Procedural Sedation and Analgesia as an Adjunct to Periprostatic Nerve Block for Prostate Biopsy: A Prospective Randomized Trial anca, MD,1 Abdurrahman Savsin, MD,2 Sarper Erdog an, MD, PhD,3 Fatis Altindas, MD,2 T€ unkut Dog 4 2 5 € € Fatih Ozdemir, MD, Birsel Ekici, MD, Can Obek, MD 1
Department of Urology, Suluova State Hospital, Amasya, Turkey Department of Anesthesiology, University of Istanbul, Cerrahpas¸a School of Medicine, Fatih, Istanbul, Turkey 34300 3 Department of Public Health, University of Istanbul, Cerrahpas¸a School of Medicine, Fatih, Istanbul, Turkey 34300 4 Department of Urology, Palandoken State Hospital, Erzurum, Turkey 5 Department of Urology, University of Istanbul, Cerrahpas¸a School of Medicine, Fatih, Istanbul, Turkey 34300 2
Received 5 September 2013; accepted 22 July 2014
ABSTRACT: Background. To assess whether patient comfort could be increased by adding procedural sedation and analgesia (PSAA) to periprostatic nerve block (PNB) in patients undergoing transrectal ultrasound-guided prostatic biopsy (TRUS-PB). Methods. This was a prospective, randomized (1:2) trial comparing PNB with the combination of PSAA1PNB in patients undergoing TRUS-PB. PNB was achieved by using lidocaine gel and lidocaine and bipuvacaine infiltration. PSAA-treated patients received midazolam and remifentanil. All biopsies were standardized and performed in a fully equipped endourology suite. PSAA was delivered by an anesthesiology nurse in the presence and availability of an anesthesiologist. An orally administered numeric scale of 0–10 was used to assess the patient’s pain, and a visual scale of 0–4 was used to quantify their satisfaction. Pain and satisfaction scores were compared between the groups. Results. Data on 331 patients were analyzed: 235 received PNB, and 96 received PSAA1PNB. Distribution within the groups by age, prostate-specific antigen serum levels, prostate volume, and number of cores obtained was similar. Airway insertion was required in 4 of 96 patients in PSAA1PNB arm (4%), with no other complications related to sedation. The average pain level was significantly lower in the Correspondence to: C. Obek C 2014 Wiley Periodicals, Inc. V
288
PSAA1PNB group than it was in the PNB group (0.88 versus 1.31; p 5 0.008). The satisfaction level was high (3.5) and alike in the two groups; however, significantly more patients reported a perfect score of 4 in the PSAA1PNB arm (p 5 0.03). Conclusions. PSAA with midazolam and remifentanil used as an adjunct to the standard PNB is safe and effective during TRUS-PB. Patients undergoing PSAA in addition to PNB experienced significantly less pain and higher satisfaction scores than did those given PNB C 2014 Wiley Periodicals, Inc. J Clin Ultrasound alone. V 43:288–294, 2015; Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jcu.22227 Keywords: transrectal utrasound-guided prostate biopsy; procedural sedation; anesthesia; analgesia; ultrasonography
P
rostate biopsy (PB) is one of the most commonly performed outpatient procedures in urology. It causes significant pain and discomfort when performed without some form of anesthesia.1–3 Local anesthesia with periprostatic nerve block (PNB) remains the current standard of care for preventing pain and discomfort during this procedure.4 However, some patients report pain despite PNB, and means to improve local anesthesia would be beneficial for these men. Procedural sedation and analgesia (PSAA) refers to techniques of managing patients’ pain JOURNAL OF CLINICAL ULTRASOUND
ANALGESIA AS NERVE BLOCK FOR PROSTATE BIOPSY
and anxiety to facilitate appropriate medical care in a safe, effective, and humane fashion.5 It creates a suppressed level of consciousness sufficient to tolerate the performance of painful or unpleasant procedures in a way that minimizes patient awareness, discomfort, and memory, while attempting to preserve spontaneous respiration and airway-protective reflexes.5 Sedative-hypnotics and opioid analgesics are frequently used in combination to provide patient comfort, sedation, anxiolysis, and supplemental analgesia during surgical procedures performed under local anesthesia.5 Although PSAA is commonly used for endoscopic procedures and biopsies in various disciplines, it has rarely been reported for PB.3,6,7 Our aim was to explore the role of PSAA during PB. We assessed the efficacy and safety of PSAA when used as an adjunct to PNB for patients undergoing transrectal utrasoundguided PB (TRUS-PB) and compared it to the current gold standard, PNB, alone.
