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Technology, Computing, and Simulation: Original Clinical Research Report

Feasibility of Automated Propofol Sedation for Transcatheter Aortic Valve Implantation: A Pilot Study

Zaouter, Cédrick MD, MSc*; Hemmerling, Thomas M. MSc, MD, DEAA†‡; Mion, Stefano MD*; Leroux, Lionel MD, PhD; Remy, Alain MD*; Ouattara, Alexandre MD, PhD*§‖

Author Information
doi: 10.1213/ANE.0000000000001737
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The past 5 decades have witnessed the emergence of closed-loop systems for IV drug delivery as a feasible way to perform general anesthesia.1 Receiving information from a control variable, they are able to adjust automatically the drug infusion rate based on built-in algorithms.2 Those systems have been shown to be safe,3 to reduce anesthesiologists’ workload,4 and to allow superior stability of the control variable compared with manual delivery.5–9 More recently, closed-loop systems for conscious sedation have outperformed manual administration for patients undergoing digestive endoscopies10 and elective lower-limb orthopedic surgery under spinal anesthesia.1 However, these robotic sedation systems have been tested mainly for American Society of Anesthesiology classification II patients <65 years of age. No studies have used them to maintain sedation in the elderly, an extremely frail population with multiple comorbidities. In an effort to demonstrate that closed-loop delivery of propofol for sedation is feasible for these patients as well, we decided to conduct a pilot study in patients undergoing transcatheter aortic valve implantation (TAVI). By definition, TAVI patients are not eligible for the standard surgical procedure because of their advanced age, diminished physiological reserve, and poor tolerance to surgery-related stress.11 According to a recent review, TAVI under sedation compared with general anesthesia is associated with excellent outcomes, such as reduced procedure time, shorter length of intensive care unit stay, and a lower rate of intraoperative vasopressor administration.12 Closed-loop systems for sedation with spontaneous breathing could offer less oscillation of the control variable than manual control.1 Consequently, they may be helpful to reduce the incidence and the effect of overshooting, which are known to trigger respiratory depression and hypercarbia that could lead to a dramatic increase in right ventricular afterload, especially in the TAVI patients.13

We conducted a pilot study using a previously described pharmacologic robot for propofol sedation, also known as a hybrid sedation system (HSS).1 The HSS allows an automated delivery of propofol for sedation with spontaneous breathing. It integrates a decision support system that detects respiratory and hemodynamic critical events and proposes relevant clinical suggestions and treatment options.14 It has been demonstrated that in the orthopedic population, the HSS could provide better control of sedation and performance indices compared with manual control.1

The primary objective of this study was to determine the feasibility of successful automated sedation without manual override by the attending anesthesiologist. Secondary qualitative objectives consisted of assessing clinical performances and controller performances.


Study Population

This was a prospective, observational, human research, single-center pilot study conducted in the Department of Anesthesia and Critical Care of Bordeaux University Hospital (Service d’Anesthésie-Réanimation II, CHU Bordeaux, France). After getting approval from our institutional ethics committee (Comité de Protection des Personnes Sud-Ouest et Outre Mer III, Bordeaux, France/agreement number DC 2014/73) and agreement from the Commission Nationale de l’Informatique et des Libertés (registry number 1786759v0), we conducted the investigation from February 1, 2015, to June 1, 2015. After having assessed the protocol, our ethics board judged the research to be an observational study that uses a closed-loop system with a set of marketed medical devices to perform sedation with continuous infusion of propofol. Because sedation using propofol is the standard of practice in our institution for TAVI procedures, the ethics board considered that the usual patients’ care was not altered. Thereby, our institutional review board did not estimate that the present trial is under the provisions governing biomedical and routine care research. Consequently, a waiver of the written informed consent was authorized because the study does not pertain to article L1121-1 of the French public health code.

Patients were recruited if they were ≥65 years of age and scheduled to undergo elective TAVI via a transfemoral route. The exclusion criteria were patients presenting neurological trouble causing a mental deficiency, patients with a history of previous cranial neurosurgical procedures, incapacity to tolerate prolonged still supine position, allergy to propofol, and baseline oxygen saturation <92% on room air (assessed with pulse oximetry [Spo2]). Twenty consecutive patients scheduled for TAVI were enrolled.

