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Anesth Analg
Anesth Analg
ANE
Anesthesia and Analgesia
0003-2999
1526-7598
Lippincott Williams & Wilkins Hagerstown, MD

39028663
AA-D-24-00114
00017
10.1213/ANE.0000000000007132
3
54
Original Research Articles
Original Clinical Research Report
End-Tidal Control Versus Manual Control of Inhalational Anesthesia Delivery: A Randomized Controlled Noninferiority Trial
McCabe Melissa D. MD, FASA, MSCR *
Dear Guy de L. MB, FRCA †
Klopman Matthew A. MD, FASA, FASE ‡
Garg Kritika MS §
Seering Melinda S. MD, FASA, MHCDS ‖
From the * Department of Anesthesiology, Loma Linda University School of Medicine, Loma Linda, California
† Department of Anesthesiology and Pediatrics, Duke University Medical Center, Durham, North Carolina
‡ Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia
§ Biostatistics Division of Clinical Operations Department, GE HealthCare, Chicago, Illinois
‖ Department of Anesthesiology, Roy and Lucille Carver College of Medicine, University of Iowa Health Care, Iowa City, Iowa.
Address correspondence to Melissa D. McCabe, MD, FASA, MSCR, Department of Anesthesiology, Loma Linda University, 11234 Anderson St MC 2352, Loma Linda, CA 92354. Address e-mail to mmccabe@llu.edu.
19 7 2024
10 2024
139 4 812820
14 6 2024
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Anesthesia Research Society.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

BACKGROUND:

Precise anesthesia delivery helps ensure amnesia, analgesia, and immobility. Conventionally, the end-tidal anesthetic concentration is maintained through manual adjustment of the fresh gas flow and anesthetic vaporizer output. Some anesthesia delivery systems can deliver and maintain clinician-selected end-tidal anesthetic agent (EtAA) concentration using a modified closed-loop system. We evaluated the performance of an End-tidal Control (EtC) system on the Aisys CS2 anesthesia machine (GE HealthCare). We hypothesized EtC anesthetic delivery would be noninferior to manually controlled anesthetic delivery.

METHODS:

The Multi-site Anesthesia randomized controlled STudy of End-tidal control compared to conventional Results (MASTER) Trial evaluated anesthetic delivery in 210 adult patients receiving inhaled anesthesia. Patients were randomized to either EtC or manual control (MC) anesthetic delivery. The primary objective was to determine whether, compared to conventional anesthesia practice, EtC achieves and maintains clinician-specified EtAA and end-tidal oxygen (Eto2) concentrations within defined noninferiority limits. Noninferiority was concluded if the lower limit of the 95% confidence interval (CI) of the difference between the percent duration within the acceptable range (5% of steady state or a margin of ~10% of each agent’s minimum alveolar concentration) for EtC and MC was ≥ −5% for both EtAA and Eto2. Secondary objectives included performance measures: response time: time required to attain 90% of the first desired EtAA, overshoot: amount the controller (or vaporizer delivery) exceeded the desired EtAA, and accuracy: average deviation from the desired EtAA.

RESULTS:

EtC achieved and sustained targeted EtAA and Eto2 concentrations within the noninferiority threshold. The EtAA was within 5% of the desired value 98% ± 2.05% of the time with EtC compared to 45.7% ± 31.7% of the time with MC (difference 52.3% [95% CI, 45.9%–58.6%], P < .0001). For Eto2, EtC was within the noninferiority limit 86.3% ± 22.8% of the time compared with MC at 41% ± 33.3% (P < .0001, difference 45.3% [95% CI, 36.1%–54.5%]). The median response time for achieving 90% of the initial EtAA desired value was 75 seconds with EtC and 158 seconds with MC (P = .0013). EtC exhibited a median overshoot of 6.64% of the selected EtAA concentration, whereas MC often failed to reach the clinician’s desired value. The difference in median percent deviation from desired EtAA value was 15.7% ([95% CI, 13.5%–19.0%], P < 0001).