PATIENTS AND METHODS
This was a prospective randomized trial comparing local anesthesia induced with PNB to that induced with PSAA1PNB for patients undergoing TRUS-PB. The primary endpoint was the effect of the additional procedural sedation on patients’ pain and satisfaction levels during TRUS-PB. The secondary endpoint was the effect on complications. The study included consecutive patients undergoing TRUS-PB within a 28-month period. Study subjects gave their written informed consent, and approval from our ethical committee was obtained. A 2:1 randomization scheme was used to reduce trial cost without compromising statistical power.8 All patients approached consented to participate in the study and randomization, and none refused the arm he was randomized to. Exclusion criteria included repeat biopsy; use of opioid drugs; allergy to midazolam, remifentanil, or propofol; and active anal or rectal problems. Demographic data and medical histories were recorded. Patients randomized to anesthesia with PSAA1PNB were evaluated by an anesthesiologist before the biopsy date. This visit included a physical examination and assessment of the patient’s coagulation profile. We complied with the American Society of Anesthesiologists recommendation for fasting: 2 hours for clear liquids and 6 hours for food before PSAA.9 AntiVOL. 43, NO. 5, JUNE 2015
biotic prophylaxis consisted of three doses of 500 mg of ciprofloxacin, and a self-administered enema was performed before the procedure. The procedures were performed in a fully equipped endourology suite with the patients in the lateral decubitus position. The TRUS-PB technique was standardized; all procedures € or were performed by the same urologist (C.O.) by his assistants using the same ultrasound (US) machine (SonolineAdara; Siemens Corp., Germany). The TRUS-PB was performed in the sagittal plane with a 25-cm-long 18-gauge TruCut–type cutting needle and a Pro-Mag biopsy gun (Angiotech, Knud Bro Alle 3, 3660 Stenlïse, Denmark). In the PNB group, lidocaine gel (2%) was applied to the anal sphincter and rectum 10 minutes before probe insertion, followed by infiltration with 5 mL of lidocaine (2%) and 5 mL of bupivacaine (0.5%) at the prostate base on both sides, as previously described.10 Five minutes was allowed for the local block to take effect and the biopsies to be obtained. In the PSAA1PNB group, lidocaine gel was initially applied to the rectum. After 10 minutes, PSAA was initiated with 0.04 mg/kg of midazolam and 1 mg/kg/min of remifentanil within the first 20 seconds, followed by infusion of remifentanil at 0.5 mg/kg/min. The PNB was achieved in exactly the same way it was in the patients in the PNB-only group, once the patient was fully sedated. If sedation with the midazolam and remifentanil was inadequate, 1 mg/kg of propofol was used as an ancillary drug. PSAA was performed by an anesthesiology nurse in the presence and availability of an anesthesiologist. Sedation was kept at level of 3 or 4 on the Ramsay sedation scale.11 Patient monitoring included electrocardiography, heart rate, noninvasive blood pressure, and peripheral oxygen saturation. Patients spontaneously breathed 5 L/min of oxygen via face mask. When oxygen saturation dropped below 90%, patients were verbally stimulated, and the remifentanil infusion was stopped. In circumstances when this maneuver was insufficient, an airway was introduced. If the patient’s oxygen saturation failed to normalize with these attempts, mechanical ventilation would be initiated with a bag-valve mask. Patients in the PSAA1PNB arm were kept in the recovery room until they fully recovered from sedation, as judged by an Aldrete score 9 (see Appendix 1) and were prohibited from driving home.12 Before discharge, they were questioned by a resident not involved in the biopsy procedure about the extent of their pain and 289
DOGANCA ET AL TABLE 1 Between-Group Distribution of Several Clinical Variables
Group PNB alone PSAA1PNB Total study population
Age (years)*
Prostate Volume (mL)*
Prostate-Specific Antigen (ng/mL)*
Number of Cores Obtained*
65.3 6 8.4 64.3 6 8.8 65.0 6 8.5
45.1 6 24.5 47.8 6 20.9 47.0 6 23.5
10.6 6 11.8 9.3 6 12.5 10.2 6 12.2
14.8 6 5.2 14.9 6 5.0 14.8 6 5.2
Abbreviations: PNB, periprostatic nerve block; PSAA, procedural sedation and analgesia. *p > 0.05.
their degree of satisfaction with the procedure. An orally administered numeric scale (0, none; 10, intolerable pain) was used to evaluate pain, and a visual numeric scale (0, terrible; 4, perfect [Appendix 2]) was used to quantify their satisfaction; only whole numbers were allowed. Complications were recorded. Statistical Analysis An a priori sample size estimation was performed with an alpha level of 0.05, power of study (beta) of 0.95, and effect size of 0.5. The calculation was made by using the program Gpower 3.1.2, developed by Franz Faul at Kiel University. This program calculates the effect size based on estimations of group means and standard deviations. The allocation ratio between the two study groups was 2; the minimum numbers in the groups were to be 157 and 79. The numeric variables of the study were pain score, satisfaction score, prostate-specific antigen serum level, age, and prostate volume. The categorical variable was the type of anesthesia. Numeric variables were calculated as means and standard deviations and presented with minimum and maximum values, whereas the categorical variable was presented as frequencies and percentages. In situations in which the data were clearly not normally distributed or had obvious outliers, the median value was used to describe the distribution. After having confirmed with the Kolmogorov-Smirnov test that the data were normally distributed, Student’s t test was used to compare the pain and satisfaction scores between the two groups. The rate of the highest satisfaction score (ie, 4) was compared between the two groups by using Pearson’s v2 test. The significance value was set at p < 0.05. SPSS, version 15.0 was used for analyzing the data.