System Specifications and Description of the HSS Incorporating a Closed-Loop System for Sedation and a Decision Support System

Closed-Loop System Features.

All patients underwent sedation with spontaneous breathing by a pharmacologic robot named the HSS. The latter was developed using LabVIEW (LabVIEW 2010, National Instruments Corporation, Austin, TX). This device has been described previously.1 In brief, it combines a proportional integral derivative-controller with a controlling feedback system using self-adaptive, rule-based algorithms. Bispectral index (BIS) was used as a control variable for sedation to calculate propofol infusion rates to maintain a BIS target as close as possible to 65. The HSS is conceived to allow spontaneous breathing. Thus, respiratory rate (RR) and Spo2 are also used as control variables. A vital signs monitor incorporating a Philips BIS module (IntelliVue MX700 patient monitor, Philips Healthcare, Suresnes, France) allowed acquisition of control variables. A standard syringe infusion pump (Graseby 3400, Graseby Medical, Watford, Hertfordshire) was employed as an actuator to administer propofol. A computer (Samsung DP700, PC, Intel Core i5-3470T 2.90GHz Processor, UE) was used to implement the sedation algorithms, provide the user interface, and close the loop between the control variables and the infusion pump. The computer regulated the syringe pump infusion rate via an RS-232 port.

When the robotic sedation system is started, the user is invited to enter patient data (patient identification, weight, height, age, and gender). After confirmation that the data entered were accurate, the system automatically started the infusion of propofol according to the algorithms implemented on the computer. Details concerning the algorithms and the interface have been described previously.1 However, for clarity, a brief description of the algorithm will follow.

Closed-Loop System Details: Description of the Algorithm.

An initial propofol bolus is administered at a rate of 250 μg/kg over a period of 2 minutes. Afterward, an infusion rate of 50 μg/kg/min is delivered for 3 minutes. After the bolus stage (2 + 3 minutes), the robotic sedation maintenance starts automatically following 2 phases. The first phase of maintenance consists of selecting the sedation profile. The program establishes the profile automatically. If 3 values of BIS are <60, the profile will be set as light (the patient would require light sedation level). If 3 BIS values are <90 and >60, the profile will be set as moderate. If 3 BIS values are >90, the profile will be set as profound (the patient would require higher infusion rate of propofol to reach a BIS of 65). The profile is not defined if no BIS values are available. The initial infusion rate of maintenance is determined by the sedation profile. A light sedation profile will deliver an infusion rate of 100 μk/kg/min. A moderate sedation profile will deliver an infusion rate of 125 μg/kg/min. A profound sedation profile will deliver an infusion rate of 150 μg/kg/min. The sedation profile also set the respiratory threshold limit, below which the program will start to decrease the propofol infusion rate. When the profile is profound, the RR threshold is set at 12. For the other 2 profiles, the threshold is set at an RR of 13. The second phase is sedation maintenance. The propofol infusion rate is calculated automatically according to the following equation:

In this equation, Km is a coefficient proportional to the difference of the actual BIS to the target BIS. Kh is a coefficient proportional to the difference of the mean BIS to the target BIS over the last time interval. The program calculates a new dose every 2 minutes based on the average of the last 6 BIS values acquired. The sedation system also combines respiratory variable to adjust the infusion rate. If Spo2 is <92 or RR is <8, the system analyzes BIS values and decreases the dose average every minute according to the following criteria: When average BIS is <53, the infusion rate decreases by 50%. If average BIS is ≤58, the infusion rate decreases by 25%. If average BIS is >58, the infusion does not decrease. When the RR is <8 and/or the Spo2 is <92% for >2 consecutive minutes, the infusion rate decreases automatically by 50% of the current propofol infusion rate. When these respiratory occurrences persist for >5 minutes, the system automatically stops the propofol infusion until the vital signs return to safe values for >30 consecutive seconds. Additional safety features include the ability for the user to just touch a dedicated button or buttons to pause, override manually, or end the application at any time.

Closed-Loop System Details: Margins of Signal Acceptance.

