Practical Use of Self-Adjusted Nitrous Oxide During Transrectal Prostate Biopsy: A Double-Blind Randomized Control Trial

You have accessJournal of UrologyOriginal Research Articles1 Feb 2024Practical Use of Self-Adjusted Nitrous Oxide During Transrectal Prostate Biopsy: A Double-Blind Randomized Controlled TrialThis article is commented on by the following:Editorial CommentEditorial Comment Abigail J. Escobar, Suprita Krishna, K. Mikayla Flowers, Alejandro Abello, Boris Gershman, Andrew A. Wagner, Peter Chang, Ruslan Korets, Christopher J. Mistretta, Kristen L. Schreiber, Aria F. Olumi, and Heidi J. Rayala Abigail J. EscobarAbigail J. Escobar Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts Co-first authors. More articles by this author , Suprita KrishnaSuprita Krishna Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts Co-first authors. More articles by this author , K. Mikayla FlowersK. Mikayla Flowers Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts More articles by this author , Alejandro AbelloAlejandro Abello Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts More articles by this author , Boris GershmanBoris Gershman Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts More articles by this author , Andrew A. WagnerAndrew A. Wagner Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts More articles by this author , Peter ChangPeter Chang Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts More articles by this author , Ruslan KoretsRuslan Korets Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts More articles by this author , Christopher J. MistrettaChristopher J. Mistretta Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts More articles by this author , Kristen L. SchreiberKristen L. Schreiber Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts More articles by this author , Aria F. OlumiAria F. Olumi Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts More articles by this author , and Heidi J. RayalaHeidi J. Rayala *Corresponding Author: Heidi Rayala, MD, PhD, Division of Urologic Surgery, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Rabb 440, Boston, MA 02215 ( E-mail Address: [email protected] https://orcid.org/0000-0003-4500-0939 Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003789AboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Abstract Purpose: Transrectal prostate biopsy is a common ambulatory procedure that can result in pain and anxiety for some men. Low-dose, adjustable nitrous oxide is increasingly being used to improve experience of care for patients undergoing painful procedures. This study seeks to evaluate the efficacy and safety of low-dose (<45%) nitrous oxide, which has not been previously established for transrectal prostate biopsies. Materials and Methods: A single-institution, prospective, double-blind, randomized, controlled trial was conducted on patients undergoing transrectal prostate biopsies. Patients were randomized to receive either self-adjusted nitrous oxide or oxygen, in addition to routine periprostatic bupivacaine block. Nitrous oxide at levels between 20% and 45% were adjusted to patients’ desired effect. Patients completed a visual analog scale for anxiety, State Trait Anxiety Inventory, and a visual analog scale for pain immediately before and after biopsy. The blinded operating urologist evaluated ease of procedure. Periprocedural vitals and complications were assessed. Patients were allowed to drive home independently. Results: A total of 133 patients received either nitrous oxide (66) or oxygen (67). There was no statistically significant difference in the primary anxiety end point of State Trait Anxiety Inventory or the visual analog scale for anxiety scores between the nitrous oxide and oxygen groups. However, patients in the nitrous oxide group reported significantly lower visual analog scale for pain scores compared to the oxygen group (P = .026). The operating urologists’ rating of tolerance of the procedure was better in the nitrous oxide group (P = .03). There were no differences in biopsy performance time. Complications were similarly low between the 2 groups. Conclusions: Patient-adjusted nitrous oxide at levels of 20% to 45% is a safe adjunct during transrectal prostate biopsy. Although there was not an observed difference in the primary end point of anxiety, nitrous oxide was associated with lower patient-reported pain scores. Transrectal ultrasound–guided (TRUS) prostate biopsy remains the foundation of prostate