RESULTS
Data from 331 patients who underwent TRUSPB and were eligible for the study were ana290
TABLE 2 Between-Group Comparison of Pain Scores Group PNB alone PSAA1PNB Total study population
No. of Patients
Pain Score*
235 96 331
1.3 6 0.8 0.9 6 0.1 1.2 6 1.2
Abbreviations: PNB, periprostatic nerve block; PSAA, procedural sedation and analgesia. *p 5 0.008, Student’s t test.
lyzed: 235 patients in the PNB arm and 96 in the PSAA1PNB arm. The patients’ average age was 65 years: serum prostate-specific antigen, 10.2 ng/mL; prostate volume, 47 mL; and number of cores obtained, 14.8. The distribution of these variables was similar between the two groups, as presented in Table 1. Propofol in addition to midazolam and remifentanil was used in 11 (11%) of the patients. The mean pain score for the entire study group was 1.2 6 1.2 (on a scale of 0–10), and the mean satisfaction score was 3.5 6 0.6 (on a scale of 0–4). When the two groups were compared, the mean pain score was significantly lower in the PSAA1PNB group: 0.9 6 0.1 versus 1.3 6 0.8 (p < 0.01; Table 2). The mean satisfaction score was very high and similar in the two arms: 3.5 6 0.7 versus 3.5 6 0.03 (p > 0.05). However, when those who scored for the highest rate of satisfaction (ie, 4) were compared, significantly more patients in the sedation arm reported a perfect score (p 5 0.03; Table 3). Complications were few. Insertion of an airway because of a drop in oxygen saturation was required in four (4%) of the patients, whereas intubation or mechanical ventilation was not mandatory in any patient. No other complications related to sedation were observed. One patient in the PNB arm had a rectal hemorrhage judged to be excessive; the department of general surgery was consulted, and the bleeding was stopped with the temporary insertion (2 hours) of a tampon in the rectum. A total of three patients (0.9%; two in the PNB arm and JOURNAL OF CLINICAL ULTRASOUND
ANALGESIA AS NERVE BLOCK FOR PROSTATE BIOPSY TABLE 3 Between-Group Comparison of Satisfaction with the Procedure
Group PNB alone PSAA1PNB
No. of Patients
No. (%) Who Chose the Highest Satisfaction Score (ie, 4)*
Mean Satisfaction Score
235 96
119 (50.6) 61 (63.5)
3.5 6 0.03 3.5 6 0.7
Abbreviations: PNB, periprostatic nerve block; PSAA, procedural sedation and analgesia. *p 5 0.032, Pearson’s v2 test.
one in the PSAA 1 PNB arm) had to be readmitted for infection and treated with antibiotics.
DISCUSSION
Pain and discomfort have been reported in 80– 96% of patients undergoing TRUS-PB without anesthesia.13,14 Current guidelines recommend PNB to alleviate pain, but means to further allay patient anxiety and discomfort are under investigation.4 Local anesthesia may be combined with intravenous drugs to provide anxiolysis, sedation, and supplemental analgesia.15 Although PSAA is used in various disciplines for endoscopic procedures and biopsies, its use for transrectal PB has been reported as extremely rarely.3,6,7 We were therefore interested in exploring the role of sedoanalgesia as an adjunct to PNB for TRUS-PB. Anesthesia for PB 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. Consequently, the ideal anesthetic agent 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.9 The combination of midazolam and remifentanil used in the present study has been proven to fulfill those criteria.16 Midazolam, a sedative, amnestic, anxiolytic, and muscle-relaxant drug without analgesic properties is commonly used with an opioid analgesic.16 Remifentanil is a potent opioid analgesic with an extremely short contextsensitive half-life (3–5 minutes) that has been proven to be a good supplement to local anesthetics during PSAA.16 Propofol is an ultrashort-acting sedative and amnestic medication6 that can be used as an ancillary drug if needed, owing to its ultra-short half-life, which allows for easy control of sedation level. VOL. 43, NO. 5, JUNE 2015
Recommendations for the performance of PSAA are well established.11,17,18 Cardiac and pulse-oximetry monitors, oxygen and delivery systems, bag-valve mask, suction, appropriately sized airways and endotracheal tubes, a laryngoscope with appropriate blades, and medications and equipment for cardiac resuscitation are essential.18 Most importantly, the person administering PSAA must have a thorough understanding of the medications, the ability to monitor the patient’s response, and the skills required to intervene to manage complications.5 An operating room is not mandatory; the technique may be applied in an appropriately equipped room by a nonanesthesiologist sedation practitioner in compliance with the American Society of Anesthesiologists guidelines for sedation and analgesia for nonanesthesiologists.9 Absolute contraindications are uncommon; the presence of comorbidity, issues with the patient’s airway, and previous problems with PSAA need to be considered preoperatively. Intravenous sedative and/or analgesic drugs demand administration in small incremental doses to minimize the risk of adverse events. The incidence of respiratory depression is correlated with the level of sedation. Of those with moderate sedation, only 6% have been reported to develop hypoxia requiring intervention by the aneshesiologist6; this is within the range of hypoxia observed in our series. The advantages of complementing PNB with PSAA are several: relieving anxiety, obviating pain from probe insertion and injection of local anesthetic, and producing amnesia. Transrectal biopsy causes significant psychological stress: the anal route of penetration, the fact that the organ under examination is part of the male sexual system, the anticipated pain, and the fear of a potential cancer diagnosis may all add up to a considerable level of anxiety.6 A correlation between prebiopsy anxiety and the magnitude of intraoperative pain has been reported in some series.2,19 This underscores the necessity of administrating anxiolytic drugs and explains in part the lower pain and higher satisfaction scores when the patients are given sedation.20 Another advantage is the elimination of pain related to the probe insertion and the local anesthetic infiltration. Hossack and Woo20 reported that the most intensive pain arose from probe insertion, which cannot be diminished by PNB. In another series, lidocaine infiltration was reported to be the most painful part of the procedure.21 Sedation would be effective in alleviating pain and enhancing comfort at 291
