Effects of adding low-dose esketamine to sufentanil and propofol sedation during cervical conization: a prospective, single-center, randomized controlled trial

doi:10.21203/rs.3.rs-2889081/v1

Background

Cervical conization is a brief but painful procedure that can be performed under deep sedation with propofol and opioids. However, this sedation approach comes with a high risk of sedation-related adverse events (SRAEs). Esketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, has the property of less cardiorespiratory depression than opioids. The aim of this study was to assess the efficacy and safety of adding a low-dose esketamine to propofol and sufentanil sedation as an opioid-reduced regimen.

Methods

122 consecutive patients with ASA Ⅰ-Ⅲ, body mass index < 30, STOP-BANG score < 3 who underwent cervical conization were enrolled and randomly divided into group S and group ES. Using a closed-loop target-controlled infusion (TCI) pump with target bispectral index (BIS) value of 60 ± 5, patients in group S were sedated with 0.2µg/kg sufentanil and propofol, while patients in group ES were sedated with 0.15mg/kg esketamine, 0.1µg/kg sufentanil and propofol. The primary endpoint was the composite incidence of SRAEs, while the second endpoints included effectiveness of sedation, awakening time, psychotomimetic side effects, postoperative pain, postoperative nausea and vomiting, and patient and gynecologist satisfaction.

Results

Data of 120 patients were analyzed. The incidence of composite SRAEs was significantly higher in group S compared to group ES (85.0% vs 56.7%, P < 0.05). Furthermore, the severity of SRAEs was higher in group S compared to group ES (P < 0.001). There were no significant differences in the success of sedation, awakening time, psychotomimetic side effects, postoperative nausea and vomiting, postoperative pain, and patient and gynecologist satisfaction between the two groups.

Conclusion

Adding a low-dose esketamine to propofol and sufentanil sedation reduces the incidence and severity of SRAEs in patients undergoing cervical conization, with equal sedation efficacy, recovery quality, and no additional psychomimetic side effects.

Trial registration

ChiCTR2000040457, 28/11/2020

Esketamine

Propofol

Sufentanil

Sedation-related adverse events

Cervical conization

Despite efforts by the World Health Organization to eliminate cervical cancer, it remains a leading cause of morbidity and mortality in developing countries []^[^]. Cervical conization is a commonly used excisional surgery for the treatment of cervical intraepithelial neoplasia (CIN) or the diagnosis of cervical cancer. As the procedure is less invasive and the operation time is usually short, this kind of surgery can be conducted with deep sedation rather than general anesthesia with tracheal intubation or laryngeal mask airway in clinical practice^[^]. The widely used sedation protocol involves TCI of propofol with titration of opioids ^[^][^], but it was noted that the combination of propofol and opioids may lead to hemodynamic and respiratory instability. What’s more, according to the definition of general anesthesia and levels of sedation/analgesia described by the American Society of Anesthesiologists, sedation and analgesia comprise a continuum of states ranging from minimal sedation through general anesthesia without obvious boundaries between each other ^[^]. Deep sedation can inadvertently transition to general anesthesia, putting patients at risk of losing responsiveness, airway protection, spontaneous respiration, or cardiovascular function. Practitioner must be ready to rescue patients from SRAEs throughout the procedure, and it’s a stressful experience. Therefore, exploring better sedation protocol to reduce the incidence of SRAEs remains of paramount importance.

Ketamine is a well-known and widely used non-competitive NMDA receptor antagonist that produces both analgesic and anesthetic effects. The combination of ketamine and propofol may produce a deeper level of analgesia and sedation with a lower risk of respiratory depression ^[^]. Furthermore, the sympathomimetic properties of ketamine can reduce the decrease in blood pressure caused by propofol ^[^]. However, the principal side effects of ketamine are undesirable psychomimetic effects such as hallucinations, vertigoes, nightmares, and extracorporeal experiences. These drawbacks have counteracted its clinical advantages and restricted its use^[^][]. Esketamine is the S(+)-isomer of ketamine, which has been proven to be three times as potent as the R(-)-isomer and twice as potent as the racemic mixture, with a significant shorter half-time and clearance-time than that of ketamine []. Increased potency and faster metabolism enable esketamine to produce the required analgesic and anesthetic effects with much lower dosages, resulting in fewer side effects as well as rapid onset and recovery [][]. A randomized controlled trial was conducted to investigate the feasibility and side effects of opioid-reduced general anesthesia based on esketamine, and the findings indicated that esketamine provided more stable hemodynamics []. However, no clinical trials are available that address the SRAEs of combination of esketamine with sufentanil as the hypnotic components in propofol sedation. In this study, we hypothesized that adding a low-dose esketamine to sufentanil and propofol sedation as an opioid-reduced regimen could mitigate the SRAEs, produce the same efficacy of sedation, and generate no additional psychomimetic side effects.