cancer diagnosis. With the rise in active surveillance protocols, it is estimated that more than 1 million biopsies are performed in the US annually.1 There have been many approaches to relieve procedural pain, with periprostatic nerve block being the primary method used in the US. However, patients still experience physical and psychological sequelae from prostate biopsies, with the 2012 ProBE study finding that 19.6% of patients considered future biopsy a “major or moderate problem” when questioned 7 days after transrectal biopsy.2 As diagnostic procedures for prostate cancer evolve, it is not yet well understood whether the periprostatic nerve block will provide adequate relief for lengthier transperineal biopsies or MRI fusion biopsies. An inexpensive, titratable, rapid-onset and -offset method for relieving patient anxiety and pain employed before the periprostatic nerve block would be of great benefit to patients. Nitrous oxide (N2O, also known as laughing gas) is one of the oldest known inhaled anesthetics. Its analgesic properties for urologic procedures were first reported in a seminal article by Hugh Hampton Young in 1939, where he reflected: In many instances the anesthesia is so imperfect that cystoscopy, especially if prolonged for ureteral catheterization or endovesical operations, is occasionally a terrifying procedure. Other urologic examinations, especially in cases with marked pathological conditions of the urethra, prostate, and bladder, are accompanied by so much pain that frequently spinal, general, or intravenous anesthesia is employed. These forms of anesthesia require expert preparation, administration, and supervision.3 Dr Young went on to describe his positive experience using N2O for “first Stage” anesthesia, which at the time was defined as that stage where “pain is abolished, but patient is conscious.” With modern-day improvements in N2O delivery and scavenging systems, there has been a resurgence in popularity of N2O for improving a patient’s experience of pain and anxiety during ambulatory procedures.4 When used as a single agent at concentrations ≤50%, the American Society of Anesthesiologists classifies N2O as minimal sedation, producing a state in which a patient responds normally to verbal commands, and maintains airway reflexes and spontaneous ventilation.5 N2O has advantages relative to other minimal sedation options, such as oral benzodiazepine, in that it has an onset and offset of approximately 3 minutes. When N2O is administered as minimal sedation, patients do not require the presence of anesthesia personnel, extended postprocedure monitoring, or escort home. Entonox, a commercial system that delivers gas mixtures of 50% N2O and 50% oxygen, is widely used in ambulatory settings in Europe. Analogously in the US, Pro-Nox also delivers gas mixtures of 50% N2O and 50% oxygen. When compared to patients receiving 50% N2O, a recent US study of N2O in the setting of depression treatment found that 25% N2O yields a fourfold decrease in adverse effects such as headache and nausea.6 These data raise the question of whether N2O at levels < 50% may preserve efficacy while reducing side effects. The primary outcome of this study was the effectiveness of low-dose (20%-45%) self-adjusted nitrous oxide (SANO) in decreasing anxiety related to transrectal prostate needle biopsy. Secondary outcomes included the impact of SANO on patient pain, ease of SANO administration, urologists’ perceptions of the procedure, and adverse events associated with SANO. METHODS Patients and Study Design Following Institutional Review Board approval (IRB No. 2021P-000715), biological males aged 21 to 85 scheduled for prostate needle biopsy at Beth Israel Deaconess Medical Center’s outpatient urology clinic were recruited between December 2021 and September 2022. Patients with N2O contraindications were excluded (Supplementary Material, https://www.jurology.com). During the first 5 months of study enrollment, patients without an escort home were excluded, after which the Institutional Review Board–approved patients driving themselves home upon completion of the Trail Making Test Part B, a verified cognitive test used to predict driving safety.7 Of the 143 patients who provided informed consent, 133 were randomized via REDCap in a 1:1 ratio. Both the patient and operating urologist were blinded to this assignment. The study design and recruitment process are illustrated in Figure 1. Figure 1. Study flow diagram. A total of 348 