Artifacts occurring during the interpretation of the electroencephalographic signal could lead to false display values on the BIS monitor. Eye movement, electrocautery, or facial muscle activity are the main reasons to induce such artifacts.15 Special filters have been integrated into the BIS monitor to detect and indicate when BIS values are not accurate because of eye movement or electrocautery. The automated sedation system considers BIS values as artifact when they are flagged by the BIS monitor as spurious via these special filters. When this happens, the program calculates a new dose based on the mean value of the rates administered over the last 5 minutes. On the other hand, when the patient is not entirely [muscle] relaxed, for instance during sedation, the facial electromyographic activity can generate frequencies that mimic the same frequency range (30–47 Hz) as the beta ratio. However, this increased facial muscle tone has been claimed to happen with opioid-induced muscle rigidity.16 Therefore, the electromyography activity values derived from the BIS monitor were not incorporated into the algorithm of the automated sedation system as a variable necessary to accept the BIS values. This decision was based on 2 main reasons. First, opioids were not used during the case. Second, the purpose of the system is to deliver sedation and not general anesthesia automatically.

Decision Support System Features.

The HSS incorporates a decision support system (DSS) that detects critical respiratory and hemodynamic events. The former events are defined as Spo2 values <92% and/or an RR <8/min; the latter are defined as mean arterial pressure <60 mm Hg and/or heart rate <40 bpm. When an event occurs, the user is informed via smart audiovisual alarms, which provide simultaneously reasons for their manifestation and related adequate treatment choices. Thorough details of this DSS have been described previously.14 When a critical event occurs, the attending anesthesiologist is able to choose decrease propofol dose as a treatment option pressing a button appearing on the DSS alarm box. By clicking this button, the system automatically reduces the current propofol dose by 10%.

Conditions to Interact With the System or Break the Loop.

The only instruction given to the attending anesthesiologist to interact with the system consisted of pressing the decrease propofol dose option when BIS values were >58, with an Spo2 <92 and/or an RR <8 judged clinically to be secondary to an airway obstruction caused by hypopharyngeal muscles hypotonia. On the other hand, the attending physician was instructed to manually override the system in case of a sedation failure defined as a respiratory failure and/or a hemodynamic compromise requiring a conversion to general anesthesia.

Perioperative Management

Before using the robotic sedation system on patients in the operating room, simulations on the HSS were conducted to ascertain that the system interacts appropriately when critical respiratory or hemodynamic events occur.

Before the beginning of each study case, an instruction session highlighted the appropriate manipulation of the syringe pump necessary to avoid communication errors between the syringe pump and the controller during the switch to a filled syringe.

One hour before the bioprosthesis implantation, a premedication with 0.1 mg/kg of oral midazolam was administered to every patient on the surgical ward. Upon arrival in the hybrid operating room, patients were transferred to the operating table in a supine position with blankets below the scapula to avoid airway obstruction. They were monitored with a 2-channel electrocardiogram, noninvasive arterial pressure, Spo2, and BIS. Then, oxygen delivery starting at a rate of 6 L/min2 was applied via a facial mask, which was endowed with a CO2 sensor for RR measurement. Afterward, 2 IV lines were inserted in all patients; one was devoted for propofol sedation only, whereas the other was dedicated for drug or fluid administration. At this point, automated propofol-induced sedation was started, and transversus abdominis plane, ilioinguinal, and iliohypogastric blocks were performed on every patient on the ipsilateral site of the delivery catheter system insertion to guarantee adequate analgesia from T7 to L2 dermatomes. Blocks were accomplished with the patient in a supine position after abdomen and groin skin prepping. A 10-MHz linear probe was placed on the patient’s abdomen to obtain a transverse view of the abdominal layers. First, a 22-G × 80-mm sonoTAP needle (Pajunk Medizintechnologie GmbH, D-78187 Geisingen, Germany) was appropriately advanced between the aponeurosis of the internal oblique muscle and the transversus abdominis muscles under ultrasound guidance using an in-plane technique. The correct placement of the needle was confirmed by injection of a mixture of 10 mL of 0.5% ropivacaine and 10 mL of 1% lidocaine. After completion of this anesthetic solution injection, the needle was removed, and the ultrasound probe was reoriented on an imaginary line starting from the anterior superior iliac spine and reaching the umbilicus to localize the ilioinguinal and iliohypogastric nerves. A needle was reinserted parallel to the ultrasound beam and advanced until the space between the transversus abdominis fascia and the internal oblique muscle was reached. Again, the correct placement of the needle was confirmed by injection of a combination of 10 mL of 0.5% ropivacaine and 10 mL of 1% lidocaine surrounding both nerves. Finally, skin analgesia was strengthened with a single shot of 5 mL of 0.5% ropivacaine and 5 mL of 1% lidocaine mixture between the fascia lata and the fascia iliaca. Before starting the procedure, external defibrillator pads and a forced-air warming blanket were applied to patients. No other sedatives or narcotic agents were administered before the procedure. Automated propofol delivery was stopped after finishing the dressings. Patients received 1 g of IV acetaminophen after the valve implantation.

