesia, and analgesia, there is still no robust research on the effects of astrocyte dysfunction on anesthetic-induced EEG biomarkers or anesthetic requirements.7 Identifying these effects could provide a method to personalize anesthetic dosing for this already at-risk population for postoperative complications.
Written consent and Health Insurance Portability and Accountability Act (HIPAA) authorization was obtained from the patient’s parents for the publication of this case report.
CASE DESCRIPTION
A 7-year-old male patient with Alexander’s disease underwent general anesthesia for an intrathecal injection of medication at Stanford Children’s Health. At 18 months, the patient was diagnosed with Alexander’s disease and presented with frequent convulsions, developmental delays, and white matter abnormalities. The patient was enrolled in a clinical trial studying the efficacy of intrathecal ION373, an antisense oligonucleotide-based therapy that inhibits the amount of GFAP protein produced.8 For this trial, the patient underwent an intrathecal infusion of ION373 every 3 months under anesthesia in the operating room. This provided an opportunity to compare patient postoperative outcomes before and after anesthetic EEG monitoring was introduced.
The patient had 9 previous lumbar punctures done at Stanford Children’s Health (Table). The patient had a body mass index (BMI) of 15.82 kg/m2, height of 115.5 cm, and weight of 21.2 kg. His epilepsy was well controlled with levetiracetam. For each of these procedures, the patient was premedicated with oral midazolam. The patient was then induced with sevoflurane and maintained on a regimen of propofol ranging from 100 µg/kg/min to 225 µg/kg/min. For the majority of the procedures, the patient required up to 7.5 mg of ephedrine to treat hypotensive episodes. After each procedure, the mother complained of the patient’s long postoperative wakeup times, many of which lasted more than 6 hours. In the most recent surgery, the patient’s postoperative wakeup recovery was so lengthy that neurology was consulted due to prolonged emergence and noncoherence.
Table.
Summary of Anesthetic Procedures Over the Past 3 Years
| Procedure no | Premedication | Duration of anesthesia (min) | Duration of PACU stay (min) | Lowest rate of propofol infusion (mcg/kg/min) | Total propofol (mg) | Boluses of vasopressor |
|---|---|---|---|---|---|---|
| Procedures before EEG monitoring | ||||||
| 1 | Midazolam | 128 | 104 | 225 | 562 | 0 |
| 2 | Midazolam | 73 | 121 | 100 | 115 | 1 |
| 3 | Midazolam | 58 | 79 | 170 | 164 | 2 |
| 4 | Midazolam | 58 | 115 | 100 | 142 | 1 |
| 5 | Midazolam | 74 | 87 | 135 | 161 | 2 |
| 7 | Midazolam | 109 | 67 | 150 | 290 | 3 |
| 8 | Midazolam | 70 | 92 | 200 | 176 | 1 |
| 9 | Midazolam | 102 | 121 | 175 | 238 | 5 |
| Procedure with EEG monitoring described in this report | ||||||
| 1 | Midazolam | 75 | 41 | 75 | 89 | 0 |
Abbreviations: EEG, electroencephalogram; PACU, postanesthesia care unit.
For the subsequent procedure described in this case report, the anesthesiologist utilized a 4-electrode frontal EEG (Masimo) to monitor the effects of anesthesia. The patient was premedicated with 0.5 mg/kg of oral midazolam and induced with sevoflurane. After placement of intravenous access, anesthesia was maintained with a propofol infusion starting at a rate of 100 µg/kg/min with the patient breathing spontaneously via oxygen mask. The anesthesiologist noticed a drop in blood pressure from 115/55 to 105/35, leading him to consider reducing the propofol infusion rate. Due to the patient’s history of higher rates of propofol use, there was a concern that lowering the infusion rate could lead to insufficient sedation. This directed the anesthesiologist to reference the EEG spectrogram, where he saw that propofol-induced alpha and delta power was very robust, signaling more than sufficient depth of anesthesia. As a result, the anesthesiologist was confident he could reduce the infusion rate to 75 µg/kg/min to achieve hemodynamic stability as well as maintain anesthesia. At this infusion rate, the EEG showed a noticeable decrease in delta power, decrease in alpha power, and increase in alpha frequency, all consistent with a decrease in the propofol infusion rate while still maintaining adequate sedation needed for the procedure. Total duration of anesthesia for this case was 75 minutes (Table).
Anesthetic wash-off time for this procedure was notably shorter: 6 minutes, vs 15 minutes from the previous 8 lumbar punctures. Further, unlike previous procedures, no significant hypotension was noted in this EEG-guided procedure. The patient had shorter emergence times from anesthesia, becoming fully oriented 3 hours postprocedure compared to the 6 hours in his previous procedure. The mother also confirmed that the patient was more responsive in a shorter amount of time than in the past.
