A Pilot Investigation Evaluating Relative Changes in Fronto-Occipital Alpha and Beta Spectral Power as Measurement of Anesthesia Hypnotic Depth

BACKGROUND:

Other than clinical observation of a patient’s vegetative response to nociception, monitoring the hypnotic component of general anesthesia (GA) and unconsciousness relies on electroencephalography (EEG)-based indices. These indices exclusively based on frontal EEG activity neglect an important observation. One of the main hallmarks of transitions from wakefulness to GA is a shift in alpha oscillations (7.5–12.5 Hz activity) from occipital brain regions toward anterior brain regions (“alpha anteriorization”). Monitoring the degree of this alpha anteriorization may help to guide induction and maintenance of hypnotic depth and prevent intraoperative awareness. However, the occipital region of the brain is completely disregarded and occipital alpha as characteristic of wakefulness and its posterior-to-anterior shift during induction are missed. Here, we propose an application of Narcotrend’s reduced power alpha beta (RPAB) index, originally developed to monitor differences in hemispheric perfusion, for determining the ratio of alpha and beta activity in the anterior-posterior axis.

METHODS:

Perioperative EEG data of 32 patients undergoing GA in the ophthalmic surgery department of Bern University Hospital were retrospectively analyzed. EEG was recorded with the Narcotrend® monitor using a frontal (Fp1-Fp2) and a posterior (T9-Oz) bipolar derivation with reference electrode over A2. The RPAB index was computed between both bipolar signals, defining the fronto-occipital RPAB (FO-RPAB). FO-RPAB was analyzed during wakefulness, GA maintenance, and emergence, as well as before and after the intraoperative administration of a ketamine bolus. FO-RPAB was compared with a classical quantitative EEG measure—the spectral edge frequency 95% (SEF-95).

RESULTS:

A significant shift of the FO-RPAB was observed during both induction of and emergence from GA (P < .001). Interestingly, the additional administration of ketamine during GA did not lead to a significant change in FO-RPAB (P = 0.81). In contrast, a significant increase in the SEF-95 in the frontal channel was observed during the 10-minute period after ketamine administration (P < .001).

CONCLUSIONS:

FO-RPAB appears to qualify as a marker of unconsciousness, reflecting physiological fronto-occipital activity differences during GA. In contrast to frontal SEF-95, it is not disturbed by additional administration of ketamine for analgesia.

KEY POINTS.

• Question: Can a combination of frontal and occipital electroencephalography (EEG) improve intraoperative neuromonitoring during general anesthesia (GA)?

• Findings: Fronto-occipital polarity in alpha and beta power showed significant differences during the different stages of GA and was not disturbed by the administration of ketamine.

• Meaning: Fronto-occipital reduced power alpha beta (FO-RPAB) could be a beneficial marker of unconsciousness during perioperative care.

The main target of hypnotic pharmacological agents during general anesthesia (GA) is the brain. The obvious choice to monitor cerebral activity is the electroencephalography (EEG). Berger¹ named the first set of observed frontal and occipital EEG oscillations alpha and beta but failed to discover alpha’s occipital predominance in relaxed awake states.²

Perioperative EEG has only been routinely used in clinical anesthesia practice since the 1990s, with the advent of processed EEG devices.³ The Narcotrend monitor uses a proprietary algorithm to generate an index composed of a letter and a 2-digit number as an indication of anesthesia depth. This index is based on pattern recognition of raw EEG of a 20-second period and classifies these traces into different stages based on the first EEG sleep classification outlined by Loomis in the late 1930s.⁴

Alpha power is maximal when awake with eyes closed in the parieto-occipital region. It disappears occipitally and increases frontally in response to the initiation of GA, a process known as “anteriorization.”^5,6 During emergence, occipital alpha power returns suggesting that a sudden return of occipital alpha/beta power in raw EEG indicates arousal.^7–9 Beta power is known to increase in the frontal brain regions as an indicator of increasing sedation.¹⁰

The administration of ketamine, often used as a component of multimodal general anesthesia, increases bispectral index (BIS) values to values wrongly suggesting light sedation or wakefulness due to increased cortical activity in the beta (15–30 Hz) and gamma (>30 Hz) frequency bands.¹¹

The spectral edge frequency 95% (SEF-95) is a measure commonly used in the literature. It is defined as the frequency value (in Hz) below which 95% of the total power of a spectrum lies. With increasing anesthesia doses, the SEF decreases as the spectral power becomes concentrated in lower frequency bands. Nonetheless, the SEF-95 is limited to one electrode location.