patients scheduled for transrectal prostate biopsy were screened for eligibility and offered participation in the study. One hundred forty-three patients were found to be eligible and agreeable to participate. Of these, 133 completed informed consent procedures and were randomized to receive self-adjusted nitrous oxide (SANO) or oxygen during their prostate biopsy. Sixty-seven patients were randomized to the oxygen group, and 66 patients were randomized to the SANO group. Five patients did not complete study procedures following randomization and were excluded from data analysis. In total, 128 patients were included in the final analysis. The study utilized the Nitrouseal system, which includes a disposable single-use full-face mask and a breathing circuit that scavenges exhaled N2O. The system allows adjustable amounts of oxygen and N2O, with N2O concentrations limited to 20% to 45% for the study. Upon entering the procedure room, all randomized patients were fitted with a Nitrouseal self-scavenging mask and instructed on how to communicate throughout the biopsy. All patients began with oxygen at 10 L/min. Subsequently, in the SANO group, N2O was initiated at 20% of the total flow, 2 to 3 minutes prior to rectal probe insertion. Throughout the procedure, a registered nurse administrating the gas asked both groups if they would like their “level” adjusted. In the SANO group, N2O was titrated to desired effect. Heart rate and oxygen saturation were monitored by the nurse administering oxygen and SANO throughout the procedure. Prostate biopsies were performed by 6 fellowship-trained urologists, with a mean of 13.3 years since completion of fellowship (range 7-23 years). All patients received periprocedural oral antibiotics and self-administered prebiopsy enema. Patients were placed in the left lateral decubitus position in preparation for the biopsy. TRUS prostate biopsy was performed with a 9-MHz probe. All urologists performed a periprostatic block with a 10-mL dose of 0.5% bupivacaine (5 mL per side) injected via a 22-gauge Chiba needle into the region just lateral to the junction between prostate base and seminal vesicle on both sides. The prostate was imaged in transverse and sagittal planes and prostate size was calculated according to the standardized method of the ultrasound machine. For patients undergoing fusion biopsy, bkFusion for prostate MRI fusion was used. Biopsies of the regions of interest were taken using an automatic biopsy gun with an 18-gauge needle. Following MRI fusion biopsies (and for patients not undergoing fusion biopsies) all patients underwent standard sextant biopsies of the base, mid gland, and apical gland from the lateral and far-lateral aspects. Patients were provided routine verbal and written postbiopsy instructions prior to discharge home. Biopsy results were reviewed at follow-up visit according to patient and/or provider preferred visit type (in-office, telephone, or video). Outcome Measures Prior to intervention, subjects completed the Brief Pain Inventory, a validated instrument designed to assess baseline patient-perceived pain.8 Preprocedural pain was measured by the Visual Analog Scale for Pain (VAS-P, range: 0-10, with greater scores indicating worse pain). Preprocedural anxiety was assessed using the State Trait Anxiety Inventory (STAI, range: 6-24, higher scores indicate worse anxiety) and the Visual Analog Scale for Anxiety (VAS-A, range: 0-10, higher scores indicating worse anxiety). Postbiopsy assessments included the VAS-P, VAS-A, STAI, and Situational Pain Catastrophizing Scale (SPCS, range: 0-30, higher scores indicating greater pain catastrophizing) to assess patients’ perception of pain, anxiety, and pain catastrophizing during the biopsy. After low-dose N2O, patients returned to normal cognitive function within 3 to 5 minutes, and postbiopsy assessments were performed at a minimum of 10 minutes postprocedure.9 The operating urologist completed a postprocedural operator survey immediately after completion of the biopsy. The survey consisted of 3 questions to assess ease of probe insertion, maintenance of position, and overall tolerance of the procedure. Responses were scored on a 3-point Likert scale as 1 (worse than expected), 2 (as expected), or 3 (better than expected). Procedure time was defined as the time the operator was present in the room. Electronic medical records were monitored for potential adverse events, and 30-day complications were reported according to the Clavien-Dindo