DOGANCA ET AL
these two stages of the procedure. It is important to note that the pain of probe insertion will further influence and intensify the pain during the taking of cores.22 As a consequence, lessening the discomfort of probe insertion may also decrease pain during the actual PB. Many men require repeat biopsies, and they may be reluctant to undergo another PB if they have unpleasant recollections of previous ones.20 However, antegrade amnesia increases patients’ tolerance to repeated procedures, and the use of midazolam has this potential advantage. Speculation is that the central striated–muscle relaxant effect of midazolam might contribute to its overall beneficial effect.7 Publications on the use of sedation for PB are rare.3,6,7 In one of the earliest series reporting on the feasibility of sedation, Turgut et al7 used midazolam and found that moderate to severe pain occurred in 3% of those given sedation, in 29% of those given PNB, and in 80% of men given neither. The pain scores in their sedation and PNB arms were only 1.4 and 2.0, respectively. Our pain scores compare favorably in both groups: 0.9 in PSAA1PNB and 1.3 in PNB patients. Moreover, only one patient in our series reported a pain score of greater than 4. Our superior outcomes in both arms may be explained by the lack of pain relief of midazolam when used alone, as in Turgut’s series, and the additional use of lidocaine gel in our patients for PNB, which further intensifies the effect of PNB.22 In one prospective randomized trial, TobiasMachado et al23 used midazolam in combination with an opiate (meperidine) and compared it with PNB. Severe pain was reported in 3% of the men receiving PNB and in 5% of those receiving sedation. They did not observe any side effects related to sedation. In addition, Peters et al3 reported significantly reduced patient discomfort with propofol. Their pain score was almost identical to that reported by Turgut with midazolam. Apparently, neither of these two agents provides sufficient comfort alone, and they need to be combined with an opioid analgesic, as in our series. By the same token, sedation with propofol alone was associated with greater pain and discomfort than was PNB or combined propofol and fentanyl.24 In another prospective randomized comparison with lidocaine jelly, the combination of propofol and remifantanil resulted in significantly less pain25 and higher satisfaction scores in the monitored anesthesia arm. However, a direct comparison of that study with ours is not possi292
ble, because lidocaine jelly has universally proved to be inferior to PNB.4 This limitation was acknowledged by the authors25 of that previous study, who highlighted the importance of further exploration of the role of sedation in comparison with PNB. Unquestionably, our technique makes the PB procedure more complicated. Caregivers must weigh the patient’s comfort against the technique’s effect on manpower and financial resources and patient inconvenience. We perform our biopsies in an endourology suite, where an anesthesiology team is available regardless of the type of anesthesia. Thus, our performance of the biopsies with PSAA was relatively less complicated under these circumstances; nevertheless, we acknowledge that our setting departs from the usual one, with PBs being mostly performed at outpatient clinics. The main inconveniences for the patients are an extra trip to the hospital for a preoperative anesthesiology visit and not being able to drive for the day after the procedure. However, the extra requirements for PSAA also increase the cost of the procedure. Various parameters account for cost analysis, mainly the presence of an anesthesiologist and the use of an operating room. Each hospital or institution would need to analyze the associated financial burden. At our facility, the additional cost was $45 American per biopsy. In another study, Kang et al25 analyzed the cost of PSAA with propofol and remifentanil at a university hospital in Seoul and reported an additional charge of $169 American. Furthermore, the supplementary charge for general anesthesia in Australia has been reported to be $766 Australian.20 It may be timely to start considering individualizing the optimum type of anesthesia for men undergoing PB. PNB may still be the best option for the majority of cases, although PSAA1PNB might be a better option for some others. It has already been shown that one may predict the level of pain the patient will experience from the biopsy by using simple measurements such as a modified submaximal tourniquet test or pain during prostate examination.26,27 Those tests might be supplemented with others and enriched with tools for establishing anxiety level, a factor known to elevate pain.19 Subsequently, it might be conceivable to ascertain the ideal type of anesthesia for the individual patient. Sedation reportedly may have potential advantages in scenarios such as repeat biopsies, extensive biopsies, patients who might require a repeat biopsy, the presence of JOURNAL OF CLINICAL ULTRASOUND
ANALGESIA AS NERVE BLOCK FOR PROSTATE BIOPSY
anal or rectal disease, younger men, and those with a high anxiety level.1,13,28 Our study was not designed to find out who would benefit from sedation; however, it would be prudent to further explore the role of PSAA in various patient subgroups. In conclusion, PSAA with midazolam and remifentanil used as an adjunct to the standard PNB is safe and effective during TRUS-PB. Patients undergoing PB with PSAA in addition to PNB experienced significantly less pain and higher satisfaction scores than did those given PNB alone.