Study design and ethics

The current study was a single-center prospective randomized controlled clinical trial. Ethical approval was obtained from the Ethics Committee of Zibo Central Hospital (No. 202009001) on 01/09/2020. We registered the study at the Chinese Clinical Trial Registry on 28/11/2020 (ChiCTR2000040457). Written informed consent was acquired from every patient before participation, and the trial report complied with Consolidated Standards of Reporting Trial guidelines.

Participants

122 patients scheduled for elective cervical conization between December 2020 and February 2022 were enrolled in this study. The inclusion criteria were between 18–60 years, American Society of Anesthesiologists (ASA) Physical Status Ⅰ to Ⅲ, body mass index (BMI) < 30kg/m², score of STOP-BANG < 3. The exclusion criteria were as follows: 1) severe respiratory disease (such as asthma or pneumonia); 2) recent history of unstable angina pectoris, myocardial infarction, congestive heart failure occurred within the past 6 months, uncontrolled hypertension; 3) central nervous system disease (such as cerebral infarction, epilepsy), increased intracranial pressure, psychiatric disease; 4) hepatic or renal failure; 5) known allergic reaction to any planned medication.

Randomization and blinding

Included patients were randomly assigned to either group S or group ES in a 1:1 ratio using SPSS 26 software. All individuals involved in the study, including gynecologists, sedation practitioners, and participants, were blinded to the group allocation, except for an independent researcher who diluted 0.2µg/kg sufentanil in group S or 0.15mg/kg esketamine plus 0.1µg/kg sufentanil in group ES to the same volume with normal saline. To account for the possibility of additional injections, a double dose of these analgesics was prepared for each patient according to their group allocation respectively.

Sedation methods and monitoring

All patients were fasted following the ASA practice guidelines for preoperative fasting. Once the patient’s information was verified and intravenous access was established, standard monitoring was initiated, which included heart rate (HR), non-invasive blood pressure (NIBP), oxygen saturation of finger pulse (SpO₂), electrocardiograph (ECG), respiratory rate (RR) via ECG analysis. Patients were positioned in a lithotomy position without a pillow. And the oxygen was administered at a rate of 2L/min via a face mask connected to the breathing circuit of the anesthesia machine before the onset of sedation, then mainstream exhaled carbon dioxide concentration (PETCO₂) could be measured through the Philips monitor and tidal volume (VT) could be measured through the anesthesia machine. The face mask was gently secured to face with a head strap to ensure patient comfort.

Patients in both groups were sedated using TCI of propofol with a Closed-loop TCI pump (BCP-100A, Slgo, China), which could automatically adjust the targeted concentration of propofol according to the patient’s BIS value as a feedback index. The initial targeted BIS was set at 60 ± 5, and the initial targeted plasma drug concentration (Cpt) was set at 2.0µg/ml, and the effect concentration (Ce) was calculated per the Marsh model. Patients in group E received 0.2µg/kg sufentanil, while patients in group ES received 0.1µg/kg sufentanil and 0.15mg/kg esketamine until the Ce reached 1.0µg/ml to avoid possible psychotomimetic side effects caused by esketamine. When the BIS value reached 75 or lower, we started the closed loop, and the automatic control device worked itself to maintain the BIS value in a range of 60 ± 5. If the BIS value could not get below 75 with the initial Cpt or rose above 75 again during the procedure, we added the target Cpt by 0.5µg/ml each time. There must be sufficient time between each adjustment until Ce equaled Cpt. A database file, including the present BIS value, Cpt, Ce, infusion speed, and total dosage of propofol injected, could be exported and analyzed from the device. These series of data were continuously written per second. The operation began when BIS value was stably within the expected range and at least 2 minutes after the administration of analgesics. If there was body movement during the operation while the BIS value still in the planned rang, one third of the initial dose of the same analgesic was administered.