classification.10 Statistical Analysis Based on a previous study by Bringman et al, the mean preintervention STAI anxiety score was 34 (SD 8) immediately before elective surgery.11 A clinically meaningful decrease, as determined by the Cochrane review group, was 0.5 SD. Thus, we hypothesized a mean STAI of 34 (SD 8) in the oxygen group and 30 (SD 8) in the N2O group. The a priori sample size calculation to detect this difference with a 2-sample t test, assuming 80% power and a 2-sided alpha of .05, yielded a required sample size of 64 evaluable participants per group. Summary data for continuous variables are described using median (Q1, Q3) for nonnormal distributions. Categorical variables are presented as counts (percentages). Given our primary outcomes were all nonnormally distributed, Wilcoxon rank sum tests were performed to examine between treatment group differences in our continuous postoperative outcomes (postoperative VAS-P, VAS-A, STAI, and SPCS), procedural end points, and severity of postprocedure 30-day complications. Spearman correlation was used to examine the relationship between postbiopsy pain (VAS-P) and anxiety (VAS-A). All analyses were conducted using SPSS v29. Primary outcome measures were calculated with Hodges-Lehmann 95% confidence intervals, and P values < .05 were deemed significant. RESULTS Baseline Patient Characteristics Study outcomes were reported in accordance with CONSORT guidelines. Table 1 summarizes baseline patient characteristics. There were no statistically significant differences between the 2 groups. Patients’ median age was 66.5 (60.5, 71) years, with 83% self-reporting as White and 13% as Black/African American. The median PSA was 7.0 (4.7, 9.6), with a median prostate size of 43.2 cc (34.4, 67.0), and 42% had a history of prior biopsy (median = 2). Sixteen percent underwent standard sextant biopsy, while 84% underwent MRI fusion biopsy. Table 1. Baseline Patient and Procedural Characteristics Characteristic SANO (n = 61) Oxygen (n = 67) Demographics ` Age, median (Q1, Q3) 66 (61.5, 70.5) 67 (60, 71) Race, No. (%) White 50 (82) 56 (84) Black/African American 8 (13) 9 (13) Other 3 (4.9) 2 (2.9) PSA, median (Q1, Q3) 7.0 (4.8, 10.1) 7.0 (4.5, 9.5) Prostate size, median (Q1, Q3), cc 43 (34.6, 70) 44 (33.7, 67) History of past biopsy, No. (%) 26 (43) 28 (42) History of prostate cancer, No. (%) 18 (30) 17 (25) History of depression, No. (%) 7 (12) 10 (16) History of anxiety, No. (%) 10 (17) 10 (16) Procedural characteristics Biopsy type, No. (%) Standard 9 (15) 11 (16) Fusion 52 (85) 56 (84) No. cores, median (Q1, Q3) 15 (15, 17.5) 15 (15, 16) If PCA, Grade Group, No. (%) 1 11 (18) 21 (31) 2 17 (28) 16 (24) 3 6 (10) 5 (7) 4 6 (10) 6 (9) 5 7 (12) 4 (6) No PCA 14 (23) 15 (22) Baseline pain and anxiety General pain severity (0-10), median (Q1, Q3) 0 (0, 1.3) 0 (0, 1.8) General pain interference in life (0-100), median (Q1, Q3) 0 (0, 10) 0 (0, 10) Prebiopsy VAS-P (0-10), median (Q1, Q3) 0 (0, 1) 0 (0, 0) Prebiopsy VAS-A (0-10), median (Q1, Q3) 3 (0, 5) 2 (0, 5) Prebiopsy STAI, median (Q1, Q3) 12 (9, 15) 12 (8, 14) Abbreviations: PCA, prostate cancer; PSA, prostate-specific antigen; Q, quartile; SANO, self-adjusted nitrous oxide; STAI, State Trait Anxiety Index; VAS-A, Visual Analog Scale–Anxiety; VAS-P, Visual Analog Scale–Pain. Treatment groups (SANO and control) were balanced across all variables. Efficacy The mean maximum N2O concentration that was reached on titration to patient-signaled comfort was 39% (Figure 2). This level was reached at a time point after probe insertion. As shown in Table 2, the median postbiopsy STAI scores were not significantly lower in the SANO group compared to the oxygen group (SANO STAI = 11 vs oxygen STAI = 12, P = .5), nor were the VAS-A anxiety scores (SANO VAS-A = 0 vs oxygen VAS-A = 1, P = .1). Similarly, the pain catastrophizing scores were not statistically different (SANO SPCS = 4 vs oxygen SPCS = 4, P = .1). In contrast, the median postbiopsy pain scores were significantly lower in the SANO group compared to the oxygen group (SANO VAS-P = 1 vs oxygen VAS-P = 1, P = .03). Postbiopsy pain was significantly correlated with postbiopsy anxiety in both groups (SANO: rs = 0.52, P < .001; oxygen: rs = 0.48, P < .001). Figure 2. Distribution box plot of maximum nitrous oxide (N2O) concentration among patients in the self-adjusted nitrous oxide group. The box is represented by the interquartile range (35%-42% N2O), with the horizontal line in the box representing