The study was conducted as a nonrandomized prospective study between April 2016 and April 2018 at the Department of Otorhinolaryngology and Cervicofacial Surgery, University Medical Centre Ljubljana, Slovenia. The selection of patients suitable for ECT was made in concordance with the inclusion and exclusion criteria listed in Standard Operating Prodecures for ECT (7, 21). The multidisciplinary head and neck tumor board confirmed the indications for ECT treatment and written informed consent was obtained from all included patients. The study protocol was approved by the National Medical Ethics Committee of the Republic of Slovenia (182/02/14 and 0120-132/2015-2).

Patients with multiple tumors or tumors greater than 1 cm in diameter were considered candidates for ECT under general anesthesia or continuous intravenous sedation. Before ECT, an anesthesiologist determined the type of anesthesia (general anesthesia or continuous intravenous sedation) for each patient according to the criteria listed below.

Criteria for patients selected for ECT under general anesthesia:

The criteria for performing ECT under continuous intravenous sedation:

General anesthesia was performed with an intravenous bolus dose of propofol according to the patient’s body weight and age (1-2 mg/kg), and it was maintained by intravenous propofol infusion (3-4 mg/kg/h) or inhalational anesthesia (sevoflurane up to 1.5 vol %). Intraoperative and postoperative pain was relieved by administering an intravenous metamizole bolus dose (2.5 g), paracetamol intravenous bolus (1 g) and remifentanil infusion (0.1 – 0.3 µg/kg/min). The muscular relaxant rocuronium (0.45 – 0.6 mg/kg) was administered in all patients where ECT was performed under general anesthesia with endotracheal intubation.

Continuous intravenous sedation was performed with intravenous propofol infusion (1-2 mg/kg/h) or propofol intravenous bolus dose according to the patient’s body weight and age (1-1.5 mg/kg). Intraoperative and postoperative pain was relieved by administering an intravenous metamizole bolus dose (2.5 g), paracetamol intravenous bolus (1 g), remifentanil intravenous infusion (0.1-0.15 µg/kg/min) or fentanyl bolus dose 1-2 µg/kg. Muscular relaxants in patients with intravenous sedation were not administered.

The bispectral index (BIS) was used to monitor the depth of general anesthesia or intravenous sedation and intraoperative awareness during anesthesia. The BIS value was expected to be between 70 and 85 during continuous intravenous sedation and between 40 and 60 during general anesthesia. The BIS sensor was placed on a patient’s forehead before starting with the application of anesthetic drugs and removed after the BIS reached 85 or over and the patient was fully awake (22, 23). Monitoring the depth of anesthesia is very important during any procedure, as anesthesia that’s too deep can cause hemodynamic changes. Awareness during anesthesia is a very serious complication with potential long-term psychological sequelae such as anxiety and post-traumatic disorder. The BIS monitor is the first method that is FDA approved to assess the hypnotic effects of drugs. The bispectral index is a statistically based, empirically derived complex parameter. It is a weighted sum of several electroencephalographic subparameters, including a time domain, frequency domain, and high-order spectral subparameters. The BIS monitor provides a single dimensionless number, which ranges from 0 (equivalent to EEG silence) to 100. A BIS value between 40 and 60 indicates an appropriate level for general anesthesia, as recommended by the manufacturer. The BIS monitor thus gives the anesthetist an indication of how “deep” under anesthesia the patient is. The essence of BIS is to take a complex signal (the EEG), analyze it, and process the result into a single number. When a subject is awake, the cerebral cortex is very active, and the EEG reflects vigorous activity. When asleep or under general anesthesia, the pattern of activity changes.

Overall, there is a change from higher-frequency signals to lower-frequency signals (which can be shown by Fourier analysis), and there is a tendency for signal correlation from different parts of the cortex to become more random. The developers of the BIS monitor collected many (around 1000) EEG records from healthy adult volunteers at specific clinically important end-points and hypnotic drug concentrations. They then fitted bispectral and power spectral variables in a multivariate statistical model to produce the BIS index. As with other types of EEG analysis, the calculation algorithm that the BIS monitor uses is proprietary (22, 24).

ECT was performed according to the updated Standard Operating Procedures (7). BLM (Bleomycin medac; Medac, Wedel, Germany) was administered as an intravenous bolus injection in 2 minutes at a dose of 10000 IU/m² to 15000 IU/m² body surface area (1000 IU is equal to 1 mg of bleomycin activity). The electric pulses were applied 8 minutes after the BLM injection by needle row electrodes with fixed geometry (N-20-4B, IGEA, s.r.l., Carpi, Italy). Electric pulses were generated by a Cliniporator Pulse Generator (IGEA, s.r.l.). The electric pulses were applied several times to the tumor with repositioning of the electrodes to cover the whole tumor area, including the safety margins. The largest tumor diameter was measured with a caliper.