When the oxygen saturation dropped to 90% or below, the following measures should be taken: airway repositioning (chin lift or chaw thrust), oral/nasal airway, or laryngeal to correct airway obstruction, and positive pressure ventilation to treat apnea. Hypotension, defined as systolic arterial pressure lower than 80mmHg or decreased exceed 25% of baseline, should be treated with 6 mg of ephedrine. Tachycardia, defined as heart rate decreased by more than 25% of baseline, should be treated with intravenous atropine.

After the completion of the operation, the TCI of propofol was stopped, and the patient’s sedation level was assessed every minute using the modified observed assessment of alertness/sedation scale (MOAA/S). Once responded readily to name spoken in a normal tone (MOAA/S score = 5), regarded as fully awake, the patient was transferred to the post-anesthesia care unit (PACU) and monitored for at least 30 minutes until the modified Steward Score reached 6. In addition to standard vital sign monitoring, the quality of the patient’s recovery from anesthesia (orientation, modified Steward Score), adverse effects of sedation (drowsiness, dreaminess, nightmare, nausea and vomiting), and pain score were assessed in PACU. The gynecologist’s satisfaction with the procedure and patient’s overall satisfaction with the sedation were also investigated.

Outcome and outcome assessment

The primary endpoint of the study was incidence of SRAEs, which were respiratory and cardiovascular adverse events including oxygen desaturation, apnea, airway obstruction, bradycardia, tachycardia, hypotension, hypertension, and interventions for these adverse events such as airway repositioning, oral/nasal or laryngeal airway application, manual artificial ventilation, pressor or atropine administration. These events were enrolled in the Adverse Event Reporting Toll recommended by the International Sedation Task Force of the World Society of Intravenous Anesthesia.

The secondary outcomes of the study included the effectiveness of sedation, awakening time, incidence of psychotomimetic effects, postoperative pain, postoperative nausea and vomiting, and the patient and gynecologist satisfaction. Effectiveness of sedation was measured by numbers of somatic motor reactions during the operation and interruptions of the surgery. Psychotomimetic side effects were evaluated based on memory for dreaming or nightmare during the sedation, drowsiness, vertigo, and orientation force during recovery period. Pain and nausea were assessed using a VAS ranging from 0 to10, with 0 regarded as no pain or nausea while 10 indicating the worst pain or nausea. Gynecologist satisfaction with the procedure was investigated immediately after the operation, while patient satisfaction with the sedation was investigated upon leaving the PACU and at follow-up the next day. All satisfaction degrees were measured using Likert scoring system, with 1 = very dissatisfied and 5 = highly satisfied.

Vital signs including HR, NIBP, SpO₂, RR, VT and PETCO₂ were recorded at the beginning of sedation (T1), Ce = 1(T2), onset of closed-loop (T3), every 5 minutes during the operation (T4), MOAA/S = 5 (T5), reaching PACU (T6) and discharging from PACU (T7). BIS value, Cpt and Ce were recorded at T1-T5.

Statistical analysis

A preliminary experiment was conducted prior to the commencement of the trail. The results of the pre-experiment revealed that the incidence of SRAEs was approximately 80% in group E and 52% in group ES. Based on a power of 0.90 and a significance level of 0.05, the calculated sample size using PASS 15.0 software was 55 in each group. Accounting for an estimated dropout rate of 10%, a total of 122 patients should ultimately be enrolled.

