Comparison Between Hyperbaric Bupivacaine with Fentanyl vs. Hyperbaric Bupivacaine with Dexmedetomidine in Reducing Visceral Pain During Cesarean Delivery Under Spinal Anesthesia, A Prospective Randomized Double-Blind Comparative Study; Clinical Trial Protocol

Comparison Between Hyperbaric Bupivacaine with Fentanyl vs. Hyperbaric Bupivacaine with Dexmedetomidine in Reducing Visceral Pain During Cesarean Delivery Under Spinal Anesthesia, A Prospective Randomized Double-Blind Comparative Study; Clinical Trial Protocol | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Comparison Between Hyperbaric Bupivacaine with Fentanyl vs. Hyperbaric Bupivacaine with Dexmedetomidine in Reducing Visceral Pain During Cesarean Delivery Under Spinal Anesthesia, A Prospective Randomized Double-Blind Comparative Study; Clinical Trial Protocol Dr Sujan Dhakal, Dr Elija Gautam, Dr Allen Suwal, Dr Salin Dhakal, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6337531/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Visceral pain during cesarean delivery under spinal anesthesia continues to pose a significant clinical challenge. This study aims to compare the effectiveness of intrathecal hyperbaric bupivacaine combined with fentanyl (Group BF) versus dexmedetomidine (Group BD) in mitigating intraoperative visceral pain. Methods A prospective, randomized, double-blind trial will enroll 116 ASA PS II & III parturients undergoing elective cesarean delivery. Participants will receive either 10mg hyperbaric bupivacaine + 10µg fentanyl (Group BF) or 10mg hyperbaric bupivacaine + 5µg dexmedetomidine (Group BD). Primary outcome: the frequency of intraoperative visceral pain during various stages of cesarean section. Secondary outcomes include hemodynamic stability, shivering, neonatal APGAR scores, and side effects such as nausea, vomiting, and pruritus. Discussion This study's findings will offer crucial insights into the impact of dexmedetomidine as the preferred adjuvant for spinal anesthesia during cesarean delivery. Potentially replacing opioids, it could reduce the incidence of opioid-related complications such as respiratory depression and pruritus, thereby enhancing recovery. This aligns with global initiatives aimed at optimizing perioperative outcomes through the adoption of non-opioid analgesia. Trial Registration: Registered at ClinicalTrials.gov (ID: NCT06367660 Trial Registration: ClinicalTrials.gov ID: NCT06367660 Anesthesiology & Pain Medicine Visceral Pain Dexmedetomidine Fentanyl Cesarean Section Spinal Anaesthesia Introduction Background and Rationale {6a}: The subarachnoid block is the most commonly employed anesthetic technique for cesarean delivery. Subarachnoid block in cesarean section is associated with better outcomes in terms of postoperative pain, duration of stay in the hospital, and patient satisfaction when compared with general anesthesia. 1 Hyperbaric Bupivacaine is most commonly employed for a subarachnoid block at different doses. Visceral pain during cesarean delivery under spinal anesthesia originates from mechanical traction on the peritoneum and intra-abdominal organs, mediated by unmyelinated C-fibers and poorly localized nociceptive pathways. This pain is particularly intense when the surgeon is handling different intraabdominal organs during cesarean delivery under subarachnoid block. The incidence of visceral pain during cesarean section is estimated to be 71% under spinal anesthesia with 7.5–10 mg and 50% with 10-12.5 mg of hyperbaric 0.5% bupivacaine, respectively. 2 , 3 With higher doses of hyperbaric bupivacaine, the incidence of intraoperative visceral pain is reduced, but increasing the dose of bupivacaine increases the risk of high block. 4 To mitigate this problem, benzodiazepines, opioids (e.g. morphine, fentanyl, and sufentanil), α-adrenergic agonists (e.g. epinephrine or phenylephrine), ketamine, and α2-adrenergic receptor agonists (e.g. clonidine or dexmedetomidine) are adjuvants of common use. 5 Adjuvants like fentanyl (a µ-opioid receptor agonist) and dexmedetomidine (a selective α2-adrenergic agonist) enhance analgesia through distinct mechanisms: Fentanyl binds spinal opioid receptors, inhibiting nociceptive transmission. Dexmedetomidine modulates pain via α2 receptors in the dorsal horn, reducing sympathetic outflow and prolonging sensory blockade. The rationale for Comparison: Visceral pain is poorly controlled with the standard dose of hyperbaric