We propose a new EEG measure based on a comparison between combined alpha and beta activity in anterior and posterior brain regions. This new measure is an application of the “reduced power alpha beta (RPAB),” a preexisting algorithm applied by the Narcotrend monitor. RPAB calculates the current percentage of the combined alpha-beta power between the left and right interhemispheric axis and is designed to detect a perfusion mismatch during surgery.¹² By mounting electrodes along the anterior-posterior axis, we define the fronto-occipital RPAB (FO-RPAB) and evaluate its preliminary performance as a new index for monitoring unconsciousness during GA.

METHODS

Patients and EEG Recording

This retrospective analysis was approved by Bern’s cantonal Ethics Committee (project-ID 2019-02370). We reviewed our database of patients undergoing GA for ophthalmic surgery at Bern’s University Hospital between June 2020 and March 2021. All patients gave written consent to evaluate their intraoperatively recorded EEG for research purposes. We identified 70 patients monitored by fronto-occipital perioperative EEGs who received GA using laryngeal masks without neuromuscular blockade. Of these, 29 were excluded because starting and stopping times of GA had not been registered on the Narcotrend device. Nine subjects were excluded because of major EEG artifacts or incomplete recordings, resulting in the inclusion of 32 patients in the present study.

EEGs were recorded with the Narcotrend device. However, the original electrode position, with only frontal and temporal electrodes (Figure 1A), was not used. Instead, the electrodes were placed between Fp1 and Fp2 (Narcotrend channels 1a and 1b) and between T9 and Oz (Narcotrend channel 2a and 2b). The reference electrode was placed over the right mastoid as in polysomnography practice (Figure 1B). We defined a frontal (Fp1-Fp2) and occipital (T9-Oz) bipolar signal.¹² In the ophthalmic surgery department of the Bern University Hospital, placing 1 frontal and 1 occipital EEG channel using the Narcotrend has been established as standard clinical practice for neuromonitoring during GA. To provide satisfactory adhesion of the electrodes on the scalp, a sand paste was applied to offer better contact with the skin, and a dressing was used to hold the electrodes in place.

Figure 1.

Situs of electrode placement contrasting traditional frontal perioperative EEG with fronto-occipital montage used in this trial. Note that reference electrode in fronto-occipital EEG moves to the mastoid (A2 position). A, Standard placement for 2-channel monitoring using in the original Narcotrend monitor. B, Electrode placement for frontal and occipital neuromonitoring during GA. EEG indicates electroencephalogram; GA, general anesthesia.

Fronto-Occipital RPAB

In the original RPAB, which was primarily designed to identify differences between brain perfusion of hemispheres, electrodes had to be placed next to frontal and temporal hairlines, with an additional reference electrode located on the forehead, as shown in Figure 1A. This placement has the disadvantage that occipital regions are not monitored. The RPAB values could not be exported directly from the Narcotrend monitor due to technical restrictions. However, for each 5 seconds, the values of absolute power, relative alpha, relative beta, and SEF-95 (the frequency below which 95% of the EEG power is located) can be extracted directly from the Narcotrend device for each EEG channel and enabled us to calculate the FO-RPAB retrospectively based on quantitative EEG values using the formula confirmed by Narcotrend:

$${\displaystyle \begin{array}{l}{\displaystyle \mathrm{F}\mathrm{O}\text{-}\mathrm{R}\mathrm{P}\mathrm{A}\mathrm{B}=100-\left(\frac{\mathrm{\alpha }\mathrm{\beta }\mathrm{f}\mathrm{r}\mathrm{o}\mathrm{n}\mathrm{t}\mathrm{a}\mathrm{l}}{\mathrm{\alpha }\mathrm{\beta }\mathrm{o}\mathrm{c}\mathrm{c}\mathrm{i}\mathrm{p}\mathrm{i}\mathrm{t}\mathrm{a}\mathrm{l}}\right)\ast 100\mathrm{i}\mathrm{f}\alpha {\beta }_{\mathrm{f}\mathrm{r}\mathrm{o}\mathrm{n}\mathrm{t}\mathrm{a}\mathrm{l}}<\alpha {\beta }_{\mathrm{o}\mathrm{c}\mathrm{c}\mathrm{i}\mathrm{p}\mathrm{i}\mathrm{t}\mathrm{a}\mathrm{l}}}\end{array}}$$

