Comparison of 2 effect-site concentrations of remifentanil with midazolam during transrectal ultrasound-guided prostate biopsy under procedural analgesia and sedation: A randomized controlled study

Background:

Until now, target-controlled infusion of remifentanil with midazolam for transrectal ultrasound-guided prostate biopsy has not been described. Here, we investigate 2 effect-site concentrations of remifentanil with intermittent bolus midazolam for transrectal ultrasound-guided prostate biopsy under procedural analgesia and sedation.

Methods:

A prospective, randomized controlled trial including patients who received a transrectal ultrasound-guided prostate biopsy between February 2019 and January 2021 was conducted. Group 1 and Group 2 were respectively administered an initial effect-site concentration of remifentanil of 1.0 ng/mL and 2.0 ng/mL by a target-controlled infusion pump with Minto model. In both groups, maintenance of the effect-site concentration of remifentanil was adjusted upward and downward by 0.5 ng/mL to keep patient comfort with acceptable pain (remaining moveless), and mean arterial pressure and heart rate within baseline levels ± 30%, and using intermittent bolus midazolam to keep the Observer’s Assessment of Alertness/Sedation scale between 2 and 4. The primary outcome was to determine which effect-site concentration of remifentanil provide adequate patient comfort with acceptable pain (remaining moveless) during the procedure.

Results:

A total of 40 patients in Group 1 and 40 patients in Group 2 were eligible for analysis. Most parameters were insignificantly different between Group 1 and Group 2, except Group 1 having higher peripheral oxygen saturation while probe insertion compared with Group 2. Group 2 patients had less intraoperative movements affecting the procedure (2 vs 18; P < .001), and less total times of target-controlled infusion pump adjustment (0 [0–1] vs 1 [0–3], P < .001) compared with group 1. However, group 1 patients had less apnea with desaturation (peripheral oxygen saturation < 90%; 0 vs 9, P = .002) and less remifentanil consumption (94.9 ± 25.5 μg vs 106.2 ± 21.2 μg, P = .034) compared to Group 2.

Conclusion:

In transrectal ultrasound-guided prostate biopsy, target-controlled infusion with remifentanil Minto model target 2.0 ng/mL with 3 to 4 mg midazolam use provided sufficient analgesia and sedation, and appropriate hemodynamic and respiratory conditions.

1. Introduction

Transrectal ultrasound (TRUS)-guided prostate biopsy has become the standard procedure for diagnosing early prostate cancer^[1]; it causes significant pain and discomfort when performed without procedural sedation and analgesia.^[2] Many anesthetic methods have been used in TRUS-guided prostate biopsy; however, there is no gold-standard method. Procedural analgesia and sedation (PAS) are one of the commonly used approaches.^[3] Besides providing effective analgesia and sedation to reduce pain and anxiety, it is necessary to maintain stable hemodynamic and respiratory conditions during diagnostic and painfully therapeutic interventional procedures.^[4,5]

For its unique properties, including rapid onset, precise intraoperative control, and a fast recovery profile, remifentanil (REMI) is preferable to other opioids administration in a target-controlled infusion (TCI) pump.^[6,7] Midazolam is widely used alone or in combination with opioids such as REMI due to its quick onset of action and relatively short duration of effect for PAS.^[8]

Previous study showed that combination of propofol and REMI was a safe and effective way to alleviate patient pain and increase patient satisfaction during TRUS-guided prostate biopsy.^[1] However, propofol and REMI are often administered with 2 TCI pumps to respectively provide hypnotic and analgesic effects, which together are considered to be an ideal anesthetic technique.^[9] In addition to a 2-fold increase in the number of TCI supplies used (including pumps, syringes, and extension tubes, etc), it takes time to set the TCI model for propofol and REMI if they are infused separately. Therefore, we conduct TCI of REMI with intermittent bolus midazolam to deal with abovementioned problem.