CONCLUSIONS:

EtC achieves and maintains the EtAA and Eto2 concentration in a manner that is noninferior to manually controlled anesthesia delivery.

OPEN-ACCESSTRUE
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pmc KEY POINTS

Question: Can an end-tidal-controlled anesthesia delivery system achieve and maintain a desired anesthesia concentration?

Findings: The end-tidal-controlled anesthesia delivery system achieves and maintains a desired anesthetic concentration.

Meaning: End-tidal-controlled anesthesia delivery is a viable alternative to conventional, manually titrated anesthesia delivery.

Anesthesia delivery demands precise fulfillment of amnesia, analgesia, and immobility. Among the approaches to anesthesia delivery, inhalational anesthetics are widely used. In the United States, anesthesia machines allow manual adjustment of fresh gas flow (FGF) and anesthetic vaporizer settings to deliver anesthetic agent and oxygen, air, and N2O.1,2 Constant vigilance and monitoring are necessary to ensure sufficient delivery of oxygen and maintenance of the clinically indicated end-tidal anesthetic agent (EtAA) concentration. Although there is interindividual variability in the relationship between EtAA and anesthesia depth, EtAA concentration remains a useful measure of anesthesia delivery.3–6 Anesthetic delivery systems have progressed and control of FGF and the concentration of anesthetic agent delivered from the vaporizer can be semiautomated, which has been shown to improve the accuracy of anesthetic agent delivery.7

The End-tidal Control (EtC) system consists of hardware and software compatible with the Aisys CS2 anesthesia machine (GE HealthCare). EtC replaces manual manipulation of FGF and vaporizer settings with software-controlled titration of the delivered anesthetic concentration to achieve and maintain the EtAA concentration selected by the clinician. A target end-tidal oxygen (Eto2) concentration can also be selected and maintained through repeated end-tidal gas measurements and FGF adjustments by the controller. The controller samples expired gas and titrate anesthesia delivery to achieve and maintain the EtAA concentration selected by the anesthesiologist.

We present the primary results of the MASTER Trial (Multi-site Anesthesia randomized controlled Study of End-tidal control compared to conventional Results), which evaluated the performance of EtC for the delivery of anesthetic agents to patients in the United States. The Primary objective was to determine whether EtC achieves and maintains targeted EtAA and Eto2 concentrations in a manner that is noninferior (within 5% of steady state or a margin of ~10% of each agent’s minimum alveolar concentration) to conventional anesthesia practice. Secondary objectives include assessments of performance measured by response time: the time required to achieve 90% of the clinician’s first desired EtAA, overshoot: the amount the controller (or vaporizer delivery) exceeded the clinician’s desired EtAA, and accuracy: the average deviation from the clinician’s desired EtAA. The amount of inhaled anesthetic agent used with EtC was also compared to manual control (MC). We hypothesized that EtC anesthetic delivery would be noninferior to conventional, manually titrated anesthetic delivery with comparable measures of performance while utilizing a less volatile agent.

METHODS

The MASTER trial (ClinicalTrials.gov Identifier: NCT02972892) was conducted at 4 sites in the United States: Duke University, Emory University, the University of Iowa, and Loma Linda University. Institutional Review Board approval was obtained from Duke University, Emory University, the University of Iowa, and Loma Linda University. Multiple sites were selected to provide a broad cross-section of the population and clinical practice paradigms; 18 clinicians participated. At each site, attending faculty anesthesiologists, nurse anesthetists, anesthesiologist assistants, and investigators (and their designees) underwent training on the use of EtC. Clinicians only received education about the use, not the potential benefits of EtC. All clinicians were encouraged to conduct anesthesia delivery per their usual practice. The study was conducted from June 2017 to September 2018. This trial was funded by GE HealthCare.