bupivacaine. However, higher doses of hyperbaric bupivacaine may reduce the incidence of intraoperative visceral pain, but increasing the dose of bupivacaine increases the risk of high block. To address this issue, opioids such as fentanyl are being widely used with varying success, and the newer adjuvant dexmedetomidine may be more promising in alleviating visceral pain during cesarean section. This trial builds on preliminary evidence (Gautam et al., 2023) 6 suggesting dexmedetomidine's superiority in reducing visceral pain. The rationale for comparing these adjuvants lies in their contrasting safety profiles: Dexmedetomidine may offer hemodynamic stability, while fentanyl poses risks of respiratory depression and pruritus. Objectives {7} Hypotheses: Null hypothesis (H 0 ): Intrathecal bupivacaine with dexmedetomidine will not reduce the incidence of visceral pain during cesarean delivery as compared to hyperbaric bupivacaine with fentanyl in spinal anesthesia. Alternative hypothesis (H 1 ): Intrathecal bupivacaine with dexmedetomidine will reduce the incidence of visceral pain during cesarean delivery compared to hyperbaric bupivacaine with fentanyl in spinal anesthesia. Primary Compare the incidence of intraoperative visceral pain between Group BF and Group BD. Secondary Objectives: To compare the occurrence of intraoperative shivering between two groups. To compare the intraoperative systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate between two groups. To compare the incidence of side effects like nausea, vomiting, respiratory depression, and pruritus, between two groups To compare the neonatal APGAR score between two groups Trial Design {8} This prospective, randomized, double-blind, parallel-group, and active-controlled trial aims to assess the effects of adjuvants to hyperbaric bupivacaine on visceral pain alleviation. The study will adhere to Consolidated Standards of Trial Reporting (CONSORT) guidelines 7 and be developed based on Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 8 . Participants will be randomly allocated to two groups: BF (bupivacaine-fentanyl) and BD (bupivacaine-dexmedetomidine), at a 1:1 ratio. Intention-to-treat analysis will be employed to ensure the inclusion of all participants from the original groups, regardless of their adherence to the study protocol. Allocation concealment and participant and clinician blinding will be implemented to minimize bias and enhance internal study validity. This methodology seeks to ensure the quality and reliability of the results obtained in evaluating the impact of these adjuvants on visceral pain relief. Methods Study Setting {9} The study will be conducted at Om Sai Pathibhara Hospital, a tertiary care teaching hospital in Nepal that provides comprehensive obstetric and anesthetic services. The facility is well equipped for the conduct of clinical research, with dedicated operating theaters, an experienced anesthesia team, and a postoperative recovery unit that meets the monitoring and safety requirements for this trial. Eligibility criteria {10} The eligibility criteria to participate in the study are established based on non-emergent operative delivery, term pregnancy, and cesarean section under subarachnoid block. These eligibility criteria are important to ensure patient education regarding visceral pain, participant homogeneity, and result validity, in addition to guaranteeing patient safety during the intraoperative and postoperative period. Inclusion Criteria: Elective cesarean under spinal anesthesia. ASA PS II-III. Age ≥ 18 years. Singleton term pregnancy (≥ 37 weeks). Height ≥ 150 cm (to standardize spinal drug spread). Exclusion Criteria: Contraindications to spinal anesthesia (coagulopathy, infection). Chronic pain disorders or opioid use. Allergy to study drugs. Patients with communication problems Fetal anomalies or placental abnormalities. Interventions {11a} Preoperative Patients will undergo screening to determine their potential eligibility for the study. All the patients participating in the study will receive a comprehensive explanation of the study's purpose, their needs, the potential benefits and risks of the procedure, and any other relevant information. They will be taught the method for sensory and motor assessments. In addition, they will be explained about the numerical rating scale of pain, its usage, and how to rate it. They will also be informed about the symptoms of visceral pain (if