the median (40% N2O). Whisker boundary was defined as the minimum and maximum values (20%-45% N2O). Table 2. Between-Group Anxiety and Pain End Points Postoperative outcomes Oxygen, median (Q1, Q3) SANO, median (Q1, Q3) Estimated differencea P valueb STAI 12 (9, 14) 11 (7, 14) 0 ( −1, 2) .5 VAS-A 1 (0, 3) 0 (0, 3) 0 (0, 1) .1 SPCS 4 (2, 9) 4 (1.5, 7) 1 (0, 2) .1 VAS-P 1 (0, 2) 1 (0, 2) 0 (0, 1) .03 Abbreviations: Q, quartile; SANO, self-adjusted nitrous oxide; SPCS, Situational Pain Catastrophizing Score; STAI, State Trait Anxiety Index; VAS-A, Visual Analog Scale–Anxiety; VAS-P, Visual Analog Scale–Pain. Descriptives presented are estimated differences between groups with 95% confidence intervals using independent-samples Hodges-Lehman median difference. Wilcoxon rank sum test. Procedural Outcomes The length of the procedure did not differ significantly between groups (Table 3; SANO: 10.6 vs oxygen: 10.3 minutes, P = .4). The urologists’ assessment of patient biopsy tolerance (Table 3; SANO: 3 vs oxygen: 2, P = .03) was better in the SANO group. Insertion of rectal probe and maintenance of positioning was similar between groups (Table 3). Table 3. Procedural End Points Oxygen, median (Q1, Q3) SANO, median (Q1, Q3) Estimated differencea P valueb Procedural end points Maximum N2O concentration (n = 47) 40 (35, 42) Maximum heart rate (n = 95) 79 (70, 88) 79 (66, 90) 0 (−6, 7) .9 Procedure time (n = 126), min 10.3 (8.5, 11.9) 10.6 (9.0, 12.6) −0.5 (−1.6, 0.6) .4 Operator survey Insertion of rectal probe (range 1-3) 2 (2, 3) 2 (2, 3) 0 (0, 0) .2 Maintenance of positioning (range 1-3) 2 (2, 3) 3 (2, 3) 0 (0, 0) .07 Tolerance of biopsy (range 1-3) 2 (2, 3) 3 (2, 3) 0 (0, 0) .03 Abbreviations: N2O, nitrous oxide; Q, quartile; SANO, self-adjusted nitrous oxide. Descriptives presented are estimated differences between groups with 95% confidence intervals using independent-samples Hodges-Lehman median difference. Wilcoxon rank sum test. No serious adverse events were observed during the trial. One patient in the SANO group developed facial redness during prostate biopsy. This was resolved upon mask removal at the conclusion of the procedure, and the patient reported that he had similar reactions when wearing COVID-19 pandemic masks. There was no between-group difference in postprocedure complication severity within 30 days (P = .2). There were 2 postprocedural complications within 30 days in the oxygen group (1 Clavien grade 1 event of urinary retention requiring urethral catheterization and 1 Clavien grade 2 episode of acute cholangitis, felt to be unrelated to the patient's prostate biopsy), and there were no complications within the SANO group. Five patients in the SANO group did not complete biopsy and were excluded from final analyses: 3 developed discomfort with the mask, prompting discontinuation of gas administration, 1 patient could not tolerate rectal probe insertion, and 1 patient opted to forgo prostate biopsy after randomization. Early in the study, some participants experienced discomfort with the mask, but we were able to mitigate this issue by enhancing preprocedure education on mask-related expectations, and there were no subsequent exclusions. DISCUSSION To our knowledge, this is the first prospective, randomized, controlled study assessing the effects of low-dose (20%-45%) N2O on patient experience during transrectal prostate biopsy. Notably, there was not an observed decrease in the study’s primary end points related to patient anxiety; however, there was an observed reduction in secondary end points of patient-perceived pain. Overall, SANO was well tolerated with no significant side effects and no impact on the ease of the operating urologist’s performance of the procedure. There has been considerable effort by urologists to alleviate the discomfort of prostate biopsies through modalities such as topical lidocaine, benzodiazepines, opioids, and relaxing music.12 A small number of European studies have evaluated the benefits of Entonox to reduce pain and anxiety during prostate biopsies. These studies demonstrated that patients receiving N2O have significantly lower pain scores than control groups, with mean postbiopsy pain scores between 2.2 and 2.8.13-16 However, in these studies either the standard periprostatic bupivacaine block in the Entonox group was omitted or the biopsy was performed without adequate analgesia in the control group. In the present study, both groups received periprostatic bupivacaine block. The