Adult male and female subjects aged 18 years or older and scheduled for surgical procedures with general inhaled anesthesia were screened for enrollment in the preoperative clinic or during the preoperative evaluation at each institution. Enrollment was performed by the investigator or designee. Screening and recruitment were conducted in compliance with applicable laws, regulations, and standard enrollment procedures at the sites. All subjects gave written informed consent. Female subjects of childbearing potential underwent a serum or urine pregnancy test before randomization.

Patients scheduled to undergo general inhalational anesthesia with a secured airway who could be safely exposed to 100% oxygen for up to 2 minutes during anesthesia were included. Only a single volatile anesthetic agent could be used for each case. Scheduled surgical procedure length was greater than or equal to 60 minutes. All patients were American Society of Anesthesiologists physical status (ASA-PS) classification system I through III. Emergency surgical procedures, female subjects who were pregnant or lactating, and any subject undergoing cardiac bypass surgery or open chest surgery were excluded.

Subjects were randomized centrally by the primary investigational site (University of Iowa) in a 1:1 ratio to either the investigational EtC arm or the MC arm. Randomization sequences were administered by a computer program, the Interactive Response Technology by Almac (Almac Group). After randomization, preoperative data collection included demographics, medical history, surgical history, medications, baseline vital signs, physical examination, and surgical procedure. All subjects were induced using intravenous agents, the airway was secured based on each investigator’s conventional practice, and mechanical ventilation was initiated. Administration of muscle relaxants, narcotics, nonnarcotic analgesics, vasoactive medications, and antiemetics was not restricted.

In the MC arm, clinicians used the Aisys CS2 anesthesia machine (GE HealthCare) to manually adjust FGF and anesthetic vaporizer settings. All clinicians in the MC arm were reminded to adjust the FGF and vaporizer as per their standard practice. Manual titration was guided by the inspired and expired anesthesia and gas concentrations as measured by the onboard gas analyzer and displayed on the Aisys CS2 interface. With every vaporizer adjustment, study personnel asked the clinician to state the desired EtAA and Eto2 concentrations and recorded the desired concentrations in real time.

For patients assigned to the EtC arm, EtC was initiated using the EtC software on the Aisys CS2 interface. EtC consists of hardware and software (Figure 1). The EtC respiratory gas module has an additional fresh gas valve for calibration sampling. The EtAA and Eto2 concentrations are measured and reported to the controller with each breath.7–10 The Aisys CS2 user interface displays the selected EtAA and Eto2 concentrations in addition to the inspired and expired gas concentration measured by the onboard gas analyzer (Figure 1). The EtC software and hardware automatically adjust the anesthetic vaporizer and FGF to meet the clinician-selected EtAA and Eto2 concentrations. The default minimum FGF in the EtC arm was 2 L/min for sevoflurane and 0.5 L/min for desflurane and isoflurane. It was not possible to blind clinicians as the EtC interface was only visible and functional in the EtC arm. Machine log data was extracted after each case, via the Aisys CS2 universal serial bus. Data collection was initiated when “start case” was selected and terminated when the “end case” event was selected on the Aisys CS.2 In the EtC arm, the machine log stored the clinician’s selected EtAA and Eto2.

Figure 1. End-tidal control hardware and user interface. End-tidal control is available with- the E-sCAiOE and E-sCAiOVE models of the CARESCAPE respiratory module (GE HealthCare), outlined in red. End-tidal Control is activated on the user interface by selecting End-tidal Control (white arrow). End-tidal oxygen and volatile anesthetic concentrations are also set on the user interface (yellow arrows). E-sCAiOE indicates E-s = single width gas module, C = carbon dioxide, Ai = anesthetic agent, O = oxygen, E = end tidal control; E-sCAiOVE, E-s = single width gas module, C = carbon dioxide, Ai = anesthetic agent, O = oxygen, V = patient spirometry, E = end tidal control.