The clinical protocol was designed to obtain data necessary for the completion of the study. Demographic data and tumor characteristics were collected as a part of the InspECT protocol (25). The latest version of the ASA physical status classification system has been used to assess a patient’s preanesthesia medical comorbidities, predict perioperative risks and determine the safety and tolerability of continuous intravenous sedation or general anesthesia (26). The American Society of Anesthesiologists (ASA) Physical Status Classification System is a tool used in preparation for surgery to help predict risks in a given patient. The system uses a scale based on the patient’s medical history, the severity of known medical conditions, and current physical state to help predict if they can tolerate anesthesia and the conditions of surgery. The ASA Physical Status Classification System has been used for more than 60 years and was updated in 2019 to include additional disease examples.

The ASA Physical Status Classification System uses a scale from I to VI, with I being a healthy patient with minimal risks, to VI being a brain-dead patient with plans for organ donation (27).

The duration of anesthesia was measured from the application of anesthetic drugs until the complete vigilance of the patient (BIS > 85). Vital signs were measured by noninvasive blood pressure measurements, peripheral blood oxygenation (pulse oximetry), electrocardiography, end-tidal CO₂ and ventilatory parameters during the entire perioperative period. Propofol bolus dose in mg, continuous propofol infusion in mg/kg/h and total propofol dosage in mg were registered for each patient. Furthermore, all the analgetic drugs (metamizole, paracetamol, remifentanil, fentanil) in standardized doses were preselected to ensure appropriate pain control.

The Ramsey Sedation Scale (RSS) was used in continuous intravenous sedation to assess the depth of sedation before, during and after the procedure. The Ramsay Sedation Scale (RSS) was the first scale to be defined for sedated patients and was designed as a test of rousability. The RSS scores sedation at six different levels (1 = Patient is anxious and agitated or restless, or both; 2 = Patient is cooperative, oriented and tranquil; 3 = Patient responds to commands only; 4 = Patient exhibits brisk response to a light glabellar tap or loud auditory stimulus; 5 = Patient exhibits a sluggish response to light glabellar tap or loud auditory stimulus; 6 = Patient exhibits no response), according to how rousable the patient is. It is an intuitively obvious scale and therefore lends itself to universal use, not only in the ICU, but wherever sedative drugs or narcotics are given. It can be added to the pain score and be considered the sixth vital sign (28).

The RSS score was measured before applying the anesthetic drug and after 5 and 10 min of sedation. During ECT procedures, the target RSS value was between 3 and 5 to assure moderate or deep sedation levels (29).

The evaluation of patient recovery time was measured with the Aldrete score based on the evaluation of vital signs and consciousness, and it was used to determine the time when a patient could safely leave the Post-Anaesthesia-Care Unit (PACU) and be transferred to the surgical ward. The patient was judged fit for discharge from the PACU when an Aldrete score > 8 was reached (30, 31).

The numeric pain scale (NPS) was used to assess pain before and after the procedure under continuous intravenous sedation and before and after general anesthesia. It was categorized into no pain = 0, mild pain = 1-3, moderate pain = 4-6, and severe pain = 7-10 (32).

Before leaving the PACU, a three-point satisfaction scale (very satisfied, satisfied or unsatisfied) was used to measure patients’ satisfaction with the procedure. Further details of the clinical study protocol and anesthesia technique are described in Supplement 1.

Preoxygenation with a 30% fraction of inspired oxygen was used to prevent hypoxemia during continuous intravenous sedation or endotracheal intubation in cases performed under general anesthesia (33, 34).

Continuous variables are presented as the mean value with standard error of the mean (SE), and categorical variables are presented as absolute numbers with percentages. Data were tested for normal distribution (D`Agostino&Pearson test). If data passed the normality test, the comparisons between groups were performed by the unpaired t-test (two-tailed). Significance was defined as p < 0.05. Data that did not pass the normality test are presented as the median and range: 25<sup>th</sup> percentile - 75<sup>th</sup> percentile, and the Mann−Whitney test was used for the comparison between groups. Categorical data were analyzed using Chi-square (and Fisher`s exact) (two-sided) test. Significance was defined as p < 0.05. Statistical analyses and graphical presentation of data were performed using GraphPad Prism 9.4.0 (673) (GraphPad Software, CA, US).