We quantitatively analyzed the patient’s EEG to determine whether this propofol infusion rate change led to meaningful changes in the anesthesia-induced EEG patterns. We calculated the delta band (0.1–4 Hz) and alpha band (8–12 Hz) signal power in 2 minutes windows before and after the propofol infusion rate change (multitaper spectral analysis, T = 2 seconds window, no overlap, time-bandwidth product TW = 3, spectral resolution 1.5 Hz; Figure). Alpha power decreased after the rate change from 25.01 dB to 13.07 dB. Delta power during the same 2 minutes windows also saw a decrease after the rate change from 28.18 dB to 19.98 dB. Total EEG power at a propofol infusion rate of 100 ug/kg/min was 31.44 dB.
Figure.
EEG spectrogram for the case annotated with procedural events. The vertical black line represents the transition of propofol dosing from 100 to 75 µg/kg/min. EEG indicates electroencephalogram.
DISCUSSION
This case report is the first to describe how EEG can be used to guide anesthetic care for a child with Alexander’s Disease undergoing general anesthesia. The EEG spectrogram showed robust, dose-dependent propofol-induced alpha and delta oscillations that the anesthesiologist used to guide the reduction of the amount of propofol used by more than 50% compared to the patient’s previous procedures, leading to a notably shorter wash-off time and time to emergence from anesthesia.
Propofol-induced frontal alpha oscillations are thought to reflect an exaggerated coherent oscillation that disrupts prefrontal thalamocortical function, while the propofol-induced delta oscillation stems from periodic silencing of cortical neuronal firing.9 When comparing this patient’s propofol-induced EEG alpha and delta power to neurotypical children of similar age at an average propofol dose of 250 ug/kg/min,5 this patient showed similar alpha and delta power but at less than half the propofol dosage of 100 ug/kg/min. We believe that this patient’s increased sensitivity to propofol measured through the EEG could be explained by the effects of Alexander’s Disease on astrocyte metabolism. Astrocytes play a key role in the regulation of neuronal metabolism through functions such as supplying energy metabolites through aerobic glycolysis and neurotransmitter recycling.10,11 Past work has shown that anesthetic drugs impair neuronal mitochondrial function, shifting brain metabolism away from oxidative phosphorylation and toward aerobic glycolysis, which produces fewer adenosine triphosphate (ATP) molecules per glucose molecule than oxidative phosphorylation.12,13 It is known that the mutations in GFAP that cause Alexander’s Disease lead to abnormal astrocyte mitochondrial morphology and reduced ATP production.14,15 This reduced capacity for ATP release could make patients with Alexander’s Disease more susceptible to further anesthesia-induced impairment in metabolic capacity, and therefore more sensitive to anesthetics overall. This case report highlights the utility of EEG monitoring to identify each patient’s individual responsiveness to anesthetics and titrate accordingly to mitigate the risk of postoperative complications.
We believe that these results motivate the expanded use of EEG monitoring to personalize anesthetic dosing for pediatric patients, especially those with neurodegenerative disease. We show that anesthetic-induced alpha and delta oscillations are not only maintained in this patient with Alexander’s Disease but also could be a direct measure of the increased sensitivity of this patient to these anesthetics. Rather than relying on anesthetic dosing schemes that are based on adult physiology and do not account for changes to anesthetic sensitivity associated with neurodegenerative disorders, the EEG can provide a real-time measure of anesthetic effect we use to minimize anesthetic exposure and improve postoperative outcomes for patients. Application of EEG monitoring to this one patient decreased anesthetic wash-off and postanesthesia care unit (PACU) recovery times by 50%, which suggests that widespread adoption of EEG monitoring could lead to system-wide efficiencies in OR scheduling, PACU resources, and both patient and caregiver satisfaction. Overall, this case highlights the potential benefits EEG monitoring could provide our pediatric patients and clinical staff with almost no additional changes to current anesthetic workflow.
Limitations of this study include the inability to generalize to all patients with Alexander’s Disease given that this report only includes 1 subject. Outcomes may also reflect practice patterns unique to our medical institution.
ACKNOWLEDGMENTS
The authors would like to thank the family for participation in this study.
This manuscript was handled by: Markus M. Luedi, MD, MBA.
Footnotes
M. Zhang and R. V. Mather contributed equally as first authors. R. J. Ramamurthi and P. L. Purdon contributed equally as senior authors.
P. L. Purdon is a co-founder of PASCALL Systems, Inc., a start-up company developing closed-loop physiological control systems for anesthesiology. All other authors declare that they have no conflicts of interest.
Funding: R. V. Mather is supported by award Number T32GM007753 and T32GM144273 from the National Institute of General Medical Sciences as well as 2T32EB001680 from the National Institute of Biomedical Imaging and Bioengineering. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences, National Institute of Biomedical Imaging or Bioengineering, or the National Institutes of Health.
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