Doğanca et al^[2] reported that REMI infusion by syringe pump was successfully used in combination with midazolam in TRUS-guided prostate biopsy under PAS.^[2] Until now, there is limited data on the use of TCI of REMI with midazolam in TRUS-guided prostate biopsy under PAS. In our previous study, we showed that TCI with REMI Ce of 2.0 ng/mL and 3 to 4 mg midazolam use provided appropriate hemodynamic and respiratory conditions, and sufficient analgesia and sedation under PAS in percutaneous transluminal balloon angioplasty for dysfunctional hemodialysis fistulas.^[10] Thus, this study investigated 2 effect-site concentration (Ce) of REMI with midazolam for TRUS-guided prostate biopsy under PAS.

2. Methods

2.1. Study Design and Setting

This prospective, randomized controlled trial was conducted at Tri-Service General Hospital (TSGH), Taipei, Taiwan, Republic of China.

2.2. Participants and Data Sources

This study was approved by the Ethics Committee (TSGHIRB No: 2-108-05-011) of TSGH, Taipei, Taiwan (Chairman, Professor Yu Mu Hsien) on February 20, 2019. Participants were recruited with written informed consent obtained before surgery. From February 2019 to January 2021, 80 cases with American Society of Anesthesiologists (ASA) physical status classifications of I–III in our hospital scheduled to receive elective TRUS-guided prostate biopsy under PAS were included in the study. Cases were randomized 1:1 into Group 1 (initial REMI Ce of 1.0 ng/mL) or Group 2 (initial REMI Ce of 2.0 ng/mL) by using a computer-generated random code. All PASs were performed by one single anesthesiologist (H.C. Lai), and data were recorded by a nurse anesthetist who was blinded. In addition, cases and the operator were blinded. Exclusion criteria were as follows: age < 20 or > 80 years, ASA classifications > III, body mass index > 30 kg/m², allergic reactions to REMI or midazolam, chronic obstructive pulmonary disease, congestive heart failure, hepatic or renal failure, chronic use of opioid drugs, and active anal or rectal problems.

2.3. Anesthesia and Monitoring

All fasted overnight cases were without premedication before anesthesia induction. Standard monitoring, such as noninvasive blood pressure, electrocardiography (lead II), pulse oximetry (SpO₂), end-tidal carbon dioxide pressure (EtCO₂) were used for each case. Cases received 100% oxygen at 6 L/min by using a facial mask throughout surgery.

At anesthesia induction, all cases received intravenous midazolam 2.0 to 2.5 mg, and then continuous infusion of REMI (50 µg/mL) were delivered using Minto model of TCI (Fresenius Kabi Injectomat TIVA Agilia Syringe Pump, Germany) with the initial Ce of 1.0 ng/mL in Group 1 and 2.0 ng/mL in Group 2. During anesthesia maintenance, the REMI Ce was adjusted upward or downward by 0.5 ng/mL to make patient remaining moveless as adequate analgesia, moderate to deep sedation with intermittent bolus midazolam 1 to 1.5 mg per time (the maximal midazolam dose was no more than 5 mg in the 2 groups) to maintain the Observer’s Assessment of Alertness/Sedation (OAA/S) scores of 2 to 4, and stable hemodynamics with mean arterial pressure (MAP) and heart rate (HR) within baseline levels ± 30%.^[10] In addition, when apnea without desaturation (SpO₂ ≥ 90%) occurred, we conducted jaw elevation to keep airway open. Whereas positive-pressure mask ventilation (with 100% oxygen at 6 L/min) and decreasing REMI Ce were conducted, while apnea with desaturation (SpO₂ < 90%) occurred. The REMI infusion was stopped after the last needle biopsy. Cases were monitored for MAP, HR, SpO₂, respiratory rate (RR), EtCO₂, the REMI Ce, and OAA/S scores at the T1: before anesthesia induction, T2: time of the probe insertion, T3: time of the needle biopsy, and T4: time of the end of surgery. After the procedure, patients were transferred to the postoperative anesthesia care unit (PACU) under clear consciousness for further observation.