any) that may occur during SAB during the intraoperative period. Written informed consent will be obtained during pre-anesthetic check-up. A fasting period will be ensured before taking to the pre-operative room. Premedication will be done with Tab. Ranitidine 150mg and Tab. Metoclopramide 10 mg at 10 pm the day before surgery and 6 am on the morning of surgery will be ensured. Before surgery In the pre-operative room, a peripheral intravenous (IV) line will be established with an 18-G IV cannula. Preloading will be done with 10 ml/kg of Lactated Ringer’s solution. Baseline blood pressure, mean arterial pressure, heart rate, respiratory rate, SpO2, and fetal heart rate will be recorded in the pre-delivery room. In the operation theater : Standard monitors including electrocardiography, non-invasive blood pressure monitoring, and pulse oximetry will be attached. The patient will be positioned in a sitting position. Painting of the patient’s back with 10% Povidone Iodine and draping with sterile drapes will be done. Identification of intervertebral space will be done by noting the location of the L 4 spinous process on Tuffier's line (the line connecting the highest point of the iliac crests). Under all aseptic precautions, the skin will be infiltrated with lidocaine 2%, then a 25-gauge Quincke’s spinal needle (Spinocan, B Braun Medical Industries, Malaysia) will be introduced at L3-L4 or L4-L5 intervertebral space using a midline approach in sitting position. After ensuring the free flow of cerebrospinal fluid, the study drug will be given over 12–15 sec. Study drugs would be prepared as: In group BD, Inj 0.5% hyperbaric bupivacaine (ANAWIN heavy, Neon Laboratories, India) 10mg (2ml) with the addition of 5 mcg (0.2ml) Dexmedetomidine (DEXTOMID, Neon Laboratories, India) with a total volume of 2.2 ml will be prepared. In group BF, Inj 0.5% hyperbaric bupivacaine (ANAWIN heavy, Neon Laboratories, India) 10 mg (2ml) with the addition of 10mcg (0.2ml) fentanyl (TROFENTYL, Troikaa pharmaceuticals, India) with a total volume of 2.2 ml will be prepared. - Immediately after the administration of spinal anesthesia, the patient will be positioned supine with a wedge under the right hip and the time will be recorded as “time-zero”. Fetal heart rates will be noted for any bradycardia. Patients will receive oxygen 3L/min via nasal cannula if SpO2 decreases to < 95% NIBP and HR will be assessed every 3 minutes following SAB for 15 minutes or until delivery of the baby and thereafter every 5 minutes till the end of surgery. SpO2 and ECG were monitored continuously throughout the study period. Hypotension will be promptly treated with intravenous fluid bolus (200 ml) and Inj. Mephentermine 6mg IV boluses, which will be repeated if necessary. If the bolus dose of Mephentermine exceeds 30mg then Inj. Phenylephrine 50 mcg IV will be given. Inj. Atropine 0.6mg will be given if bradycardia occurs. If respiratory depression occurs, it will be recorded and managed as: RR ≤ 10 breaths /min physical stimulus will be given (tapping a patient’s shoulder with calling her name) If RR is still not increased or RR ≤ 8 breaths /min Inj Naloxone 0.4 mg IV will be given and will be repeated after 2–3 min if necessary. The dose of Naloxone will not exceed 10mg/ day. The sensory level will be assessed bilaterally along the midclavicular line using spirit-soaked cotton until the block reaches up to the T6 dermatome and time will be noted. The motor block will be assessed based on the Modified Bromage Scale 9 and time will be noted. Surgery will be allowed as soon as the upper sensory level reaches T 6 and the Bromage scale of M3. Thereafter, the level will be checked every 2 min until the maximal sensory block level is confirmed. Intraoperative pain will be assessed whenever the patient complains of pain or discomfort during surgery. If somatic pain occurs (at the time of incision to skin or subcutaneous tissue), spinal anesthesia will be converted to general anesthesia and excluded from the study. Whenever visceral pain occurred, participants were encouraged to self-report such experience and were enquired every five-minute interval during surgery. For analysis, visceral pain outcome was categorized as follows: 6 1 = Excellent, no complaints, 2 = Mild discomfort, requiring no analgesia, 3 = Intermediate discomfort accompanied by nausea requiring anti-emetic, 4 = Severe discomfort accompanied by pain requiring analgesic, and 5 = Failed