APPENDIX 2
Satisfaction Evaluation
APPENDIX 1
Modified Aldrete Scoring This system is designed to assess the patient’s transition from phase I recovery to phase II recovery, from discontinuation of anesthesia until return of protective reflexes and motor function. Respiration 2 5 Able to take deep breath and cough 1 5 Dyspnea/shallow breathing 0 5 Apnea O2 Saturation 2 5 Maintains >92% on room air 1 5 Needs O2 inhalation to maintain O2 saturation >90% 0 5 Saturation
Department of Urology, Suluova State Hospital, Amasya, Turkey Department of Anesthesiology, University of Istanbul, Cerrahpas¸a School of Medicine, Fatih, Istanbul, Turkey 34300 3 Department of Public Health, University of Istanbul, Cerrahpas¸a School of Medicine, Fatih, Istanbul, Turkey 34300 4 Department of Urology, Palandoken State Hospital, Erzurum, Turkey 5 Department of Urology, University of Istanbul, Cerrahpas¸a School of Medicine, Fatih, Istanbul, Turkey 34300 2
Received 5 September 2013; accepted 22 July 2014
ABSTRACT: Background. To assess whether patient comfort could be increased by adding procedural sedation and analgesia (PSAA) to periprostatic nerve block (PNB) in patients undergoing transrectal ultrasound-guided prostatic biopsy (TRUS-PB). Methods. This was a prospective, randomized (1:2) trial comparing PNB with the combination of PSAA1PNB in patients undergoing TRUS-PB. PNB was achieved by using lidocaine gel and lidocaine and bipuvacaine infiltration. PSAA-treated patients received midazolam and remifentanil. All biopsies were standardized and performed in a fully equipped endourology suite. PSAA was delivered by an anesthesiology nurse in the presence and availability of an anesthesiologist. An orally administered numeric scale of 0–10 was used to assess the patient’s pain, and a visual scale of 0–4 was used to quantify their satisfaction. Pain and satisfaction scores were compared between the groups. Results. Data on 331 patients were analyzed: 235 received PNB, and 96 received PSAA1PNB. Distribution within the groups by age, prostate-specific antigen serum levels, prostate volume, and number of cores obtained was similar. Airway insertion was required in 4 of 96 patients in PSAA1PNB arm (4%), with no other complications related to sedation. The average pain level was significantly lower in the Correspondence to: C. Obek C 2014 Wiley Periodicals, Inc. V
288
PSAA1PNB group than it was in the PNB group (0.88 versus 1.31; p 5 0.008). The satisfaction level was high (3.5) and alike in the two groups; however, significantly more patients reported a perfect score of 4 in the PSAA1PNB arm (p 5 0.03). Conclusions. PSAA with midazolam and remifentanil used as an adjunct to the standard PNB is safe and effective during TRUS-PB. Patients undergoing PSAA in addition to PNB experienced significantly less pain and higher satisfaction scores than did those given PNB C 2014 Wiley Periodicals, Inc. J Clin Ultrasound alone. V 43:288–294, 2015; Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jcu.22227 Keywords: transrectal utrasound-guided prostate biopsy; procedural sedation; anesthesia; analgesia; ultrasonography
P
rostate biopsy (PB) is one of the most commonly performed outpatient procedures in urology. It causes significant pain and discomfort when performed without some form of anesthesia.1–3 Local anesthesia with periprostatic nerve block (PNB) remains the current standard of care for preventing pain and discomfort during this procedure.4 However, some patients report pain despite PNB, and means to improve local anesthesia would be beneficial for these men. Procedural sedation and analgesia (PSAA) refers to techniques of managing patients’ pain JOURNAL OF CLINICAL ULTRASOUND
ANALGESIA AS NERVE BLOCK FOR PROSTATE BIOPSY
and anxiety to facilitate appropriate medical care in a safe, effective, and humane fashion.5 It creates a suppressed level of consciousness sufficient to tolerate the performance of painful or unpleasant procedures in a way that minimizes patient awareness, discomfort, and memory, while attempting to preserve spontaneous respiration and airway-protective reflexes.5 Sedative-hypnotics and opioid analgesics are frequently used in combination to provide patient comfort, sedation, anxiolysis, and supplemental analgesia during surgical procedures performed under local anesthesia.5 Although PSAA is commonly used for endoscopic procedures and biopsies in various disciplines, it has rarely been reported for PB.3,6,7 Our aim was to explore the role of PSAA during PB. We assessed the efficacy and safety of PSAA when used as an adjunct to PNB for patients undergoing transrectal utrasoundguided PB (TRUS-PB) and compared it to the current gold standard, PNB, alone.