We conducted statistical analysis using SPSS software version 25.0 (SPSS Inc., Chicago, USA). Firstly, we verified the normality of measurement data with Shpiro-Wilk test. Quantitative data with normal distribution were expressed as mean ± standard deviation, and the difference between two groups was compared using independent-samples T test. Quantitative data with abnormal distribution were expressed as median [interquartile range], and the comparison between two groups was verified using Mann-Whitney U test. Qualitative data expressed as a percentage were analysed using Pearson Chi-Square test or Fisher’s exact test. Repeated measurement data were analysed using Two-way Repeated Measures ANOVA. A two-sided P-value < 0.05 was considered statistically significant.

Patients’ characteristics

From September 2021 to February 2022, a total of 131 patients were evaluated for eligibility in this study. Of these, nine of them were deemed ineligible based on the inclusion criteria. The remaining 122 patients were randomly allocated to group S and group ES, with 61 patients in each group. However, one patient in group S did not undergo the planned procedure and one patient in group ES withdraw from the study. As a result, the final analysis included 60 patients in each group (Fig. 1). As listed in Table 1, there were no statistically significant differences between the two groups in terms of patients’ characteristics.

Table 1. Patients’ baseline characteristics

	Group S (n = 60)	Group ES (n = 60)	P-value
Age (years)	42.7 ± 11.0	43.5 ± 10.2	0.687
Weight (kg)	58.4 ± 8.6	60.6 ± 8.6	0.866
Length (cm)	161.1 ± 4.5	162.1 ± 4.7	0.654
BMI (kg/m²)	22.6 ± 3.1	23.0 ± 2.9	0.618
ASA score	1 [1 to 1]	1 [1 to 1]	0.488
STOP-BANG score	0 [0 to 1]	0.5 [0 to 1]	0.787
Smoker	3 (5.0%)	1 (1.6%)	0.619
Alcohol	4 (6.7%)	1 (1.6%)	0.364
Hypertensive disease	6 (10.0%)	3 (5.0%)	0.491
Diabetes	4 (6.7%)	1 (1.6%)	0.364
Coronary heart disease	2 (3.3%)	0 (0)	0.496
Surgery time (min)	27.5 [20.0 to 34.5]	26 [21.0 to 33.8]	0.678
Volume of intraoperative infusion (ml)	430.2 ± 101.9	400.1 ± 115.5	0.133
0.01% epinephrine cervical injected (ml)	25.7 ± 20.4	22.5 ± 13.6	0.318
Values are summarized by mean (95%CI) ± standard deviation, median [interquartile range], or number (%). ASA, American Society of Anesthesiology; BMI, body mass index; CI, confidence interval.

Primary endpoint

Table 2. Incidence and severity of SRAEs

	Group S (n = 60)	Group ES (n = 60)	P-value
Total incidence	51 (85.0%)	34 (56.7%)	0.001
Oxygen desaturation (75–90%) for 30 ~ 60s	38 (63.3%)	14 (23.3%)	< 0.001
Oxygen desaturation (75–90%), severe (< 75% at any time) or prolonged (< 90% for > 60s)	28 (46.7%)	7 (11.7%)	< 0.001
Apnea, not prolonged (30 ~ 60s)	44 (73.3%)	17 (28.3%)	< 0.001
Apnea, prolonged (> 60s)	32 (53.3%)	8 (13.3%)	< 0.001
Airway obstruction / airway repositioning	50 (83.3%)	30 (50.0%)	< 0.001
Artificial assisted ventilation	36 (60.0%)	10 (16.7%)	< 0.001
Oral/nasal airway	22 (36.7%)	8 (13.3%)	0.003
Laryngeal airway	0	0
Bradycardia	5 (8%)	0	0.057
Tachycardia	6 (10.0%)	2 (3.3%)	0.272
Hypotension / ephedrine as pressor	17 (28.3%)	8 (13.3%)	0.043
Hypertension	3 (5.0%)	1 (1.7%)	0.619
Minimum SpO₂ (%)	86.0 ± 8.6	91.6 ± 7.7	< 0.001
Maximum PETCO₂ (mmHg)	53. 7 ± 8.6	51.1 ± 7.1	0.080
Severity of SRAEs			< 0.001
No SRAE	5	15
Minimal	0	6
Minor	18	26
Moderate	12	8
Sentinel	25	5
Data were presented as mean (95%CI) ± standard deviation; or number (%). SpO₂, pulse oxygen saturation; PETCO₂, end tidal carbon dioxide concentration; SRAEs, sedation-related adverse events.