The TAVI procedure has been reported previously.17

The current pilot study determined the success rate of sedation for the TAVI procedure. Successful robotic sedation was defined as sedation requiring no manual override by the attending anesthesiologist. Secondary outcomes were clinical and controller sedation performances. Clinical performance of sedation was defined as the efficacy to maintain the BIS value as close to target (BIStarget = 65) as possible. Four categories defined the clinical performance: excellent, very good, good, and inadequate control, when the measured BIS values were within 10%, from 11% to 20%, 21% to 30%, or >30% from the BIS target, respectively. Varvel parameters were used to evaluate controller performances.18 Our tertiary outcomes were the dose of propofol consumed, the frequency of modifications of the infusion rate, and the time of BIS values <55, <60, >75, and >80 (describing overshoot or undershoot of propofol sedation) during the maintenance period.

Data Collection and Statistical Analysis

Vital signs, BIS values, infusion rates, and doses of propofol were automatically recorded on an Excel datasheet every 5 seconds for the entire length of sedation. Investigators also recorded the number and type of critical events that the DSS detected during the sedation period. The changes in propofol infusion performed by the robotic system when a critical event arose were noted. Finally, postoperative data of interest were also collected.

The sample size was chosen according to the range of 12–30 patients suggested for pilot studies.19 We decided to recruit 20 patients and expected a 20% dropout rate caused by loss of recorded signal or communication errors between the syringe pump and the controller. The 95% confidence interval (CI) to attain the successful proportion for the primary outcome of the planned proportion was 56% to 94%. Data were collected for descriptive purposes. The Shapiro–Wilk test was used to verify the normality (all P > .322). Quantitative data are presented as mean (SD) or median (interquartile range [IQR]) according to their distribution and categorical data as frequency (proportion). CIs were also calculated for the outcome data using the Clopper–Pearson method.


Twenty patients were enrolled in the study, showing faultless communication between the controllers and the syringe pump with a proficient application of the sedation algorithms. Robotic sedation was successful in 19 patients, which is equivalent to 95% (99% CI, 68%–100%) of the patients undergoing TAVI. No miscommunication occurred between the controller and the syringe pump. One manual override happened because of a cardiac arrest caused by a pericardial tamponade, which required conversion to general anesthesia.

Table 1.
Table 1.:
Patient Characteristics and Procedure Data
Table 2.
Table 2.:
Clinical and Controller Performance
Table 3.
Table 3.:
Overshoot or Undershoot of BIS Values (Percentage of Sedation Time)
Table 4.
Table 4.:
Decision Support System Outcomes
Table 5.
Table 5.:
Postoperative Data of Interest
Figure 1.
Figure 1.:
Time course of all individual bispectral index values from the end of the bolus stage to discontinuation.
Figure 2.
Figure 2.:
Time course of all individual propofol infusion rates from the end of the bolus stage to discontinuation.
Figure 3.
Figure 3.:
Time course of all individual pulse oximetry values from the end of the bolus stage to discontinuation.