The primary objective was to determine whether, compared to conventional anesthesia practice, EtC achieves and maintains clinician-specified EtAA and Eto2 concentrations within defined noninferiority limits in an adult surgical population. For this study, acceptable performance was defined as maintaining EtAA and Eto2 concentrations within a 5% margin. The limit of deviation to conclude noninferiority for EtAA was defined as a threshold exceeding either a 5% departure from the steady-state inhaled anesthetic agent concentration or a margin of 0.6% volume per volume (v/v) for desflurane, 0.2% v/v for sevoflurane, or 0.1% v/v for isoflurane (approximately 10% of each agent’s minimum alveolar concentration). EtAA and Eto2 were analyzed independently as coprimary end points. Performance was measured by the percentage duration without >5% deviation of EtAA and Eto2 from the clinician’s desired values during steady state. In the EtC arm, the clinician’s desired values were defined by the EtAA and Eto2 selected on the EtC system user interface and recorded in the anesthesia machine database. In the MC arm, the clinician’s desired EtAA and Eto2 were manually recorded in real time when vaporizer settings or FGF rates were changed. The percent duration of deviation is the weighted average of all steady states for a subject using the duration of steady state as the weight, and is expressed as follows:

PercentDuration=∑i∑jtijIij∑jTj×100%

where tij is the ith duration of EtAA concentration maintained within the acceptable limit during the jth steady state,

Tj is the total duration of the jth steady state, and

Iij is an indicator for whether EtAA was maintained within the acceptable limit of ith duration in jth steady state, which is given as follows:

I={1ifDesfluraneandΔEtAA≤max(0.6%,5%XsteadystateEtAA)ifSevofluraneandΔEtAA≤max(0.2%,5%XsteadystateEtAA)ifIsofluraneandΔEtAA≤max(0.1%,5%XsteadystateEtAA)0otherwise 

where ∆EtAA is the absolute difference between measured EtAA concentrations and steady-state EtAA concentrations.

Similarly, for Eto2, the percent duration of deviation is the weighted average of all steady states for a subject using the duration of steady state as the weight. The limit of deviation for Eto2 was defined as 5% v/v.

Secondary objectives were assessments of performance were measured by (1) response time: the time to reach 90% of the first desired EtAA concentration after intubation, (2) overshoot: the amount the output of the controller (or vaporizer delivery) exceeded the desired EtAA concentration, and (3) accuracy: the average percent deviation from clinician’s desired value.

Tertiary objectives included calculation of the amount of each inhaled anesthetic agent used with EtC as compared to MC.

Statistical Analysis

The power for each of the end points in the primary objective was set to 0.95 for an overall power of 0.9 for the study. The alpha was set at 0.025 1-sided, to conclude noninferiority, both null hypotheses must be rejected, therefore multiplicity adjustment was not needed.11 The sample size was calculated from the results of a feasibility study (unpublished data from GE HealthCare) comparing the steady-state concentration of EtAA and Eto2 between the EtC and MC arms. The feasibility study assessed the weighted average of the percent duration EtAA and Eto2 were maintained within the limits of deviation (as defined above). The difference between Et Control and manually controlled anesthesia delivery was assumed to be 50% less than observed in the tightly controlled feasibility study. The largest observed standard deviation (19%) was used to calculate the sample size using the 2-sample t test method. The larger sample size calculated for EtAA and Eto2 was selected as the size of the study and adjusted to account for a 15% dropout rate. The calculated sample size was 124 per arm.