As shown in table 2, it was found that 51 patients in group S and 34 patients in group ES experienced SRAEs. The incidence of the SRAEs of patients in group S was significantly higher than that in group ES (85.0% vs 56.7%, P < 0.05). Specifically, the incidences of respiratory SRAEs, including severe oxygen desaturation (46.7% vs 11.7%, P < 0.001) or non-severe (63.3% vs 23.3%, P < 0.001), prolonged apnea (53.3% vs 13.3%, P < 0.001) or no- prolonged (73.3% vs 28.3%, P < 0.001), and airway obstruction (83.3% vs 50.0%, P < 0.001), as well as the interventions performed to treat these adverse events, including airway repositioning (83.3% vs 50.0%, P < 0.001), artificial assisted ventilation (60.0% vs 16.7%, P < 0.001), and oral/nasal airway (36.7% vs 13.3%, P < 0.05), were all statistically higher in group S than in group ES. The minimum SpO₂ during the entire procedure in patients in group S was significantly lower than that in group ES (86.0 ± 8.6 vs 91.6 ± 7.7, P < 0.001), but there was no significant difference in maximum PETCO₂ during the entire procedure between the two groups. Regarding cardiovascular adverse events, more patients experienced intraoperative hypotension and received ephedrine in group S than in group ES (28.3% vs 13.3%, P < 0.05). Furthermore, there was statistically significant difference in severity of the adverse events between the two groups, the severity of SRAEs in group S was higher than that in group ES (P < 0.001).

Secondary endpoints

Table 3

Secondary outcomes
	Group S (n = 60)	Group ES (n = 60)	P-value
Sufentanil or esketamine and sufentanil consumption (ml)	3 [3 to 3]	3 [3 to 3]	0.174
Times of somatic motors during the surgery	0 [0 to 1]	0 [0 to 0]	0.080
Times of Sedation-related procedure interruption	0 [0 to 0]	0 [0 to 0]	0.139
Awakening time (min)	7 [6 to 8]	7 [6 to 8]	0.323
Psychotomimetic side effects
Drowsiness	1 (1.7%)	2 (3.3%)	1.000
Memory for dreaming	3 (5.0%)	8 (13.3%)	0.204
Memory for nightmare	1 (1.7%)	0	1.000
NRS of pain in PACU	2 [1 to 4]	3 [2 to 5]	0.193
Additional analgesics in PACU	8 (13.3%)	14 (23.3%)	0.239
NRS of pain the next 24 hours	3 [2 to 5]	3 [2 to 5]	0.755
NRS of nausea in PACU	0 [0 to 0]	0 [0 to 0]	0.319
NRS of nausea the next 24 hours	0 [0 to 1]	0 [0 to 0]	0.518
Vomiting in PACU	1 (1.7%)	0	1.000
Vomiting the next 24 hours	6 (10.0%)	6 (10.0%)	1.000
Patient satisfaction after wake up	5 [5 to 5]	5 [5 to 5]	0.791
Patient satisfaction in the next 24h	5 [5 to 5]	5 [5 to 5]	0.434
Gynecologist satisfaction	5 [5 to 5]	5 [5 to 5]	0.574
Data were presented as median [IQR] or number (%). NRS, numeric rating scale; PACU, post-anesthesia care unit; IQR, interquartile range.

Table 3 present data on secondary endpoints. There were no differences between groups in terms of somatic motors during surgery or sedation-related interruptions of operation. No significant difference in awakening time was observed between the two groups, with a median awakening time of 7 minutes in both groups. Psychotomimetic side effects also revealed no significant difference between the two groups, with 3 patients in group S and 8 patients in group ES experienced memory of dreaming, and 1 patient in group S reporting a bad dream during the surgery. No patient in either group experienced vertigo during recovery time, and all patients had an orientation score of 6 upon transfer to the PACU and at discharging from the PACU. These data were constants and therefore not presented in the table. No statistically significant difference was found in postoperative pain, additional analgesics in the PACU, postoperative nausea and vomiting during the PACU time and the next 24 hours between the two groups. The median of satisfaction degree of patients and gynecologists at any time point was all 5, indicating highly satisfied, and no statistical difference was found between the groups.