Overall, 27 patients (78% male and 22% female) with 113 nonmelanoma skin cancers in the head and neck region treated with ECT were included in the study. Except for one, all tumors were treatment naïve. The mean age of the group that underwent general anesthesia and continuous intravenous sedation was 69.1 and 74.8 years (p = 0.3580), respectively ( Table 1 ).

The largest diameters of the treated tumors in both treatment groups were similar ( Figure 1 ). General anesthesia was performed in 10 patients (8 male, 2 female). In this group, ECT was performed in 73 tumors, with a mean largest diameter of 30.0 mm, and four patients had multiple tumors. Continuous intravenous sedation was used in 17 patients (13 male, 4 female), with ECT performed in 40 tumors, with a mean largest diameter of 21.2 mm. Six patients had multiple tumors ( Table 1 ). There was no significant difference in gender distribution in the group of general anesthesia and continuous intravenous sedation (p = 0.8313). According to Standard Operating Procedures, all the patients were treated by ECT 8 minutes after i.v. BLM injection (7). Both the general anesthesia group and the group treated with continuous intravenous sedation were well matched regarding the demographics and tumor characteristics.

The physical status of patients before anesthesia was scored by the ASA classification system. The group treated in general anesthesia had a higher percentage of ASA 3 (80%) patients than the group treated in continuous intravenous sedation (65%) (p = 0.4202) ( Table 1 ). All ASA 3 patients had two or more systemic diseases (arterial hypertension, chronic atrial fibrillation on therapy with anticoagulant drugs, previous cardiac events, diabetes mellitus, pulmonary diseases, chronic kidney failure 1^st and 2^nd degree).

The average loading dosage of the propofol bolus used during continuous intravenous sedation was significantly lower (73.5 ± 9.2 mg) than that used in the general anesthesia group (121.0 ± 20.1 mg; p = 0.0222) ( Figure 2A ). Continuous intravenous sedation was maintained with continuous intravenous infusion of 1-2 mg/kg/h of propofol, whereas under general anesthesia, continuous intravenous infusion of propofol was 1-6 mg/kg/h ( Table 1 ). The mean value of total propofol used during continuous intravenous sedation was significantly lower (82.7 ± 10.3 mg) compared to the general anesthesia group (274.0 ± 50.6 mg; p < 0.0001) ( Table 1 ; Figure 2B ).

The anesthesia duration under continuous intravenous sedation was significantly shorter than that under general anesthesia (p = 0.0001) ( Table 1 ; Figure 3 ).

The recovery of patients after anesthesia was faster after continuous intravenous sedation than after general anesthesia. The patients who underwent continuous intravenous sedation achieved an Aldrete score > 8 in the average time of 3.4 ± 0.8 min, while in the general anesthesia group, an Aldrete score > 8 was obtained in an average time of 6.2 ± 1.8 min, which was not significantly prolonged (p = 0.1103) ( Table 1 ; Figure 4 ).

After the procedure, the patients were asked about the pain and discomfort. In the general anesthesia group, the numerical pain score (NPS) score was 3 or more in 60% of the patients. In the continuous intravenous sedation group, the NPS score after the procedure was 3 or more in 53% of the patients. There was no difference in NPS score between the patients in the general anesthesia group and the continous intravenous sedation group (p = 0.1683). Patients mainly complained of lumbar pain or pain caused by body positioning during the operation ( Table 1 ).

In the PACU, patients were asked about their satisfaction with the procedure and general anesthesia/sedation (very satisfied, satisfied, not satisfied). Generally, patients were satisfied and very satisfied with the procedure and selected anesthesia. Patients who underwent continuous intravenous sedation were defined to be very satisfied after the procedure under sedation in 64.7%, while 60.0% of patients in the general anesthesia group were very satisfied (p > 0.9999) ( Table 1 ). Additionally, the surgeons who performed ECT were very satisfied with general intravenous sedation (70%) as were with general anesthesia (76.5%) (p > 0.9999) ( Table 1 ).

Complications during general anesthesia and continuous intravenous sedation were few. The most common expected event during continuous intravenous sedation was short episodes of transient apnea in 47% of patients. Otherwise, there were no significant adverse effects during continuous intravenous sedation and general anesthesia. The complications during and after ECT treatment in general anesthesia compared to the continuous intravenous sedation group were statistically nonsignificant (0.0717) ( Table 1 ).

ECT proved to be effective similarly in patient groups of general anesthesia and continuous intravenous sedation (p = 0.1299). Two months after therapy a complete response (CR) rate of 78% and partial response (PR) rate 21.9% in the group of general anesthesia and CR rate of 90% and PR rate of 10% in the group of continuous intravenous sedation was observed ( Table 1 ).