The primary and secondary end points calculated in this study were summarized using descriptive statistics. For continuous variables, mean and standard deviation (or median and interquartile range) are reported. Categorical variables were summarized using frequency and percentages. When crossover occurred, data was analyzed per protocol. For comparison between the 2 arms, categorical variables were tested using appropriate contingency table analyses (Fisher exact or χ2 approximations). The distribution of continuous variables was assessed with the Shapiro-Wilk test and compared using t test or Wilcoxon rank sum test, depending on variable distribution. The Hodges Lehmann estimator for the difference and 95% 2-sided confidence interval (CI) was used for nonparametric variables. Noninferiority was concluded, if the lower limit of the 95% CI of the difference in percent duration within the limits of deviation between EtC and MC was ≥−5% for both EtAA and Eto2. Both null hypotheses had to be rejected for EtAA and Eto2 to conclude noninferiority, mitigating the need to correct for multiple comparisons. If EtC were deemed noninferior, superiority was assessed. EtC was considered superior if the lower limit of the 95% CI of the difference between EtC and MC was >0 for EtAA and the lower limit of the 95% CI of the difference between EtC and MC for Eto2 was ≥−5%. Superiority was only tested after noninferiority of both primary end points was concluded. Both EtAA and Eto2 had to meet these tests to conclude superiority. This sequential or hierarchical testing approach does not inflate the type 1 error and mitigates the need for multiplicity adjustment.

Analysis of primary end points used the clinician’s desired EtAA and Eto2 concentration as recorded in the MC arm or machine log for the EtC arm. The percent duration of EtAA and Eto2 maintenance within the acceptable range was calculated for each steady state. Steady state was defined as any period exceeding 2 minutes where the EtAA rate of change was less than 0.2% per minute. The per subject weighted average of the percent duration was calculated for each subject using the duration of each steady state as the weight. Using t test, comparison of the weighted average percent duration between the EtC and MC arms was performed by calculating the difference and its 95% 2-sided CI between the 2 arms. If the lower limit of the 95% CI was within a 5% margin for both EtAA and Eto2 then EtC was deemed noninferior to MC.

Response time was evaluated for the first desired EtAA and Eto2 concentration and compared between EtC and MC using the Wilcoxon rank sum test. Response times for changes after the first steady-state period were not evaluated. Overshoot was only evaluated when the clinician’s desired EtAA concentration was selected, and not altered, for at least 2 minutes and the EtAA concentration achieved a steady state. Overshoot was summarized with descriptive statistics. To assess the accuracy of EtC in maintaining the desired EtAA and Eto2 concentration for each steady state, mean percent difference between measured end-tidal and the desired value was calculated. The mean percent difference of all steady states was compared between the EtC arm and the MC arm using the Wilcoxon rank sum test.

Additionally, the agent usage rate (mL/h) from induction to patient disconnect was calculated for each agent (desflurane, isoflurane, and sevoflurane). The rate of use was compared between the 2 arms for each agent separately. The statistical analysis presented herein was designed and directed by the authors and performed by a GE HealthCare statistician (K.G.). All data visualization was done using GraphPad Prism 10.0.0 for Windows (GraphPad Software) or R Studio 2022.07.1 (Posit) and calculations were done using SAS 9.4 (SAS Institute).

RESULTS

Two hundred and forty-eight patients were enrolled in the study. After 20 patients failed screening questionnaires on the day of service, 228 were randomized. After randomization, 8 withdrew before any surgical procedure because the anesthetic plan was changed from general anesthesia to sedation (n = 4), an Aisys CS2 machine with EtC software was unavailable (n = 3), or a study-trained anesthesia provider was unavailable (n = 1). There was one crossover from EtC into the MC arm; however, the patient was withdrawn from the study because the clinician’s desired EtAA and Eto2 concentration were not recorded, and steady state was not achieved. A total of 10 patients were withdrawn after study completion because the breath logs were inadvertently deleted (n = 3) or the EtAA or Eto2 concentration failed to reach steady state (n = 7). The analyzed population was comprised of 210 subjects (Figure 2) and included all randomized subjects with at least 45 minutes of inhalation anesthesia data collected during the procedure. Demographics are shown in the Table.