Vital parameters during the sedation

Patients’ vital parameters during sedation and recovery period were presented in Fig. 2. The results showed significant RR fluctuations in both groups. In group S, RR was significantly lower at T3 (P = 0.002) and T4 (P < 0.001) compared to T1. In group ES, the same difference was only found at T4 (P = 0.006). Additionally, the RR fluctuation levels at T4 and T5 was significantly less in group S compared to group ES (P = 0.001 and 0.002 respectively). The magnitude of SpO₂ fluctuations showed no significant difference between the two groups. Compared to T1, SpO₂ was significantly declined at T4 in group S (P < 0.001), while no such result was found in group ES. Patients in both groups experienced a fall in mean arterial pressure (MAP) during the procedure, with patients in group S experiencing a decline from T2 to T5 and patients in group ES experiencing a decline from T2 to T4. The MAP of patents in group S was significantly lower than that in group ES at T4 (P < 0.001). The HR of patients in groups S was higher compared to group ES upon reaching the PACU (T6, P = 0.001) and discharging from the PACU (T7, P = 0.025). Compared to T1, HR was significantly lower at T2, T3, T7 and higher at T5 in group S, while lower at T2, T3, T6, T7 and higher at T5 in group ES.

Table 4

Comparison of VT, Cpt, Ce and BIS between the two groups
	Group S (n = 60)	Group ES (n = 60)	P-value
VT at the beginning of surgery (ml)	135.0 [0.0 to 226.8]	194.0 [121.5 to 253.8]	0.007
Cpt during the operation (µg/ml)	2.8 [2.4 to 3.4]	3.4 [3.0 to 3.8]	< 0.001
Cpt at OAA/S = 5 (µg/ml)	1.3 [1.0 to 1.8]	1.6 [1.4 to 1.9]	0.002
Ce during the operation (µg/ml)	2.7 [2.4 to 3.1]	3.3 [2.9 to 3.7]	< 0.001
Ce at OAA/S = 5 (µg/ml)	1.8 [1.4 to 2.6]	2.3 [1.9 to 2.7]	0.002
BIS at OAA/S = 5 (µg/ml)	81.0 [78.0 to 82.7]	78.5 [76.0 to 81.0]	0.003
Data were presented as median [interquartile range]; Cpt, plasma target concentration; Ce, effect concentration; BIS, bispectral index.

VT of patients in both groups decreased after sedation, with VT of patients in group S being significantly lower than that in group ES at the beginning of the surgery (T3, P = 0.015). Propofol Cpt of patients in group S was significantly lower compared to that of patients in group ES during the operation ( T4, 2.8µg/ml vs 3.4µg/ml, P < 0.001) and at OAA/S = 5 (T5, 1.3µg/ml vs 1.6µg/ml, P = 0.002). The same difference was observed in Ce. Additionally, the BIS of patients in group S was significantly higher than that of patients in group ES when OAA/S = 5 (T5, P < 0.005). Above data can be found in Table 4.

The main objective of this randomized controlled trial was to investigate whether the addition of low-dose esketamine to propofol and sufentanil sedation could reduce the occurrence of SRAEs. Results of this study revealed that the combination of 0.15mg/kg esketamine with 0.1µg/kg sufentanil as analgesic component was associated with fewer and less severe SRAEs. Moreover, this combination showed equal sedation efficacy and recovery quality with no additional psychotomimetic side effects compared to 0.2µg/kg sufentanil as an analgesic during BIS-guided propofol sedation for cervical conization.