and

$${\displaystyle \begin{array}{l}{\displaystyle \mathrm{F}\mathrm{O}\text{-}\mathrm{R}\mathrm{P}\mathrm{A}\mathrm{B}=-100+\left(\frac{\mathrm{\alpha }\mathrm{\beta }\mathrm{o}\mathrm{c}\mathrm{c}\mathrm{i}\mathrm{p}\mathrm{i}\mathrm{t}\mathrm{a}\mathrm{l}}{\mathrm{\alpha }\mathrm{\beta }\mathrm{f}\mathrm{r}\mathrm{o}\mathrm{n}\mathrm{t}\mathrm{a}\mathrm{l}}\right)\ast 100\mathrm{i}\mathrm{f}\alpha {\beta }_{\mathrm{f}\mathrm{r}\mathrm{o}\mathrm{n}\mathrm{t}\mathrm{a}\mathrm{l}}>\alpha {\beta }_{\mathrm{o}\mathrm{c}\mathrm{c}\mathrm{i}\mathrm{p}\mathrm{i}\mathrm{t}\mathrm{a}\mathrm{l}}}\end{array}}$$

This measure compares the reduction of combined alpha (7.5–12.5 Hz) and beta (>12.5 Hz) power in 1 channel compared to the other. The Narcotrend device does not differentiate between beta and gamma power; hence, gamma waves, commonly defined as 30 Hz or more, are also integrated into the beta power. If frontal absolute alpha-beta power is reduced compared to occipital alpha power (such as occurs during wakefulness), the FO-RPAB points toward +100. In contrast, during maintenance of GA, frontal alpha-beta power is dominant compared to occipital alpha-beta activity, and the FO-RPAB values are negative (Figure 2). Narcotrend only calculates positive RPAB values with an additional reference to right or left, indicating the channel with lower alpha and beta power. To visualize the data in a clear and comprehensive way, we portrayed values ranging from 100 to −100. As an example, a value of 80 denotes the absolute alpha-beta power of the frontal channel to be 80% reduced compared to the occipital channel (wakefulness). Negative values correspond to a reduced alpha and beta power in the occipital channel compared to the frontal channel, respectively (unconsciousness). We think it is both important and conceptually stringent to understand topological changes in alpha and beta power. As there is overlap in transitions from fast to slow EEG oscillations in both anesthesia and ischemia detection, using an implemented algorithm may help to illustrate alpha anteriorization and illustrate fronto-occipital polarity in sufficiently deep anesthesia.

Figure 2.

An illustration of practical use of the FO-RPAB; the upper screen illustrates the raw EEG of the frontal EEG channel (white) and the occipital channel (yellow). The upper field in the RPAB schematic (K1) denotes the frontal brain, and the RPAB curve pointing to K2 signifies reduction of alpha and beta oscillations occipitally. Below the data of the same patient in a schematic diagram of the calculated RPAB. Blue line = awake/preanesthesia; magenta line = induction; red = perioperative steady state; black = emergence. EEG indicates electroencephalography; FO-RPAB, fronto-occipital reduced power alpha beta; GA, general anesthesia; SEF-95, spectral edge frequency 95%.

Study Outcomes

Our primary outcome was the difference in FO-RPAB during the 3 essential stages of GA.

• -Preanesthesia and awake (P; start of the recording until the timestamp “start propofol” administration),
• -Maintenance or steady state (M; 5 minutes after timestamp “start propofol” until stop of propofol administration) and
• -Emergence (E; from timestamp “stop propofol” administration until end of recording). For each patient, we computed the temporal mean of the RPAB values over each of the 3 phases.

For visual display and to compare surgeries of different durations, the preanesthesia stage was divided into 2 subphases of equal duration (P1, P2); the maintenance stage into 10 subphases (M1–M10); and the emergence stage into 4 subphases (E1–4).

As a secondary outcome, we investigated the changes in FO-RPAB after a ketamine bolus in 24 patients receiving the drug during maintenance. Therefore, we compared 2 subphases: a 10-minute period before the administration of ketamine (M_preK), and a 10-minute period after the bolus was administered (M_postK). These 2 subphases were compared with the first 5 minutes of the P stage and the last 5 minutes of the E stage. In addition to FO-RPAB values, frontal and occipital SEF-95 were compared.