Table. Demographics of the Study Completion Population

	Manual control
(n = 112)	End-tidal control
(n = 98)	P value	
Sex
 Female
 Male	58 (51.8%)
54 (48.2%)	45 (45.9%)
53 (54%)	.3961	
Age in years
(median, IQR)	51 (39.5–63)	51 (36–60)	.2426	
Body mass index
(median, IQR)	29.1 (24.5–34.8)	28.7 (24.4–33.3)	.3650	
ASA-PS
 I
 II
 III	15 (13.4%)
53 (47.3%)
44 (39.3%)	18 (18.4%)
50 (51%)
30 (30.6%)	.3526	
Race
 Black
 White	19 (17%)
78 (69.6%)	18 (18.4%)
70 (71.4%)	.9249	
Ethnicity
 Hispanic
 Not Hispanic/Latino	11 (9.8%)
101 (90.2%)	9 (9.2%)
89 (90.8%)	.8752	
Abbreviations: ASA-PS, American Society of Anesthesiologists physical status; IQR, interquartile range.

Figure 2. CONSORT diagram. CONSORT indicates Consolidated Standards of Reporting Trials.

This study included general surgery, gynecologic, orthopedic, and otolaryngology cases. The length of surgery was comparable for each arm; the median duration was 103 (50–157) minutes versus 94.5 (58–151) minutes for MC and EtC, respectively (P = .361). Desflurane was used in 17% of cases in the MC arm, and in 27.5% in the EtC arm. Isoflurane was chosen for 13.4% of MC cases compared to 16.3% of EtC cases, and sevoflurane was used for 69.6% versus 56.1% of MC and EtC cases, respectively. None of these differences were significant. The median estimated blood loss was 25 (5–75) mL in the MC arm and 25 (5–50) mL in the EtC arm (P = .492).

The percentage of time that the EtAA was within the noninferiority limit with EtC was 98% ± 2.05% (Figure 3A) and with MC was 45.7 ± 31.7 % (Figure 3B; P < .0001, difference 52.3% [95% CI, 45.9%–58.6%]). For Eto2, EtC was within the noninferiority limit 86.3% ± 22.8% of the time compared with MC at 41% ± 33.3% (P < .0001, difference 45.3% [95% CI, 36.1%–54.5%]). The response time was significantly shorter with EtC than MC (Figure 4). The median response time for the initial desired EtAA concentration was 75 (35–144) seconds for EtC and 158 (41–402) seconds for MC (P = .0013, difference 62 [95% CI, 20–128] seconds; Figure 4). For the 32 subjects that met the criteria for evaluation of overshoot in the EtC arm, the median overshoot was 6.64% (4.9–9.42) of the selected EtAA concentration. The median overshoot in the MC arm was 0% (0–14.3) because the EtAA failed to reach the clinician’s desired value for most subjects. The median percent deviation from clinician’s desired EtAA value was 1.68% (1.29–2.42) for EtC and 17.6% (11.2–28.5) for MC (P < .0001, difference 15.7 [95% CI, 13.5–19.0]). For Eto2, deviation was 1.63% (1.18–2.69) in the EtC arm and 16% (7.2–28.4) for MC (P < .0001, difference 13.7 [95% CI, 10.5–18.9]).

Figure 3. Comparison of performance between End-tidal Control and manual control. A, Representative case from the End-tidal Control arm using desflurane. The solid black line represents the user-selected anesthetic concentration and the fraction of inspired anesthetic agent is shown in blue. The controller response is seen in gray. EtAA concentration is shown in red, during steady state the end-tidal anesthetic concentration consistently overlays the user-selected anesthetic concentration. B, Representative case from the manual control arm using desflurane. The clinician’s desired EtAA concentration is shown in black. The duration of time required for the fraction of inspired anesthetic agent (blue) and end-tidal concentration (red) to achieve a steady state. EtAA indicates end-tidal anesthetic agent.

Figure 4. Response time. The median response time required to achieve 90% of the clinicians’ first desired end-tidal anesthetic agent concentration after endotracheal intubation is shown for End-tidal Control and for manual control. *The 9 outlier response times >1000 s for manual control are not shown in this graphic (range: 0.6–2168 s).