2.4. Surgical procedure

The elective TRUS-guided prostate biopsies were conducted by the same urologist (CL Chen). All cases were placed in the lithotomy position, and digital rectal examinations were followed by rectal cleaning with Betadine. About 10 mL of 2% intrarectal lidocaine gel was instilled into the rectum while probe insertion. All cases underwent a 12-core prostatic biopsy (without targeted biopsy or additional biopsies for visualized lesions) under ultrasound guidance using the same ultrasound machine (Hawk 2102, BK Medical, Copenhagen, Denmark), a biplane TRUS probe (Type 8818 biplane TRUS probe; BK Medical, Copenhagen, Denmark), and an 18‐gauge 25‐cm‐long cutting needle with a Pro-Mag biopsy gun (Angiotech, Stenlose, Denmark). A Betadine pack was used at the end of the procedure.

2.5. Outcomes

The primary outcome was to determine which REMI Ce provide patients adequate analgesia (remaining moveless) during the procedure. Secondary endpoints included hemodynamic and respiratory conditions (such as MAP, HR, EtCO₂, SpO₂, and RR), adverse events such as hypotension (MAP < 60 mm Hg), ephedrine requirements (systolic blood pressure [SBP] < 80 mm Hg), apnea with desaturation (SpO₂ < 90 %), postoperative nausea and vomiting (PONV), REMI-induced hyperalgesia at PACU, total dosage of anesthetics, and frequency of TCI pump adjustments (including upward or downward) during surgery. In addition, visual analog scale (VAS) at PACU, and patient or surgeon satisfaction (0–4) were recorded. Patient satisfaction levels were evaluated at discharge on a 0 to 4 point numerical scale: 0, extremely dissatisfied; 1, dissatisfied; 2, neither satisfied nor dissatisfied; 3, satisfied; 4, extremely satisfied.^[10]

2.6. Statistical analysis

Based on the same surgical procedures in our institution, the sample size and power analysis were conducted by reducing patient movements which affect surgery proceeding as the primary variable. To reduce the incidence of patient movements affecting procedures from 45% to 15%. A size of 35 patients in each group was required at a power of 80% and a type I error of 0.05. Considering loss to follow-up, as this was ambulatory surgery, the sample size was calculated to be 40 patients per group. Data were expressed as numbers, means ± standard deviations, and medians with the range or percentage, unless otherwise indicated. Demographic and perioperative variables were compared using Student t tests or Mann-Whitney test if the data were not normally distributed. Categorical variables were compared using chi-square or Fisher exact test if needed. A P value < 0.05 is statistically significant. Statistics were performed by using SigmaPlot version 14.5 for Windows.

3. Results

A total of 80 patients undergoing TRUS-guided prostate biopsy with PAS were enrolled; ultimately, 40 patients in Group 1 and 40 patients in Group 2 (Fig. 1). The demographic data and analysis of anesthetic management for the 2 groups are shown in Table 1. The patients’ characteristics were similar between groups. Total prostate volume was 46.7 ± 1.7 mL in Group 1 and 47.2 ± 1.5 mL in Group 2 (P = .167). There was no significant difference between Group 1 and Group 2 in terms of anesthesia time (P = .117) or procedure time (P = .249). There was no significant difference in midazolam consumption during surgery (Group 1: 3.80 ± 0.98 mg vs Group 2: 3.65 ± 0.94 mg; P = .643). REMI consumption in Group 2 (106.2 ± 21.2 μg) was higher than that in Group 1 (94.9 ± 25.5 μg) during surgery (P = .034). The median of upward adjustments was 1 (0–3) in Group 1 and 0 (0–1) in Group 2 (P < .001) and the median of downward adjustments was 0 (0–0) in Group 1 and 0 (0–1) in Group 2, respectively (P = .001). The total number of TCI pump adjustments was higher in Group 1 than in Group 2 (1 [0–3] vs 0 [0–1], respectively, P < .001) (Table 1). The surgeon satisfaction level was higher in Group 2 (3 [3–4]) than in Group 1 (3 [3–4]) (P < .001; Table 1). There was no significant difference in VAS between groups (Group 1: 3 [2–3] vs Group 2: 3 [2–3]; P = .849) in the PACU.