PATIENTS AND METHODS
This was a prospective randomized trial comparing local anesthesia induced with PNB to that induced with PSAA1PNB for patients undergoing TRUS-PB. The primary endpoint was the effect of the additional procedural sedation on patients’ pain and satisfaction levels during TRUS-PB. The secondary endpoint was the effect on complications. The study included consecutive patients undergoing TRUS-PB within a 28-month period. Study subjects gave their written informed consent, and approval from our ethical committee was obtained. A 2:1 randomization scheme was used to reduce trial cost without compromising statistical power.8 All patients approached consented to participate in the study and randomization, and none refused the arm he was randomized to. Exclusion criteria included repeat biopsy; use of opioid drugs; allergy to midazolam, remifentanil, or propofol; and active anal or rectal problems. Demographic data and medical histories were recorded. Patients randomized to anesthesia with PSAA1PNB were evaluated by an anesthesiologist before the biopsy date. This visit included a physical examination and assessment of the patient’s coagulation profile. We complied with the American Society of Anesthesiologists recommendation for fasting: 2 hours for clear liquids and 6 hours for food before PSAA.9 AntiVOL. 43, NO. 5, JUNE 2015
biotic prophylaxis consisted of three doses of 500 mg of ciprofloxacin, and a self-administered enema was performed before the procedure. The procedures were performed in a fully equipped endourology suite with the patients in the lateral decubitus position. The TRUS-PB technique was standardized; all procedures € or were performed by the same urologist (C.O.) by his assistants using the same ultrasound (US) machine (SonolineAdara; Siemens Corp., Germany). The TRUS-PB was performed in the sagittal plane with a 25-cm-long 18-gauge TruCut–type cutting needle and a Pro-Mag biopsy gun (Angiotech, Knud Bro Alle 3, 3660 Stenlïse, Denmark). In the PNB group, lidocaine gel (2%) was applied to the anal sphincter and rectum 10 minutes before probe insertion, followed by infiltration with 5 mL of lidocaine (2%) and 5 mL of bupivacaine (0.5%) at the prostate base on both sides, as previously described.10 Five minutes was allowed for the local block to take effect and the biopsies to be obtained. In the PSAA1PNB group, lidocaine gel was initially applied to the rectum. After 10 minutes, PSAA was initiated with 0.04 mg/kg of midazolam and 1 mg/kg/min of remifentanil within the first 20 seconds, followed by infusion of remifentanil at 0.5 mg/kg/min. The PNB was achieved in exactly the same way it was in the patients in the PNB-only group, once the patient was fully sedated. If sedation with the midazolam and remifentanil was inadequate, 1 mg/kg of propofol was used as an ancillary drug. PSAA was performed by an anesthesiology nurse in the presence and availability of an anesthesiologist. Sedation was kept at level of 3 or 4 on the Ramsay sedation scale.11 Patient monitoring included electrocardiography, heart rate, noninvasive blood pressure, and peripheral oxygen saturation. Patients spontaneously breathed 5 L/min of oxygen via face mask. When oxygen saturation dropped below 90%, patients were verbally stimulated, and the remifentanil infusion was stopped. In circumstances when this maneuver was insufficient, an airway was introduced. If the patient’s oxygen saturation failed to normalize with these attempts, mechanical ventilation would be initiated with a bag-valve mask. Patients in the PSAA1PNB arm were kept in the recovery room until they fully recovered from sedation, as judged by an Aldrete score 9 (see Appendix 1) and were prohibited from driving home.12 Before discharge, they were questioned by a resident not involved in the biopsy procedure about the extent of their pain and 289
DOGANCA ET AL TABLE 1 Between-Group Distribution of Several Clinical Variables
Group PNB alone PSAA1PNB Total study population
Age (years)*
Prostate Volume (mL)*
Prostate-Specific Antigen (ng/mL)*
Number of Cores Obtained*
65.3 6 8.4 64.3 6 8.8 65.0 6 8.5
45.1 6 24.5 47.8 6 20.9 47.0 6 23.5
10.6 6 11.8 9.3 6 12.5 10.2 6 12.2
14.8 6 5.2 14.9 6 5.0 14.8 6 5.2
Abbreviations: PNB, periprostatic nerve block; PSAA, procedural sedation and analgesia. *p > 0.05.
their degree of satisfaction with the procedure. An orally administered numeric scale (0, none; 10, intolerable pain) was used to evaluate pain, and a visual numeric scale (0, terrible; 4, perfect [Appendix 2]) was used to quantify their satisfaction; only whole numbers were allowed. Complications were recorded. Statistical Analysis An a priori sample size estimation was performed with an alpha level of 0.05, power of study (beta) of 0.95, and effect size of 0.5. The calculation was made by using the program Gpower 3.1.2, developed by Franz Faul at Kiel University. This program calculates the effect size based on estimations of group means and standard deviations. The allocation ratio between the two study groups was 2; the minimum numbers in the groups were to be 157 and 79. The numeric variables of the study were pain score, satisfaction score, prostate-specific antigen serum level, age, and prostate volume. The categorical variable was the type of anesthesia. Numeric variables were calculated as means and standard deviations and presented with minimum and maximum values, whereas the categorical variable was presented as frequencies and percentages. In situations in which the data were clearly not normally distributed or had obvious outliers, the median value was used to describe the distribution. After having confirmed with the Kolmogorov-Smirnov test that the data were normally distributed, Student’s t test was used to compare the pain and satisfaction scores between the two groups. The rate of the highest satisfaction score (ie, 4) was compared between the two groups by using Pearson’s v2 test. The significance value was set at p < 0.05. SPSS, version 15.0 was used for analyzing the data.