Inhalational anesthetic agent use was less with EtC than MC. With EtC, isoflurane use was reduced 34% (P < .001), and desflurane use decreased 31% (P = .025). Sevoflurane use decreased 4% with EtC; however, this reduction was not significant (Figure 5). Fresh gas flow rates were at the clinician’s discretion and were not restricted to low flow in the MC group.

Figure 5. Comparison of anesthetic agent use with End-tidal and manual control. The mean volatile inhalational agent usage with End-tidal Control versus manually controlled inhalational anesthetic delivery is shown. The error bars represent the standard deviation.

Deactivation of EtC was both infrequent and of short duration. Specifically, EtC was deactivated during vaporizer refill (n = 3) and when recalibrating/reinstalling the respiratory gas module (n = 3). Additionally, EtC was deactivated when the target EtAA was rapidly decreased at the end of the case (n = 4). As intended, the EtC system deactivated when the system controller detected a higher-than-expected EtAA for 3 breaths (n = 4) or when the EtC system check detected a lower-than-expected EtAA value when switching to bag mode with EtC running (n = 1).

Seven critical protocol deviations were identified which included anesthesia staff who participated in study procedures without recorded EtC training (n = 4) and in the MC arm, the desired EtAA/Eto2 concentration was not recorded in 3 cases. Protocol deviations were reviewed by the Data and Safety Monitoring Board and were determined not to impact subject safety.

DISCUSSION

Performance of EtC was found to be noninferior to conventional anesthesia delivery, achieving and maintaining selected concentrations of EtAA and Eto2 within the limits of deviation across the entire range of concentrations. When compared to MC, the desired EtAA concentration was achieved significantly faster with EtC. The EtC system differs from conventional MC by constantly adapting FGF and agent delivery to precisely attain the targeted EtAA concentration. During the initial titration phase, response time was significantly faster for EtC. When the selected EtAA concentration was reached, EtC maintained the steady-state concentration within 98% of the set value for sevoflurane, desflurane, and isoflurane; comparable results were shown for oxygen. Comparatively, steady-state deviation in EtAA concentration with MC was more than 15%.

GE’s EtC system was introduced to the European market in 2010 for use with the Aisys CS2 anesthesia machine. EtC software automatically adjusts vaporizer delivery and FGF based on selected EtAA and Eto2 concentration. Like conventional anesthesia delivery systems, the maximum concentration of volatile anesthetic delivered by the EtC system varies by agent: 8% for sevoflurane, 18% for desflurane, and 5% for isoflurane. FGF may range from 0.3 to 10 L/min. During the initial titration phase, the vaporizer output of volatile anesthetic agent is maximized before the FGF is increased to limit volatile agent use. The typical FGF rate during initial titration is 2 to 6 L/min. Once the desired EtAA concentration is reached, the controller prioritizes reduction of FGF to a basal rate of 0.5 L/min (2 L/min for sevoflurane in our study) approximately 1 minute after the desired EtAA is achieved. Volatile agent delivery is only decreased after FGF has been reduced to the basal rate. Subsequent titration of the desired EtAA maintains the same general principles, volatile anesthetic concentration is altered before any change in the FGF rate. Outside of the United States, EtC has been shown to deliver inhaled anesthetics with greater accuracy and with fewer manual interactions with the anesthesia machine.7,9,10 The intrinsic response time for Eto2 concentration changes was designed to be slower than EtAA concentration changes to provide a margin of safety. EtC helps prevent delivery of hypoxic gas mixtures and provides tight control of Eto2. Setting a desired Eto2 concentration provides a secondary protective mechanism to the standard primary fresh gas hypoxic mixture guard. In the EtC mode, fresh gas is sampled every 3 minutes, to prevent delivery of a gas mixture that could result in an Eto2 concentration less than 25%. Eto2 control may be particularly useful for maintaining a safe oxygen concentration when using electrosurgery or laser therapy in or near the airway.12–14

In prior studies, EtC was shown to reduce volatile anesthetic consumption and environmental pollution.8,15 In this study, isoflurane and desflurane consumption were significantly reduced with EtC. The default basal FGF was increased for sevoflurane due to a Food and Drug Administration black box warning regarding compound A formation, although the authors recognize this concern is mitigated with suitable absorbents. Importantly, the basal FGF rate can be altered by the clinician for any individual case but was not during this study.