Anesthetics Used

All patients received an IV induction with propofol followed by total intravenous anesthesia (TIVA) with propofol for maintenance. As part of the multimodal intravenous anesthesia approach routinely used in the ophthalmic surgery department of the Bern University Hospital, most patients additionally received an I bolus of ketamine (30/32) and dexmedetomidine (28/32), as well as magnesium sulphate (14/32%). An analgetic remifentanil infusion was only used in 5 out of the 32 patients. The most commonly used opioid administered before intubation was alfentanil (30/32), followed by low-dose fentanyl (19/32). More than half of the patients (19/32) received local anesthesia in the form of a sub-Tenon’s block, either performed by the anesthetist or by the ophthalmic surgeon (see Table 1).

Table 1.

Description Anesthetic Dosing

Variable		Median dose (IQR)
Local anesthesia (sub Tenon’s)	19 (59%)
Propofol, mg/kg/min	32 (100%)	0.14 (0.11–0.16)
Ketamine, mg	30 (94%)	50 (40–50)
Dexmedetomidine, mcg	28 (88%)	10 (8–12)
Fentanyl, mcg	19 (59%)	62.5 (50–100)
Alfentanil, mg	30 (94%)	1
Remifentanil, mcg/kg/min	5 (16%)	100 (50–150)
Magnesium sulfate, g	14 (44%)	2

Abbreviation: IQR, interquartile range.

Statistical Analysis

We used Friedman’s test to assess if the measured variables (preanesthesia, maintenance, and emergence) differed. For post hoc analysis, we used the paired Wilcoxon signed-rank test. To adjust for multiple comparisons, the Bonferroni correction was applied. A P-value of <.05 was considered statistically significant.

RESULTS

Patients’ Characteristics

The median age of the 32 patients included for analysis was 64 years (interquartile range [IQR], 49–71). Eleven patients were women (34%). The median duration of the anesthesia was 89 minutes (range, 72–116 minutes). The majority of patients (69%) were classified as ASA II (see Table 2).

Table 2.

Description of Demographic Factors

Variable
Age (y)	64 (17–90)
Sex (female)	11 (34%)
ASA I	4 (12%)
ASA II	22 (69%)
ASA III	6 (19%)
Anesthesia duration (min)	89 (72–116)

Abbreviation: ASA, American Society of Anesthesiologists.

FO-RPAB Values in Response to Propofol

In response to induction of GA, the FO-RPAB value dropped immediately in all subjects. A representative individual is shown in Figure 2, a 36-year-old male patient receiving multimodal anesthesia for VR surgery (vitrectomy, encircling band).

Median group values of all the 14 subphases are shown in Figure 3. The median (IQR) FO-RPAB values were significantly higher during the preanesthesia awake phase than during the maintenance phase (18.9 [3.7–34.1] versus –74.7 [–83.2 to –66.2]; P < .001) or in the emergence phase, respectively (18.9 [3.7–34.1] vs –35 [–48.9, –22.6]; P < .001). There were statistically significant differences between all the preanesthesia, maintenance, and emergence phases (P < .001). The differences remained significant after Bonferroni corrections (P < .001). Trajectories of FO-RPAB at an individual level are included as spaghetti plots in Supplemental Digital Content 1, Figure 1, http://links.lww.com/AA/E200.

Figure 3.

Overview of fronto-occipital RPAB and SEF95 during GA phases. These depict characteristic changes during induction, maintenance, and emergence. Contrary to frontal SEF-95, the FO RPAB integrating fronto-occipital EEG does not change after ketamine administration (see text). A, Summary plot of the temporal evolution of FO-RPAB for all patients, preanesthesia phase (P1, P2, blue), the maintenance phase (M1–M10, red), and the emergence phase (E1–E4, gray). B, Summary plot of the temporal evolution of FO-RPAB for all patients who received ketamine. Preanesthesia phase (P1, P2, blue), the maintenance phase before ketamine administration (M1, M2, red), the ketamine phase (K1, K2), the maintenance phase after ketamine administration (M5–M10), and the emergence phase (E1–E4, gray). Summary plot of SEF-95 frontal (C) and occipital (D) for all patients who received ketamine. Preanesthesia phase (P1, P2, blue), the maintenance phase before ketamine administration (M1, M2, red), the ketamine phase (K1, K2), the maintenance phase after ketamine administration (M5–M10), and the emergence phase (E1–E4, gray). FO-RPAB indicates fronto-occipital RPAB; GA, general anesthesia; SEF-95, spectral edge frequency 95%.