Figure 1.

Flow diagram showing patient flow according to the study protocol.

Table 1.

Patients’ characteristics and analysis of anesthetic management.

	Group 1 (n = 40)	Group 2 (n = 40)	P value
ASA II/III	37/3	38/2	0.644
Age (yr)	65.4 ± 6.4	65.2 ± 7.4	0.897
Height (cm)	167.2 ± 6.4	169.1 ± 5.9	0.171
Weight (kg)	70.9 ± 9.1	69.1 ± 9.5	0.389
Total prostate volume (mL)	46.7 ± 1.7	47.2 ± 1.5	0.167
Anesthesia time (min)	20.7 ± 4.8	19.1 ± 4.2	0.117
Procedure time (min)	13.5 ± 3.8	12.6 ± 3.1	0.249
Midazolam consumption (mg)	3.80 ± 0.98	3.65 ± 0.94	0.643
REMI consumption (μg)	94.9 ± 25.5	106.2 ± 21.2	0.034
Total times of TCI pump adjustment (n)	1 (0–3)	0 (0–1)	<0.001
Upward (n)	1 (0–3)	0 (0–1)	<0.001
Downward (n)	0 (0–0)	0 (0–1)	0.001
VAS at PACU	3 (2–3)	3 (2–3)	0.849
Patient satisfaction (0–4)	3 (3–4)	3 (3–4)	0.704
Surgeon satisfaction (0–4)	3 (3–4)	3 (3–4)	<0.001

Data are shown as mean ± SD or median (range) or number. Group 1: initial REMI Ce of 1.0 ng/mL; Group 2: initial REMI Ce of 2.0 ng/mL;

ASA = American Society of Anesthesiology, Ce = effect-site concentration, PACU = postanesthesia care unit, REMI = remifentanil, SD = standard deviation, TCI = target-controlled infusion, VAS = visual analogue scale.

There was no significant difference in MAP, HR, RR, and EtCO₂ pressure between groups at each time point (Fig. 2). There was also no significant difference in SpO₂ between groups at each time point (except T2). At T2 (time of the probe insertion), the SpO₂ in Group 1 was significantly higher (99.4 ± 0.5 %) than that in Group 2 (97.2 ± 4.7 %; P = .005; Fig. 2B). However, it was not clinically significant.

Figure 2.

(A) Changes of MAP and HR during every step of transrectal ultrasound-guided prostate biopsy. Time point: before anesthesia induction, time of the probe insertion, time of the needle biopsy, time of the end of procedure. Data were presented as mean ± SD; *P < .05 compared with Group 1 at each time point measurement. (B) RR [times/min], EtCO₂ [mm Hg], and SpO₂ [%] during every step of transrectal ultrasound-guided prostate biopsy. Time point: (1) before anesthesia induction, (2) time of the probe insertion, (3) time of the needle biopsy, (4) time of the end of procedure. Data were presented as mean ± SD. *P < .05 compared with Group 1 at each time point measurement. bpm = beats per minute, EtCO₂ = end-tidal carbon dioxide pressure, HR = heart rate, MAP = mean arterial pressure, RR = spontaneous respiratory rate, SD = standard deviation, SpO₂ = peripheral oxygen saturation.

Table 2 indicated adverse events that occurred during the procedure for the 2 groups. Eighteen patients (45.0%) in group 1 and 2 patients (5.0%) in group 2 moved and affected surgery proceeding (P < .001; Table 2). After judicious adjustment of the REMI Ce, the procedures were completed without any incident. There was no occurrence of hypotension (MAP < 60 mm Hg) in both groups, and there was no patient requiring ephedrine administration due to SBP < 80 mm Hg in either group. Moreover, there was no patient (0%) undergoing apnea with desaturation (SpO₂< 90%) in group 1, but 9 patients (22.5%) undergoing apnea with desaturation (SpO₂< 90%) in Group 2 (P = .002; Table 2). The SpO₂ was within 88% to 89% and returned to normal range immediately after jaw trust or mask ventilation and reducing REMI Ce.