Limitations and Safety Considerations

This study was performed with ASA-PS I to III subjects in a range of hospital settings, but we did not examine performance of EtC in many cases with a duration of >3 hours, significant blood loss, or in patients with comorbidities warranting ASA-PS IV to V classification. The wide variety of cases performed in this study suggests results of this study are generalizable to a wider population. The ease of provider training and provider comfort with device use were not evaluated. The experience level of the provider dictating the desired EtAA concentration was not recorded and results were not stratified by experience level. Constraints related to system cost and availability were not assessed but remain an important consideration in the evaluation of new technology. Moreover, it is feasible the anesthesiologists in this study altered their practice to allow the “machine to win.” However, the anesthesiologists were not informed about assessment of performance metrics, therefore it is unlikely that participation may have influenced their practice.

There were no safety concerns identified with the use of EtC. Even when the EtC system is installed and in use, the clinician can revert to conventional manual anesthesia/fresh gas delivery mode at any time by selecting “End-tidal Control” and pressing “stop” on the user interface. Under specific circumstances, the EtC control software includes safety features that temporarily revert the system to conventional delivery. The system automatically deactivates EtC if it detects issues such as software malfunction or gas module calibration errors. In 3 patients, the fresh gas module was not connected when the user attempted EtC initiation. After the fresh gas module was connected, EtC functioned normally. If EtC is deactivated, the user is returned to conventional manual anesthesia delivery. Importantly, EtC does not set or adjust ventilator parameters.

Ultimately, anesthesiologists play a crucial role in ensuring the safety and well-being of patients during surgery. The primary goal of anesthesia is to achieve both amnesia and analgesia while maintaining the patient’s physiologic stability. Anesthetic depth, a critical aspect of anesthesia, requires vigilant monitoring and adjustment. The EtAA concentration is 1 estimate of anesthetic delivery.3,16 Traditionally, anesthesia vaporizer delivery is manually adjusted to achieve and sustain a desired EtAA concentration. With the EtC system, the selected EtAA and Eto2 concentrations can be achieved and sustained through automated control of delivery and an internal feedback control system.17 This study demonstrates EtC effectively achieves and maintains desired EtAA and Eto2 concentration, in a manner that is noninferior to conventional anesthesia practice.

CONCLUSIONS

EtC was noninferior compared to conventional manually titrated anesthesia delivery. These results suggest EtC may increase the accuracy of volatile agent delivery through enhanced responsiveness and reduced deviation from the desired concentration. EtC lowered the consumption of isoflurane and desflurane which may decrease the environmental impact of anesthesia. Our findings of the EtC system performance may suggest broader clinical application of EtC is feasible.

ACKNOWLEDGMENTS

The authors thank their respective institutions for supporting this work and Dr Richard Applegate for his valuable mentorship.

DISCLOSURES

Conflicts of Interest: G. L. Dear received lecture fees from GE HealthCare and these funds were subsequently shared with M.M. and M.S. K. Garg is employed by GE HealthCare. Statistical analysis was performed under the direction of the authors by a GE HealthCare statistician (K.G.). No other authors declared Conflicts of Interest. Funding: This research received funding from GE HealthCare. This manuscript was handled by: Christina M. Pabelick, MD.

Reprints will not be available from the authors.

Conflicts of Interest, Funding: Please see DISCLOSURES at the end of this article.

Prior presentations: American Society of Anesthesiologists Annual Meeting, New Orleans, LA, October 22, 2022.

ClinicalTrials.gov Identifier: NCT02972892, date of registration: November 11, 2016, principal investigator: M. Seering.
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