Figure 3A is a summary plot of the temporal evolution of FO-RPAB for all patients, preanesthesia phase (P1, P2, blue), the maintenance phase (M1–M10, red), and the emergence phase (E1–4, gray). The boxplots show median, IQR, and 95% confidence interval of patients’ FO-RPAB value distribution. A clear drop in FO-RPAB is seen immediately after the start of propofol, whereas the FO-RPAB increases gradually after stopping the TIVA (ie, over the later emergence period).

Robustness of FO-RPAB to Ketamine

All the median group values of RPAB and SEF-95 are shown in Figure 3B–D. Consistent with our hypothesis, frontal SEF-95 shifted to significantly higher values after administration of ketamine during propofol anesthesia, while FO-RPAB remained more stable. This is demonstrated visually in a vector plot in Figure 4, where it can be seen that frontal SEF-95 changes substantially after a bolus of ketamine while the RPAB does not. Our sample estimate of the direction of change shows a mean angle of 1.9° (95% CI, −32° to 28.1°).

Figure 4.

Vector plot of averaged frontal SEF-95 values over averaged FO-RPAB values for time windows “preketamine” and “postketamine.” The arrows’ steepness reflects SEF-95’s tendency to stronger reflect frontal beta oscillation after ketamine administration than FO-RPAB. FO-RPAB indicates fronto-occipital RPAB; SEF-95, spectral edge frequency 95%.

DISCUSSION

We used the RPAB from the Narcotrend monitor between frontal and occipital derivations as a parameter to estimate anesthetic hypnotic state during GA. The FO-RPAB showed a marked decrease to strongly negative values, with loss of consciousness (LOC) after induction of anesthesia with propofol, indicative of reduced occipital alpha power. Median group values turned positive again during the emergence period. Additionally, the FO-RPAB value remained stable in response to a bolus of ketamine, whereas the frontal SEF-95 showed a significant increase in frequency.

We chose SEF-95 as a comparison because it is easily understandable as the upper cutoff frequency under which 95% of spectral power lies. Additionally, the SEF-95 is displayed on the majority of commonly used anesthesia monitors and can also be accurately calculated from the raw EEG, meaning that it can serve as an independent comparator in the literature. Practically, an SEF-95 of 10 to 12 Hz likely represents adequate anesthesia, indicating alpha oscillation presumably underscored by prominent delta and slow waves.¹³ In contrast, a low SEF-95 between 2 and 6 Hz likely represents a delta-dominated EEG as during hypothermy and cardiopulmonary bypass.¹⁴

During preanesthesia, we often observed a wide range of FO-RPAB values in the recording. We interpreted this to be caused by movement with the patient still awake. Adjustments of occipital electrodes often took a few minutes until satisfactory conduction had been established. Noticeably, SEF-95 during preanesthesia is significantly lower than during GA. Evaluating the EEG of each patient separately, it became evident that the percentage of delta power in the wake condition is abnormally high, up to 70%. We interpreted this to be due to artifacts created by eye movement and blinking, which unfortunately cannot be purged retrospectively.

The anteriorization of alpha oscillations during induction of GA has been repeatedly demonstrated,^5,8,15 but to date, it has never been used as a confirmative measure of LOC in everyday clinical practice. The significant decrease in median FO-RPAB value during maintenance anesthesia as compared to the awake state suggests that this approach is sensitive to onset of anesthesia with LOC. To what degree FO-RPAB is influenced by the increase in the frequency of the alpha oscillation during emergence, a proposed marker of decreasing hyperpolarization, is not known.¹⁶

Processed EEG indices are known to react with delay to altered raw-EEG patterns, complicating the detection of arousal.¹⁷ The administration of ketamine, often used as a component of multimodal GA, increases values wrongly suggesting light sedation or wakefulness due to increased cortical activity in the beta and gamma (>30 Hz) frequency bands.¹¹ Another limitation of proprietary indices is their sole use of frontal derivations. By doing so, the potentially relevant information of occipital brain regions is missed.

In our study, administration of ketamine did not lead to significant changes in median RPAB values, unlike frontal spectral edge frequency values, which did increase. The occipital SEF value also remained unchanged, which suggests that ketamine may have a minimal effect in occipital regions, supporting the use of EEG recorded from this area.