Table 2.

Adverse events during the procedure.

	Group 1 (n = 40)	Group 2 (n = 40)	P value
Patient movements affecting the procedure	18 (45.0%)	2 (5.0%)	<0.001
Hypotension (mean arterial pressure < 60 mm Hg)	0 (0%)	0 (0%)	1.000
Patients requiring ephedrine (systolic blood pressure < 80 mm Hg)	0 (0%)	0 (0%)	1.000
Apnea with desaturation (SpO2 < 90%)	0 (0%)	9 (22.5%)	0.002
Postoperative nausea and vomiting	0 (0%)	0 (0%)	1.000
REMI-induced hyperalgesia	0 (0%)	0 (0%)	1.000

Data are shown as number (percentage). Group 1: initial REMI Ce of 1.0 ng/mL; Group 2: initial REMI Ce of 2.0 ng/mL.

Ce = effect-site concentration; REMI = remifentanil, SpO₂ = peripheral oxygen saturation.

In addition, no one suffered from REMI-induced hyperalgesia and PONV (during follow-up within 24 hours) in each group (Table 2).

Table 3 compared the REMI Ce and OAA/S scale during TRUS-guided prostate biopsy between groups. There were significant differences in REMI Ce between groups at each time point except T1(before anesthesia induction). At T2, time of the probe insertion, the REMI Ce was 1.44 ± 0.25 ng/mL in Group 1 and 1.89 ± 0.21 ng/mL in Group 2 (P < .001); at T3, time of the needle biopsy, the REMI Ce was 1.70 ± 0.33 ng/mL in Group 1 and 1.91 ± 0.25 ng/mL in Group 2 (P = .002); at T4, time of the end of procedure, the REMI Ce was 1.70 ± 0.33 ng/mL in Group 1 and 1.91 ± 0.25 ng/mL in Group 2 (P = .002; Table 3). There was no significant difference in OAA/S scale between groups at each time point (Table 3).

Table 3.

REMI Ce and OAA/S score during the procedure.

		T1	T2	T3	T4
REMI Ce	Group 1	0 ± 0	1.44 ± 0.25	1.70 ± 0.33	1.70 ± 0.33
	Group 2	0 ± 0	1.89 ± 0.21†	1.91 ± 0.25*	1.91 ± 0.25*
OAA/S score	Group 1	5 (5–5)	3 (2–3)	3 (2–3)	3 (2–3)
	Group 2	5 (5–5)	3 (2–4)	3 (2–4)	3 (2–4)

Data are shown as mean ± SD. Group 1: initial REMI Ce of 1.0 ng/mL; Group 2: initial REMI Ce of 2.0 ng/mL.

Ce = effect-site concentration, OAA/S = observer assessment of alertness/sedation, REMI = remifentanil, SD = standard deviation, T1 = before anesthesia induction, T2 = time of the probe insertion, T3 = time of the needle biopsy, T4 = time of the end of procedure.

^*P < .05 compared with Group 1 at each time point measurement.

^†P < .001 compared with Group 1 at each time point measurement.

4. Discussion

REMI infusion by syringe pump with midazolam has been administrated to offer PAS for TRUS-guided prostate biopsy and breast biopsies.^[2,11] However, to the best of our knowledge, there are no data on the use of TCI of REMI with midazolam in TRUS-guided prostate biopsy under PAS. Here, we first reported that REMI Ce of 2.0 µg/mL by TCI pump with 3 to 4 mg midazolam and intrarectal lidocaine gel use provided adequate analgesia and sedation, appropriate hemodynamic conditions, acceptable adverse events (apnea with desaturation; SpO₂ 88%–89%), and better surgeon satisfaction in TRUS-guided prostate biopsy under PAS as our previous research in percutaneous transluminal balloon angioplasty for dysfunctional hemodialysis fistulas.^[10]