Esketamine, as an NMDA receptor antagonist, interacts with numbers of different targets including opioid, monoaminergic, muscarinic receptors, and voltage-sensitive calcium channels et al []. It exhibits a higher receptor affinity and shorter metabolism than ketamine. In this study, the incidence and severity of SRAEs were significantly lower in group ES, potentially due to the gentle respiratory depression properties of esketamine in comparison to opioids. Eberl S et al. [] assessed the effectiveness of esketamine versus alfentanil as an adjunct to propofol TCI for deep sedation during ambulant endoscopic retrograde cholangiopancreatography, and found that low-dose esketamine reduces the total amount of propofol necessary for sedation, without affecting recovery time and respiratory or cardiovascular adverse events compared to alfentanil. Another study by Zhu T et al. [14] found that administering an additional 0.2mg/kg loading dose followed by a 0.5mg/kg/h infusion of esketamine provided more stable hemodynamics in opioid-reduced general anesthesia. The current study also showed a lower incidence of hypotension and a relative higher MAP during the procedure with a combination of esketamine and sufentanil sedation. The cardiovascular stimulating properties of esketamine may contribute to remaining hemodynamic stability during sedation. These findings are consistent with previous studies [¹⁴][15]^[^].

There is an ongoing debate about the optimal anesthetic approach, deep sedation versus general anesthesia, for minimally traumatic and minimally painful procedures such as endoscopic retrograde cholangiopancreatography, transcatheter aortic valve implantation, cervical conization, and retrograde ureteral catheterization et al ^[^]. For short procedures that do not interfere with airway management, deep sedation has been shown to have similar safety and suitability profiles as general anesthesia ^[^]. The most widely used sedation protocol involves titration of opioids with TCI of propofol. However, there are significant disadvantages to deep sedation, particularly the risk of SRAEs, especially respiratory-related SRAEs. Sedation practitioner must intensively monitor respiratory rate, SpO₂, PETCO₂ and observe closely for apnea or airway obstruction throughout the entire anesthesia procedure. Esketamine provides both anesthetic and analgesic effects and has less respiratory and circulatory depression properties compared to other anesthetics and analgesics. A previous study reported that compounding low-dose esketamine could reduce opioids consumption and provide better circulatory stability in general anesthesia []. However, in deep sedation, we are more concerned with patient’s ability to maintain spontaneous ventilation and a patent airway. To the best of our knowledge, this is the first paper to focus on the SRAEs especially respiratory-related SRAEs of the combination of esketamine with sufentanil and BIS-guided propofol TCI.

In this study, the sedation was deeper than deep sedation with sufficient analgesics, and some would argue that it may result in more cardiopulmonary side effects, especially respiratory depression. In fact, our results showed a relatively higher total incidences of SRAEs, 85% in group S and 57% in group ES respectively. However, the minor adverse events accounted for a large proportion of them. For example, 83.3% of patients in group S and 50.0% of patients in group ES experienced airway obstruction, which was conducted with a simple chin lift or chaw thrust. Few of them needed a nasal airway, and no patient in either group required laryngeal or tracheal intubation. In the study, Group ES exhibited a lower total incidence of SRAEs as well as a lower incidence of composite SRAEs compared to Group S. Additionally, the severity of SRAEs was less in Group ES than in Group S. Thus, the sedation protocol that combines a low dose of esketamine with reduced sufentanil is considered safer for patients and more convenient for anesthesiologists.

Many previous studies have reported psychic side effects of ketamine such as the induction of nightmares, hallucinations, extracorporeal experiences, and other psychic sensations [13] [], the same could happen with esketamine. However, combination with propofol or benzodiazepines can reduce these adverse events. Gruber et al. [] identified only one of 134 patients with hallucinations or nightmare after sedation with ketamine and midazolam. Results of current study revealed no more memory of dreaming or bad dreams or other psychic side effects in patients sedated with a combination of esketamine and sufentanil. This is in accord with the results of St Pierre [] and S. N. Piper [].

Daniela et al. [¹¹] reported that esketamine rapidly decreases after administration and that redosing does not comprise recovery quality. Interestingly, we found that patient sedated with combination of esketamine fully woke up with a higher Ce, higher Cpt, and a lower BIS value. This has never been reported before, and we think it may be related to the psychoactive effects of esketamine.