This study has several limitations. First, we performed a retrospective analysis of previously collected data from a clinically heterogeneous group of patients whose anesthetic protocols were not controlled, so there is an uncertain degree of selection bias. As this is a hypothesis-forming study, we applied FO-RPAB to different anesthesia protocols, reflecting the wide variety of multimodal anesthesia. The common aim in all protocols was to reduce opioid administration. In this study, we did not compare performance of the FO-RPAB with Narcotrend index values, as the latter was not designed and calibrated for a frontal-occipital montage and may not be accurate. Further study is needed to determine whether FO-RPAB reacts faster to arousal or is as susceptible to artifacts as the Narcotrend index or BIS.

Our results also need to be interpreted with caution regarding montage. Although we named the described method “fronto-occipital RPAB (FO-RPAB),” a more accurate name might be “fronto-parieto-occipital,” as electrode 2a was placed on the left mastoid (M1), which was chosen merely for practical reasons. Mounting a 5-electrode EEG with 2 occipital electrodes at the back of the head in dense hair is challenging given the high turnover of ophthalmic anesthesia. The left mastoid (M1) is easily accessible, and asking the patient to lift his head for a protracted period to place a second occipital EEG electrode is not warranted.

Choosing a more neurophysiological basis for perioperative EEG monitoring has repeatedly been suggested, as too many inconsistencies have surfaced in dosing anesthesia using processed EEG indices alone.¹⁸ We need to find physiological variables to perform consistently in the face of confounding factors or artifacts. Reliable reflection of neurophysiology is key for anesthetists to rely on. FO-RPAB could prove to be such a variable.

It remains to be seen how FO-RPAB performs together with other physiological EEG signals that have received only limited attention in the past. The most eminent example is anesthesia spindles.¹⁶ These are easy to teach and observe in perioperative EEGs, and their quantity has been related to important end points after anesthesia: postoperative delirium¹⁹ and perioperative pain.²⁰ FO-RPAB could be studied in the future together with the physiological raw EEG signals unfolding in the frontal brain. This way, a fundamental topographical physiological factor like alpha anteriorization would add information to classify frontal anesthesia phases in “spindle-rich,” “delta-rich,” or “beta-enhanced” general anesthesia.

We believe that FO-RPAB has the potential to contribute important information for practicing anesthetists through integration of occipital cortical activity. Given the physiological significance of occipital alpha during induction and arousal, EEG data from this region might better signal impending arousal from anesthesia. During wakefulness, occipital and frontal regions generate spontaneous alpha rhythms independently.²¹ Significant BIS value differences were shown during induction and maintenance with frontal and occipital sensor placement.²² By the same token, FO-RPAB might help improve EEG-based guidance through anesthesia maintenance. Visualization of an easily comprehensible measure, itself based on clear physiological processes, may have an advantage over proprietary processed EEG indices, and their limited specificity and sensitivity.

CONCLUSIONS

In this retrospective study, we show how FO-RPAB, a computed single-numbered index, shows statistically significant changes in awake and anesthetized patients. In contrast to frontal SEF-95, it is not disturbed by additional administration of ketamine for analgesia. FO-RPAB could thus be a beneficial marker of unconsciousness.

DISCLOSURES

Name: Eloy S. Fehrlin, MD.

Contribution: This author helped analyze and extract the data, write the manuscript, and design the figures with support from Friedrich Lersch.

Name: Darren Hight, PhD.

Contribution: This author contributed to the design and implementation of the research and provided essential support in writing the paper.

Name: Heiko A. Kaiser, MD.

Contribution: This author provided critical feedback and helped shape the research, analysis, and manuscript.

Name: Markus M. Luedi, MD, MBA.

Contribution: This author provided critical feedback and helped shape the research, analysis, and manuscript.

Name: Markus Huber, PhD.

Contribution: This author verified the analytical methods and provided assistant with statistics.

Name: Frédéric Zubler, MD, PhD.

Contribution: This author provided critical feedback and helped shape the research, analysis, and manuscript.

Name: Friedrich Lersch, MD, MSc.

Contribution: This author conceived the study, took anesthesiologic care of the patients, informed and consented the patients, and cowrite the manuscript.

This manuscript was handled by: Oluwaseun Johnson-Akeju, MD, MMSc.