SANO group’s postbiopsy pain score was lower than that previously published in the literature and may suggest that the combination of SANO with bupivacaine block is superior to either one alone.17-19 The effects of N2O on reducing a patient's discomfort during a painful medical procedure involves multiple modes of action, including amnesia, anesthesia, and anxiolysis. The relative contribution of each of these effects has not been fully elucidated, though, in general, N2O is thought to have more of an effect on anxiety than on pain. In considering prostate biopsies, anxiety has not been as extensively studied as pain. While the present study observed a significant correlation between postbiopsy pain (VAS-P) and anxiety (VAS-A), SANO did not demonstrate a significant outcome in the primary anxiety end points (STAI, VAS-A). This aligns with the findings of a 2008 study by Spie et al comparing Entonox and intrarectal lidocaine gel for TRUS prostate biopsy, which also failed to demonstrate significant improvement in anxiety scores with N2O, whereas there was a trend towards less pain.20 Interestingly, the 2008 study noted a linear correlation between anxiety and pain in the lidocaine gel group, but not in the N2O group. This is in contrast to our study which found a significant correlation between anxiety and pain in both control and N2O groups. These findings may highlight the complex intersection of patient-perceived pain and anxiety, suggesting that one may not be solely dependent on the other. When assessing the safety of N2O, it is important to consider both potential side effects for patients and risks to practitioners. Although this study found no significant complications in the 61 men who received SANO, common side effects of receiving ≤ 50% N2O can include headache, dizziness, and nausea (<2%).6 Historical studies on the risks of occupational exposure by staff to N2O led to reduced utilization of N2O in medical procedures in the US. In a1992 New England Journal of Medicine study of female dental assistants, reduced fertility was observed following exposure to high levels of unscavenged N2O.21 This same study did not find reduced fecundability when using N2O with a scavenging system. The Nitrouseal system used at this study’s institution is self-scavenging, and personal N2O badge monitors for operators demonstrate levels that are well within acceptable limits. Rectal probe insertion has previously been shown to be the greatest source of pain during prostate biopsy.19 Ease of rectal probe insertion, as measured by the operating urologist, was not markedly different between the 2 groups. However, a limitation of this current study was that N2O was initiated at 20%, and though a mean maximum of 39% N2O was ultimately achieved, this was generally at a time after probe insertion. Thus, this current study may not have reached sufficient analgesia before rectal probe insertion. In follow-up protocols, SANO was initiated at 30% prior to the intervention, which appears to provide improved analgesia. Future studies should investigate the optimal mechanism and timing for titration of optimal N2O concentrations. Regarding limitations, it should be noted that this study’s operator survey has not been validated and may not accurately reflect urologists’ experience. This was a single-center study, and the sample was predominantly White, which could affect the generalizability of its findings. Future research should focus on the inclusion of more diverse patient groups and expansion across multiple institutions. The presence of a study team may have been a confounding factor influencing the patients’ anxiety and pain during the study. Five patients in the SANO group were withdrawn and did not complete postbiopsy surveys after randomization, which precluded an intention-to-treat analysis of our outcomes. Finally, there is a potential lack of generalizability of this protocol due to institutional barriers in establishing an N2O program. Currently, there are few established guidelines in the medical field for the use of N2O for procedural sedation. The development of a successful SANO project requires the approval of hospital policy and procedure committees, N2O education and training modules, and is facilitated by anesthesia advocacy. Cost is also an important consideration. We used the Nitrouseal system by Sedation Systems, with 2023 system cost of $7995.00 and disposable single-use face mask price of $37.50. At our institution, an N2O E cylinder