RESULTS
Data from 331 patients who underwent TRUSPB and were eligible for the study were ana290
TABLE 2 Between-Group Comparison of Pain Scores Group PNB alone PSAA1PNB Total study population
No. of Patients
Pain Score*
235 96 331
1.3 6 0.8 0.9 6 0.1 1.2 6 1.2
Abbreviations: PNB, periprostatic nerve block; PSAA, procedural sedation and analgesia. *p 5 0.008, Student’s t test.
lyzed: 235 patients in the PNB arm and 96 in the PSAA1PNB arm. The patients’ average age was 65 years: serum prostate-specific antigen, 10.2 ng/mL; prostate volume, 47 mL; and number of cores obtained, 14.8. The distribution of these variables was similar between the two groups, as presented in Table 1. Propofol in addition to midazolam and remifentanil was used in 11 (11%) of the patients. The mean pain score for the entire study group was 1.2 6 1.2 (on a scale of 0–10), and the mean satisfaction score was 3.5 6 0.6 (on a scale of 0–4). When the two groups were compared, the mean pain score was significantly lower in the PSAA1PNB group: 0.9 6 0.1 versus 1.3 6 0.8 (p < 0.01; Table 2). The mean satisfaction score was very high and similar in the two arms: 3.5 6 0.7 versus 3.5 6 0.03 (p > 0.05). However, when those who scored for the highest rate of satisfaction (ie, 4) were compared, significantly more patients in the sedation arm reported a perfect score (p 5 0.03; Table 3). Complications were few. Insertion of an airway because of a drop in oxygen saturation was required in four (4%) of the patients, whereas intubation or mechanical ventilation was not mandatory in any patient. No other complications related to sedation were observed. One patient in the PNB arm had a rectal hemorrhage judged to be excessive; the department of general surgery was consulted, and the bleeding was stopped with the temporary insertion (2 hours) of a tampon in the rectum. A total of three patients (0.9%; two in the PNB arm and JOURNAL OF CLINICAL ULTRASOUND
ANALGESIA AS NERVE BLOCK FOR PROSTATE BIOPSY TABLE 3 Between-Group Comparison of Satisfaction with the Procedure
Group PNB alone PSAA1PNB
No. of Patients
No. (%) Who Chose the Highest Satisfaction Score (ie, 4)*
Mean Satisfaction Score
235 96
119 (50.6) 61 (63.5)
3.5 6 0.03 3.5 6 0.7
Abbreviations: PNB, periprostatic nerve block; PSAA, procedural sedation and analgesia. *p 5 0.032, Pearson’s v2 test.
one in the PSAA 1 PNB arm) had to be readmitted for infection and treated with antibiotics.
DISCUSSION
Pain and discomfort have been reported in 80– 96% of patients undergoing TRUS-PB without anesthesia.13,14 Current guidelines recommend PNB to alleviate pain, but means to further allay patient anxiety and discomfort are under investigation.4 Local anesthesia may be combined with intravenous drugs to provide anxiolysis, sedation, and supplemental analgesia.15 Although PSAA is used in various disciplines for endoscopic procedures and biopsies, its use for transrectal PB has been reported as extremely rarely.3,6,7 We were therefore interested in exploring the role of sedoanalgesia as an adjunct to PNB for TRUS-PB. Anesthesia for PB 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. Consequently, the ideal anesthetic agent 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.9 The combination of midazolam and remifentanil used in the present study has been proven to fulfill those criteria.16 Midazolam, a sedative, amnestic, anxiolytic, and muscle-relaxant drug without analgesic properties is commonly used with an opioid analgesic.16 Remifentanil is a potent opioid analgesic with an extremely short contextsensitive half-life (3–5 minutes) that has been proven to be a good supplement to local anesthetics during PSAA.16 Propofol is an ultrashort-acting sedative and amnestic medication6 that can be used as an ancillary drug if needed, owing to its ultra-short half-life, which allows for easy control of sedation level. VOL. 43, NO. 5, JUNE 2015
Recommendations for the performance of PSAA are well established.11,17,18 Cardiac and pulse-oximetry monitors, oxygen and delivery systems, bag-valve mask, suction, appropriately sized airways and endotracheal tubes, a laryngoscope with appropriate blades, and medications and equipment for cardiac resuscitation are essential.18 Most importantly, the person administering PSAA must have a thorough understanding of the medications, the ability to monitor the patient’s response, and the skills required to intervene to manage complications.5 An operating room is not mandatory; the technique may be applied in an appropriately equipped room by a nonanesthesiologist sedation practitioner in compliance with the American Society of Anesthesiologists guidelines for sedation and analgesia for nonanesthesiologists.9 Absolute contraindications are uncommon; the presence of comorbidity, issues with the patient’s airway, and previous problems with PSAA need to be considered preoperatively. Intravenous sedative and/or analgesic drugs demand administration in small incremental doses to minimize the risk of adverse events. The incidence of respiratory depression is correlated with the level of sedation. Of those with moderate sedation, only 6% have been reported to develop hypoxia requiring intervention by the aneshesiologist6; this is within the range of hypoxia observed in our series. The advantages of complementing PNB with PSAA are several: relieving anxiety, obviating pain from probe insertion and injection of local anesthetic, and producing amnesia. Transrectal biopsy causes significant psychological stress: the anal route of penetration, the fact that the organ under examination is part of the male sexual system, the anticipated pain, and the fear of a potential cancer diagnosis may all add up to a considerable level of anxiety.6 A correlation between prebiopsy anxiety and the magnitude of intraoperative pain has been reported in some series.2,19 This underscores the necessity of administrating anxiolytic drugs and explains in part the lower pain and higher satisfaction scores when the patients are given sedation.20 Another advantage is the elimination of pain related to the probe insertion and the local anesthetic infiltration. Hossack and Woo20 reported that the most intensive pain arose from probe insertion, which cannot be diminished by PNB. In another series, lidocaine infiltration was reported to be the most painful part of the procedure.21 Sedation would be effective in alleviating pain and enhancing comfort at 291