Limitations

There were some limitations in our study. Firstly, deep sedation is defined as a depression of consciousness during which patients cannot be easily aroused but respond purposefully following repeated or painful stimulation, while a state of losing consciousness and not arousable even by painful stimulation should be classified as general anesthesia. This issue has puzzled us, as we aim to achieve an anesthesia level that can provide the same analgesic effects as general anesthesia and as mild cardiopulmonary inhibition as deep sedation for short-duration and micro-invasive procedures. This type of anesthesia is more accurately referred to as Monitored Anesthesia Care. Many studies, including ours, have been helpful in exploring ways to reduce the SRAEs of deep sedation. Regardless of whether it is called deep sedation or monitored anesthesia care or non-tracheal intubation general anesthesia, it has been proven to be as safe as tracheal intubation general anesthesia when performed by skilled anesthesiologists in numerous studies ^[^][^].Secondly, the sedation was performed using a BIS-guided regimen with a closed-loop propofol TCI. It is known that ketamine and esketamine can trigger an increase in rapid γ-waves, resulting in an incorrect high BIS value despite deep anesthetic level ^[^{] [}^]. Therefore, the BIS-guided sedation regimen with esketamine may induce an unexpected deeper level of sedation with a greater Ce of propofol. This deeper level of sedation may counteract the benefit of positive cardiovascular effects of esketamine. However, in the current study, despite the higher Cpt and Ce of propofol in group ES, the MAP was higher and the SRAEs were less than those sedated without esketamine. Finally, worrying about the negative effects on recovery quality and psychotomimetic side effects that may be caused by esketamine, sedation with esketamine and propofol without sufentanil was not included in our study. The results of this study suggested that this compromise protocol of mixing a half dosage of both sufentanil and esketamine for propofol sedation was an appropriate regimen. The safety and effectiveness of esketamine and propofol sedation without opioids deserve further study.

Adding a low dose esketamine to sufentanil and propofol sedation can reduce the incidence and severity of SRAEs in patients at average risk for SRAEs undergoing cervical conization. This sedation regimen provides equal sedation efficacy, recovery quality, and patients’ and gynecologists’ satisfaction without additional psychomimetic side effects compared to sedation regimen with sufentanil and propofol. The compromise protocol of administering a half dosage of both sufentanil and esketamine during BIS-guided propofol TCI sedation is an appropriate regimen.

SRAEs: sedation-related adverse events; NMDA: N-methyl-d-aspartate; TCI: target-controlled infusion; BIS: bispectral index; CIN: cervical intraepithelial neoplasia; BMI: body mass index; ASA: American Society of Anesthesiologists; HR: heart rate; SpO2: pulse oxygen saturation; RR: respiratory rate; PETCO2: end tidal carbon dioxide concentration; VT: tidal volume; MAP: mean arterial pressure; Cpt: target plasma concentration; Ce: effect site concentration; MOAA/S: modified observed assessment of alertness/sedation; PACU: post anesthesia care unite.

Ethics approval and consent to participate

Ethical approval was obtained from the Ethics Committee of Zibo Central Hospital (No. 202009001) on September 1, 2020. Written informed consent to participate was acquired from every patient before participation, and the research was carried out in accordance with the Declaration of Helsinki.

Consent for publication

Not applicable.

Availability of data and materials

The datasets supporting the conclusions of this article are available in the Clinical Trial Management Public Platform, http://www.medresman.org.cn/uc/project/projectedit.aspx?proj=7307. The datasets analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declared that they have no competing interests.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author’s contributions

JS was the major contributor to the design of the work, analyzing data and drafting the manuscript. XL was responsible for the thesis writing and language polishing. YW performed data collection. MT and NF helped supervise data collection, data analysis and interpretation. MC supervised the data collection and analysis, edited the final manuscript. All authors read and approved the final manuscript.

Acknowledgements

Not applicable.

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No competing interests reported.

Effects of adding low-dose esketamine to sufentanil and propofol sedation during cervical conization: a prospective, single-center, randomized controlled trial

Status:

Journal Publication

Version 1

Abstract

Background

Methods

Results

Conclusion

Trial registration

Figures

Background

Methods

Study design and ethics

Participants

Randomization and blinding

Sedation methods and monitoring

Outcome and outcome assessment

Statistical analysis

Results

Patients’ characteristics

Primary endpoint

Secondary endpoints

Vital parameters during the sedation

Discussion

Limitations

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1