Patients’ anthropomorphic data, baseline comorbidities, and procedure-related data are described in Table 1. Clinical and control performance values of the HSS are presented in Table 2. Overshoot and undershoot of the BIS target are depicted in Table 3. The closed-loop system made 15 (SD, 3) modifications per hour of the propofol infusion rate, and the median infusion rate administered was 65 (IQR, 53–75) μg/kg/min. After the procedure, no patient was discontent of the robotic sedation received. Surgeons and the interventional cardiologists who implanted the valves were unanimous on the sedation conditions, claiming that they were suitable to perform the implantation. Fifteen and 6 patients presented critical respiratory and hemodynamic events, respectively. The system detected a median of 3 and 2 critical respiratory and hemodynamic events per hour of procedure, respectively. Nine patients who presented low respiratory rate events had an automated 50% reduction of their propofol infusion rate. For 5 of those 9 patients, the attending anesthesiologist pressed the decrease propofol dose button. One patient had an automated interruption of the propofol infusion for 2 minutes until vital signs returned to an acceptable level because of a low respiratory rate lasting for a period >5 minutes. The time course of all individual BIS values, propofol infusion rates, and Spo2 values from the end of the bolus stage to discontinuation are presented in Figures 1–3, respectively. Overall, none of the patients had a right ventricular failure because of the critical respiratory episodes. None of the 6 patients presenting hemodynamic events had a heart rate <40 bpm. However, the 6 of them presented the episodes of mean arterial pressure <60 mm Hg not related to the rapid ventricular pacing nor the deployment of the bioprosthesis. During these periods of hypotension, the median mean arterial pressure was 56 (IQR, 55–57) mm Hg. For these low blood pressure occurrences, all patients received ephedrine followed by a fluid bolus therapy of crystalloid (5 mL/kg). No patient was transfused during the procedure. The details of the occurrences of critical alarms are presented in Table 4. No in-hospital mortality occurred after the procedure, and all patients were discharged from the hospital. Postoperative data of interest are shown in Table 5.


This study validates that automated sedation for propofol delivery in elderly and very sick patients undergoing TAVI is feasible because no manual override by the attending anesthesiologist occurred. Sedation was deemed satisfactory because neither hemodynamic life-threatening events nor respiratory failure related to the robotic sedation triggered a conversion to general anesthesia. The closed-loop system maintained sedation for the valve implantation in 95% (99% CI, 68%–100%) of cases, with no human override. No communication errors occurred between the syringe pump and the computer, but a conversion to general anesthesia occurred secondary to a pericardial tamponade.

To the best of our knowledge, this is the first trial to test a robotic sedation delivery system in an elderly and extremely frail population with several comorbidities. The proof that automated sedation could be offered to these subjects is of importance because the elderly population (>65 years of age) has increased significantly during the past 50 years, and it will rise by more than 3-fold in the next years.20 Thereby, the number of surgeries will increase considerably in this type of patients. To minimize surgical-related stress, interventions are performed with a minimally invasive approach with patients often receiving regional anesthesia combined with sedation. Closed-loop sedation could help anesthesiologists taking care of such a fragile population. As demonstrated in a recent investigation, the present system tested for patients undergoing lower-limb orthopedic surgery showed better maintenance of the target BIS value compared with manual administration.1 The superior quality and precision of a closed-loop drug administration system can be explained by the frequent data sampling from the control variables that tailors unceasingly the appropriate drug infusion rate corresponding to the patients’ clinical need, providing less oscillation of the control variables subsequently.21 Thus, fewer life-threatening events occur when closed-loop sedation is employed.14