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these two stages of the procedure. It is important to note that the pain of probe insertion will further influence and intensify the pain during the taking of cores.22 As a consequence, lessening the discomfort of probe insertion may also decrease pain during the actual PB. Many men require repeat biopsies, and they may be reluctant to undergo another PB if they have unpleasant recollections of previous ones.20 However, antegrade amnesia increases patients’ tolerance to repeated procedures, and the use of midazolam has this potential advantage. Speculation is that the central striated–muscle relaxant effect of midazolam might contribute to its overall beneficial effect.7 Publications on the use of sedation for PB are rare.3,6,7 In one of the earliest series reporting on the feasibility of sedation, Turgut et al7 used midazolam and found that moderate to severe pain occurred in 3% of those given sedation, in 29% of those given PNB, and in 80% of men given neither. The pain scores in their sedation and PNB arms were only 1.4 and 2.0, respectively. Our pain scores compare favorably in both groups: 0.9 in PSAA1PNB and 1.3 in PNB patients. Moreover, only one patient in our series reported a pain score of greater than 4. Our superior outcomes in both arms may be explained by the lack of pain relief of midazolam when used alone, as in Turgut’s series, and the additional use of lidocaine gel in our patients for PNB, which further intensifies the effect of PNB.22 In one prospective randomized trial, TobiasMachado et al23 used midazolam in combination with an opiate (meperidine) and compared it with PNB. Severe pain was reported in 3% of the men receiving PNB and in 5% of those receiving sedation. They did not observe any side effects related to sedation. In addition, Peters et al3 reported significantly reduced patient discomfort with propofol. Their pain score was almost identical to that reported by Turgut with midazolam. Apparently, neither of these two agents provides sufficient comfort alone, and they need to be combined with an opioid analgesic, as in our series. By the same token, sedation with propofol alone was associated with greater pain and discomfort than was PNB or combined propofol and fentanyl.24 In another prospective randomized comparison with lidocaine jelly, the combination of propofol and remifantanil resulted in significantly less pain25 and higher satisfaction scores in the monitored anesthesia arm. However, a direct comparison of that study with ours is not possi292
ble, because lidocaine jelly has universally proved to be inferior to PNB.4 This limitation was acknowledged by the authors25 of that previous study, who highlighted the importance of further exploration of the role of sedation in comparison with PNB. Unquestionably, our technique makes the PB procedure more complicated. Caregivers must weigh the patient’s comfort against the technique’s effect on manpower and financial resources and patient inconvenience. We perform our biopsies in an endourology suite, where an anesthesiology team is available regardless of the type of anesthesia. Thus, our performance of the biopsies with PSAA was relatively less complicated under these circumstances; nevertheless, we acknowledge that our setting departs from the usual one, with PBs being mostly performed at outpatient clinics. The main inconveniences for the patients are an extra trip to the hospital for a preoperative anesthesiology visit and not being able to drive for the day after the procedure. However, the extra requirements for PSAA also increase the cost of the procedure. Various parameters account for cost analysis, mainly the presence of an anesthesiologist and the use of an operating room. Each hospital or institution would need to analyze the associated financial burden. At our facility, the additional cost was $45 American per biopsy. In another study, Kang et al25 analyzed the cost of PSAA with propofol and remifentanil at a university hospital in Seoul and reported an additional charge of $169 American. Furthermore, the supplementary charge for general anesthesia in Australia has been reported to be $766 Australian.20 It may be timely to start considering individualizing the optimum type of anesthesia for men undergoing PB. PNB may still be the best option for the majority of cases, although PSAA1PNB might be a better option for some others. It has already been shown that one may predict the level of pain the patient will experience from the biopsy by using simple measurements such as a modified submaximal tourniquet test or pain during prostate examination.26,27 Those tests might be supplemented with others and enriched with tools for establishing anxiety level, a factor known to elevate pain.19 Subsequently, it might be conceivable to ascertain the ideal type of anesthesia for the individual patient. Sedation reportedly may have potential advantages in scenarios such as repeat biopsies, extensive biopsies, patients who might require a repeat biopsy, the presence of JOURNAL OF CLINICAL ULTRASOUND
ANALGESIA AS NERVE BLOCK FOR PROSTATE BIOPSY
anal or rectal disease, younger men, and those with a high anxiety level.1,13,28 Our study was not designed to find out who would benefit from sedation; however, it would be prudent to further explore the role of PSAA in various patient subgroups. In conclusion, PSAA with midazolam and remifentanil used as an adjunct to the standard PNB is safe and effective during TRUS-PB. Patients undergoing PB with PSAA in addition to PNB experienced significantly less pain and higher satisfaction scores than did those given PNB alone.
APPENDIX 2
Satisfaction Evaluation
APPENDIX 1
Modified Aldrete Scoring This system is designed to assess the patient’s transition from phase I recovery to phase II recovery, from discontinuation of anesthesia until return of protective reflexes and motor function. Respiration 2 5 Able to take deep breath and cough 1 5 Dyspnea/shallow breathing 0 5 Apnea O2 Saturation 2 5 Maintains >92% on room air 1 5 Needs O2 inhalation to maintain O2 saturation >90% 0 5 Saturation