Anesthesia for TRUS-guided prostate biopsy should be quick in onset of action, have an easily reversible effect, and result in minimal adverse effects while allowing the procedure to be performed on an outpatient basis. The Urological Society of Australia and New Zealand prostate biopsy survey in 2013 showed that 57% of urologists used PAS or general anesthesia, 28% periprostatic nerve block (PNB), and 4% no analgesic agent.^[12] However, using no analgesia for this procedure is no longer considered to be acceptable,^[13] and PAS is one of the commonly used techniques.^[3] The ideal anesthetics should have a rapid onset and short duration of action, be safe, and possess analgesic and amnestic properties while allowing for rapid recovery and discharge.^[2] The concurrent use of midazolam and REMI in this study has been verified to achieve these criteria.^[11] Midazolam, a sedative, amnestic, anxiolytic, and muscle-relaxant drug is commonly used with an opioid analgesic.^[11] REMI is a potent opioid analgesic with an ultrashort half-life (3–5 minutes) that has been proven to be a good supplement to local anesthetics during PAS.^[11] Propofol is an ultrashort-acting sedative and amnestic medication that can be used as an ancillary drug if needed, due to its short half-life, which allows for easy control of sedation level.^[14] Therefore, propofol is the mainstay drug for PAS due to its pharmacodynamic and pharmacokinetic property.^[15] But propofol may result in cardiovascular and respiratory depression, with a greater extent compared with other intravenous sedative drugs in geriatric cases.^[16] Besides, propofol and REMI are usually delivered by 2 TCI pumps to respectively offer sedative and analgesic effects.^[9] Sometimes, multiple TCI systems are unavailable or time- and cost-consuming, such as sedation/anesthesia outside the operating room or short-term procedures. However, REMI-midazolam offers sufficient analgesia and sedation, less hemodynamic and respiratory changes, and less side effects compared with REMI-propofol under PAS.^[17] Accordingly, TCI of REMI with intermittent bolus midazolam might be more suitable for TRUS-guided prostate biopsy under PAS.

This study is in accordance with the results of Doğanca et al,^[2] which revealed that TRUS-guided prostate biopsy was performed with PAS using 0.04 mg/kg of midazolam and 1 µg/kg/min (about Ce 2.0 ng/mL) of REMI within the first 20 seconds, followed by infusion of REMI at 0.5 µg/kg/min (about Ce 1.0 ng/mL) in combination with PNB. In this previous study, 4 cases (4.2%) under PAS with PNB encountered apnea with desaturation requiring airway insertion, but not intubation.^[2] Our results showed that 9 cases (11.3 %) undergoing PAS without PNB encountered apnea with desaturation requiring mak ventilation and decrement of REMI Ce, which was similar to the previous study.^[2] Ozveri et al^[18] showed that VAS in the patients with PNB was significantly better compared to the patients without PNB. However, Klein et al^[19] reported that PNB seem to have a lasting impact on voiding function in prostate biopsy. In addition, Izol et al^[20] reported that the VAS under PAS (midazolam and fentanyl) was lower than under PNB or intrarectal lidocaine gel use in TRUS-guided biopsy. Moreover, Naidoo et al^[21] reported an acceptance rate of 87.0% versus 95.7% in the intrarectal lidocaine gel and PNB groups, which was not significantly different between both groups. Aslan et al^[22] reported that pudendal nerve blockade, another technique, might provide more effective pain control compared to PNB. But it might contribute to the reduction in voiding efficiency just like PNB.^[19,23] In this study, TCI of REMI with intermittent bolus midazolam with intrarectal lidocaine gel without PNB was applied based on an easier and similar way for our daily clinical practice. Finally, we chose the initial REMI Ce of 1.0 or 2.0 ng/mL with midazolam loading dose of 2 to 2.5 mg that was resulted from our clinical experience in the presented and previous studies.^[10] Additionally, parameters, such as MAP and HR, were maintained at baseline levels ± 30%, the OAA/S scores of 2 to 4, and patient comfort (remaining moveless) by adjusting the REMI Ce and intermittent bolus midazolam by OAA/S scores during surgery, making our findings more clinically feasible.