costs approximately $30.00, which provides sufficient coverage for ∼30 cases. An additional individual in the room to provide patient education and monitoring is useful, but not mandatory. CONCLUSIONS The results of this study demonstrate that delivery of low-dose N2O (20%-45%) titrated to patient’s desired effect during transrectal prostate biopsy is well tolerated and safe, with a reduction of patient’s pain during prostate biopsy, but no discernable impact on anxiety. These results suggest that the option of adjuvant N2O may improve patients’ experience of care as they undergo diagnostic evaluation for prostate cancer. REFERENCES 1. . Five-year nationwide follow-up study of active surveillance for prostate cancer. Eur Urol. 2015; 67(2):233-238. Crossref, Medline, Google Scholar 2. . Short term outcomes of prostate biopsy in men tested for cancer by prostate specific antigen: prospective evaluation within ProtecT study. BMJ (Online). 2012; 344(1):d7894. Google Scholar 3. . Self-induction analgesia with nitrous oxide for urologic examinations and minor procedures. J Urol. 1939; 41(1):95-102. Link, Google Scholar 4. . The analgesic effects of low concentrations of nitrous oxide compared in man with morphine sulphate. J Clin Invest. 1943; 22(6):872. Crossref, Google Scholar 5. Practice guidelines for moderate procedural sedation and analgesia 2018. Anesthesiology. 2018; 128(3):437-479. Crossref, Medline, Google Scholar 6. . A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression. Sci Transl Med. 2021; 13(597):eabe1376. Crossref, Medline, Google Scholar 7. . Trail Making Test, Part B as a measure of executive control: validation using a set-switching paradigm. J Clin Exp Neuropsychol. 2000; 22(4):518-528. Crossref, Medline, Google Scholar 8. . Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singap. 1994; 23(2):129. Medline, Google Scholar 9. . Recovery from nitrous oxide-oxygen psychosedation as determined by the fusion frequency of flicker. Anesth Prog. 1978; 25(4):121-122. Medline, Google Scholar 10. . Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol. 1992; 45(6):613-619. Crossref, Medline, Google Scholar 11. . Relaxing music as pre-medication before surgery: a randomised controlled trial. Acta Anaesthesiol Scand. 2009; 53(6):759-764. Crossref, Medline, Google Scholar 12. . Current methods of analgesia for transrectal ultrasonography (TRUS)-guided prostate biopsy—a systematic review. BJU Int. 2014; 113(suppl 2):48-56. Crossref, Medline, Google Scholar 13. . A 50-50% mixture of nitrous oxide-oxygen in transrectal ultrasound-guided prostate biopsy: a randomized and prospective clinical trial. PLoS One. 2018; 13(4):e0195574. Medline, Google Scholar 14. . Use of MEOPA (nitrogen monoxide-oxygen mixture) as analgesic for prostate biopsies. Prog Urol. 2004; 14(6):1167-1170. Medline, Google Scholar 15. . Nitrous oxide vs periprostatic nerve block with 1% lidocaine during transrectal ultrasound guided biopsy of the prostate: a prospective, randomized, controlled trial. J Urol. 2003; 170(5):1881-1883. Link, Google Scholar 16. . Nitrous oxide (Entonox) inhalation and tolerance of transrectal ultrasound guided prostate biopsy: a double-blind randomized controlled study. J Urol. 2002; 168(1):116-120. Link, Google Scholar 17. . Intraprostatic local anesthesia with periprostatic nerve block for transrectal ultrasound guided prostate biopsy. J Urol. 2009; 182(2):479-484. Link, Google Scholar 18. . Periprostatic nerve block (PNB) alone vs PNB combined with an anaesthetic-myorelaxant agent cream for prostate biopsy: a prospective, randomized double-arm study. BJU Int. 2009; 103(9):1195-1198. Crossref, Medline, Google Scholar 19. . A prospective study analysing the effect of pain on probe insertion, and the biopsy strategy, on the patients' perception of pain during TRUS-guided biopsy of the prostate. N Z Med J. 2008; 121(1287):39-43. Medline, Google Scholar 20. . Value of nitrous oxide-oxygen mixture (Entonox) in transrectal prostate biopsies. Prog Urol. 2008; 18(6):358-363. Crossref, Medline, Google Scholar 21. . Reduced fertility among women employed as dental assistants exposed to high levels of nitrous oxide. N Engl J Med. 1992; 327(14):993-997. Crossref, Medline, Google Scholar Support: This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center, National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR002541, and financial contributions from Harvard University and its affiliated academic health care centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, or the National Institutes of Health. Sedation Systems, LLC provided the Nitrouseal machine and masks for the duration of the study. Conflict of Interest Disclosures: The Authors have no conflicts of interest to disclose. Ethics Statement: This study received Institutional Review Board approval (IRB No. 2021P-000715). All human subjects provided written informed consent with guarantees of confidentiality. Author Contributions: Study conception and design: S.K., A.A., K.S., H.R.; Protocol implementation: A.E., C.M., B.G., P.C., A.W., R.K., A.O., H.R.; Data analysis and interpretation: A.E., K.F., K.S., H.R.; Manuscript writing and preparation: A.E., S.K., A.A., H.R. All authors have reviewed and approved the final manuscript. Clinical trial registration number: NCT05803096. Editor's Note: This article is the second of 5 published in this issue for which Category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 337 and 338. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsCited bySiemens D and Wan J (2023) Editors’ Choice: February 2024Journal of Urology, VOL. 211, NO. 2, (203-204), Online publication date: 1-Feb-2024.Ramacciotti L and Abreu A (2023) Editorial CommentJournal of Urology, VOL. 211, NO. 2, (222-222), Online publication date: 1-Feb-2024.Azhar R (2023) Editorial CommentJournal of Urology, VOL. 211, NO. 2, (221-222), Online publication date: 1-Feb-2024.Related articlesJournal of Urology6 Dec 2023Editorial CommentJournal of Urology6 Dec 2023Editorial Comment Volume 211 Issue 2 February 2024 Page: 214-222 Supplementary Materials Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.Keywordsnitrous oxideprostate biopsyprostate cancerambulatorypatient experience of careMetrics Author Information Abigail J. Escobar Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts Co-first authors. More articles by this author Suprita Krishna Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts Co-first authors. More articles by this author K. Mikayla Flowers Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts More articles by this author Alejandro Abello Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts More articles by this author Boris Gershman Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts More articles by this author Andrew A. Wagner Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts More articles by this author Peter Chang Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts More articles by this author Ruslan Korets Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts More articles by this author Christopher J. Mistretta Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts More articles by this author Kristen L. Schreiber Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts More articles by this author Aria F. Olumi Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts More articles by this author Heidi J. Rayala Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts *Corresponding Author: Heidi Rayala, MD, PhD, Division of Urologic Surgery, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Rabb 440, Boston, MA 02215 ( E-mail Address: [email protected] More articles by this author Expand All Support: This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center, National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR002541, and financial contributions from Harvard University and its affiliated academic health care centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, or the National Institutes of Health. Sedation Systems, LLC provided the Nitrouseal machine and masks for the duration of the study. Conflict of Interest Disclosures: The Authors have no conflicts of interest to disclose. Ethics Statement: This study received Institutional Review Board approval (IRB No. 2021P-000715). All human subjects provided written informed consent with guarantees of confidentiality. Author Contributions: Study conception and design: S.K., A.A., K.S., H.R.; Protocol implementation: A.E., C.M., B.G., P.C., A.W., R.K., A.O., H.R.; Data analysis and interpretation: A.E., K.F., K.S., H.R.; Manuscript writing and preparation: A.E., S.K., A.A., H.R. All authors have reviewed and approved the final manuscript. Clinical trial registration number: NCT05803096. Editor's Note: This article is the second of 5 published in this issue for which Category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 337 and 338. Advertisement Advertisement PDF downloadLoading ...