Conversion to general anesthesia is an unusual incident that does not justify abandoning the sedation principle.12 Most of the conversions described in the literature occur secondary to vascular complication bleeding necessitating a surgical intervention.12 However, an appropriate regional anesthesia technique, such as the one used in the present investigation, allows excellent analgesia from T7 to L2 and does not compel conversion to general anesthesia if a surgical approach is needed. In addition, according to recent recommendations for the “optimal perioperative management of the geriatric surgical patient,” general anesthesia should be avoided when possible to reduce the incidence of postoperative confusion.22 Therefore, it could be stated that cognitive impairment should be prevented by avoiding general anesthesia in the TAVI population. Sedation for TAVI patients presents several significant advantages, such as fewer episodes of severe hypotension requiring the use of vasopressors, faster operating room turnover, and shorter intensive care stay.12 It appears that cardiothoracic patients receiving BIS-guided anesthesia are prone to postoperative delirium when their EuroSCORE is high.23 By definition, patients scheduled to undergo a TAVI have very high EuroSCOREs. It could be advocated that this population with little physiologic reserve is more sensitive to anesthetics. Our results corroborate this statement because we found a divergence in the clinical sedation performance of the same robotic sedation system when tested in the current subjects who were 82 years of age (SD, 8) compared with a 64-year-old (SD, 27) orthopedic population recruited in a previous study.1 In the present investigation, the excellent, very good, and good sedation control was obtained during 69% of the sedation time, whereas, in the orthopedic subjects, who were younger, the same cumulative categories of sedation were achieved robotically in 90% of the sedation time.1 Although the excellent to good sedation time was shorter with a longer profound sedation period (BIS <55) for the TAVI procedure compared with the orthopedic population, the impact of propofol infusion on the cardiorespiratory system was similar in both populations.14 This discrepancy could be explained by the lower median dose administered in the TAVI patients compared with the orthopedic patients who were 65 (IQR, 53–75) μg/kg/min versus 87 (SD, 38) μg/kg/min, respectively. Thus, it could be advocated that elderly patients have a relative sedative overdose that could affect brain activity but does not disturb the tidal volume and the RR excessively. In contrast, hypopharyngeal muscle hypotonia affecting three-fourths of the elderly population and leading to obstructive sleep apnea12 could be the reason that in the present study, 79% of the cases (15 patients) presented critical respiratory events, with a similar number of episodes per hour of intervention despite the lower median propofol dose infused.

The incidence of patients presenting critical hemodynamic events requiring vasopressors was analogous to that reported in the literature.24 It has been speculated that a preoperative hypovolemic state or perioperative bleeding incidents might be the factors responsible for these episodes of hypotension during a TAVI procedure under sedation.12

In this trial, we present a second automated sedation system. Recently, researchers developed a device called the SEDASYS to perform endoscopies with automatic propofol administration for sedation. This system modifies automatically both the infusion rate of propofol and the oxygen delivery based on 2 controlled variables. The first variable is patients’ response to verbal and tactile stimuli that the system generates. The second is patients’ desaturation or apnea.25 This system showed that hypoxemia occurred significantly more often in patients receiving the standard care.10 The main differences of this device compared with the system tested in the current article are mainly 2. First, the SEDASYS prompts the patients with audio/tactile stimuli every 2 minutes to determine the sedation level, whereas our system evaluated the sedation depth with BIS values every 5 seconds. In that respect, the main disadvantage of the SEDASYS is its lack of feedback for 2 minutes, during which critical events could potentially occur. In contrast, our system receives information every 5 seconds without disturbing patients’ comfort with neither audio nor tactile reiterated stimuli. Second, the SEDASYS increased the O2 delivery when desaturation occurred, whereas, for safety reasons, our system decreased the propofol infusion rate by 50% instead. It has to be highlighted that the SEDASYS system is not commercially available anymore because of the failure of adoption in the marketplace.

The current investigation has some limitations. As a pilot study, the sample size does not provide data on the efficacy of the robotic sedation system to reduce the incidence of critical events compared with the manual administration. Moreover, it does not determine whether the treatment options offered by the DSS increase patient safety. Another limitation consists in the nongeneralizeability of the present findings because the subjects studied were not morbidly obese, thus prone to respiratory obstruction even with very light sedation.


To the best of our knowledge, this is the first trial demonstrating that automated sedation is feasible for elderly and very frail patients. The closed-loop delivery system integrating a DSS may play a crucial role in increasing patients’ safety, standardizing sedation delivery on expert-based principles, and offering pertinent clinical suggestion and dedicated treatment options.


We would like to express our gratitude to the anesthesia nurses for helping us conduct the present trial.


Name: Cédrick Zaouter, MD, MSc.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Name: Thomas M. Hemmerling, MD.

Contribution: This author helped design the study, analyze the data, and write the manuscript.

Name: Stefano Mion, MD.

Contribution: This author helped conduct the study, analyze the data, and write the manuscript.

Name: Lionel Leroux, MD.

Contribution: This author helped conduct the study, analyze the data, and write the manuscript.

Name: Alain Remy, MD.

Contribution: This author helped conduct the study.

Name: Alexandre Ouattara, MD, PhD.

Contribution: This author helped design the study, analyze the data, and write the manuscript.

This manuscript was handled by: Maxime Cannesson, MD, PhD.


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