The total times of TCI adjustment in group 1 was significantly higher than in group 2. The REMI Ce of 2.0 ng/mL could offer sufficient analgesia and the incremental dose of midazolam could deepen sedation with adequate hemodynamics, nevertheless, elevating the incidence of respiratory depression. There were 9 cases undergoing apnea with desaturation in Group 2, but no case in Group 1. The apnea with desaturation occurred during probe insertion, however, after jaw thrust, mask ventilation, and decreasing REMI Ce of 0.5 ng/mL, the surgery was finished without any accident. Therefore, we believed these effects were not of clinical significance or concern. Prior research revealed that the risk of respiratory depression is higher while concurrent use of midazolam and an opioid.^[24,25] Nausea and vomiting was the other concern for the anesthesiologists, but no case suffered from PONV during follow-up (within 24 hours). Concurrent use of REMI and midazolam may induce serious respiratory depression, so we recommend that this type of anesthesia should only be conducted by trained anesthetists.

One of the crucial things is the patient or surgeon satisfaction in this study. The patient satisfaction is similar between groups; however, the surgeon satisfaction is higher in Group 2 based on less patient movements which affect surgery proceeding. Our results show that keeping patient moveless under PAS offers higher surgeon satisfaction.

There are a few limitations in the presented study. First, we do not use bispectral index (BIS) and analgesia nociception index (ANI) monitoring in TRUS-guided prostate biopsy under PAS. The BIS index correlates well with hypnotic state and could decrease the risk of intraoperative awareness.^[26,27] However, further evaluation of economic effect is needed due to the short duration of surgery under PAS. Besides, OAA/S score is correlated with BIS index.^[28] Funcke et al^[29] demonstrated that clinical signs such as HR and MAP are inferior in detecting painful stimuli under sedation compared with ANI. Nevertheless, until now, most anesthesiologists do not apply BIS and ANI in this minor procedure under PAS. Second, we choose the initial REMI Ce of 1.0 or 2.0 ng/mL with midazolam loading dose of 2 to 2.5 mg based on our clinical experience. And we only investigate 2 concentrations of REMI in this study. Further research is required to find out the optimal REMI Ce in different kinds of surgery or procedures. Third, several factors might influence the outcome of the study, such as relatively high dose of midazolam (3–4 mg) to keep moderate sedation during PAS, combination use of intrarectal lidocaine gel, and only one anesthesiologist or urologist in this study. However, in our country, most patients prefer moderate sedation rather than light sedation, and 3 to 4 mg of midazolam with continuous infusion of REMI is feasible and safe for patients during PAS.^[10] In addition, the use of intrarectal lidocaine gel might only diminish the sensation of pain while probe insertion, but not during insertion of needles.^[30] Moreover, only one anesthesiologist or urologist is based on our study design. All these factors should be analyzed in the future studies.

In conclusion, in elective TRUS-guided prostate biopsy with intrarectal lidocaine gel under PAS, REMI infusion by TCI with target concentration of 2.0 ng/mL in combination with use of 3 to 4 mg midazolam offered adequate anesthesia, appropriate hemodynamic conditions, acceptable adverse events, and better surgeon satisfaction.

Author contributions

1. Author: Hou-Chuan Lai, MD

• Contribution: This author designed and conducted the study, and wrote the main article text.

2. Author: Chin-Li Chen, MD

• Contribution: This author designed the study, helped with data analysis, and prepared the main article text.

3. Author: Yi-Hsuan Huang, MD

• Contribution: This author helped with data collection and analysis.

4. Author: Ke-Li Wu, MD

• Contribution: This author helped with data collection and analysis.

5. Author: Ren-Chih Huang, MD.

• Contribution: This author helped with data collection and analysis.

6. Author: Bo-Feng Lin, MD

• Contribution: This author helped with data collection and analysis.

7. Author: Shun-Ming Chan, MD, PhD

• Contribution: This author helped with data collection and analysis.

8. Author: Zhi-Fu Wu, MD

• Contribution: This author designed the study, and wrote the main article text.