SA, requiring GA. Assessment of visceral pain will be mainly done during; Delivery of baby with fundal pressure application: When pulling out the head of the baby from the uterus Exteriorization of the uterus: Temporary extraction of the uterus outside the abdominal cavity to facilitate uterine incision repair Handling of other intraperitoneal organs like bowels and adnexa to clear off the secretions and blood Suturing of visceral peritoneum Placement of the uterus back to the abdominal cavity after repair The occurrence of nausea will be correlated with the decrement of SBP and/or HR will be addressed first. Nausea-vomiting occurring otherwise was treated with Ondansetron, Metoclopramide, and Dexamethasone as needed. Anxiety was addressed with Midazolam (maximum three mg). Each time NRS is 4 or more it will be considered as inadequate analgesia 10 , and inj. Fentanyl 25 mcg will be given IV bolus. We will wait for 3 min for its adequate effect. If still pain persists, then the dose of fentanyl will be increased to 1 mcg/kg. After 2 doses of fentanyl, if pain persists then Inj. Ketamine 0.5mcg/kg IV will be given. If pain is still unbearable, general anesthesia will be administered. The need to convert to GA will be noted. The level of consciousness will be measured using the sedation scale (POSS scale) 11 The incidence of shivering will be noted during the intraoperative period, where the temperature of OR will be kept between 18–21 degrees Celsius. Occurrences of side effects such as nausea, vomiting, dizziness, pruritus, bradycardia, decrease in SPO2, and respiratory rate will be recorded and treated according to severity. Any patients who will have these signs and symptoms will be assessed every 15 min in the OR and recovery room. Following the delivery of the baby, Inj. Oxytocin 3 IU will be administered bolus. Continuous infusion of oxytocin drip will be given as needed after communicating with an obstetrician. The APGAR score 12 of the neonate will be evaluated at 1 minute and 5 minutes. The weight of the baby will be noted. Postoperatively, patients will be monitored hourly for hemodynamic changes and any side effects of study drugs up to 6 hours. Outcomes {12} Primary Outcome: The primary outcome will be the occurrence of Visceral pain, assessed using the Numerical Pain Scale (NPS) at five different stages of cesarean section as mentioned above. For analysis, visceral pain outcome was categorized as follows: 6 1 = Excellent, no complaints, 2 = Mild discomfort, requiring no analgesia, 3 = Intermediate discomfort accompanied by nausea requiring anti-emetic, 4 = Severe discomfort accompanied by pain requiring analgesic, and 5 = Failed SA, requiring GA. NRS (Numerical Pain Rating Scale): A subjective measure of pain assessment in which individual verbally rate their pain on an eleven-point numerical scale. 13 Scale composed of 0 (no pain at all) − 10 (worst imaginable pain). 13 Secondary Outcomes : Hemodynamic parameters (SBP, DBP, HR). Neonatal APGAR scores (1/5 minutes). Incidence of shivering, pruritus, nausea, vomiting. Assessment of sedation : Pasero Opioid-Induced Sedation Scale (POSS) 11 POSS score Features S Sleepy, easy to arouse 1 Awake and alert 2 Slightly drowsy, easily arousable 3 Frequently drowsy, arousable, drift off to sleep during conversation 4 Somnolent, minimal or no response to verbal or physical stimulation A POSS score of S, 1, or 2 indicates an acceptable level of sedation, whereas a score of 3 or 4 indicates over-sedation and the need for a reversal agent. Pruritus: Scratch or itching complained by the patient and its Intensity will be assessed as: 2 , 14 Mild – itching will be only a minor concern Moderate- itching will be a primary concern, although bearable Severe- unbearable, patients requiring treatment Secondary Outcomes: Hemodynamic parameters (SBP, DBP, HR). Neonatal APGAR scores (1/5 minutes). Incidence of shivering, pruritus, nausea, vomiting. Participant timeline {13} Patients will be randomly distributed in the two groups using computed generated numbers that will be concealed in sequentially numbered opaque sealed envelopes. The envelopes will be opened by an anesthesia assistant not involved in the study. The proforma will be filled by the investigating anesthesist. Sample Size {14} From the study conducted by Gautam B et al. 6 Pain in Group BF- 48% Pain in Group BD-17% So, comparing this % of the incidence of pain in each group {2(z α + z β ) 2 pq}/(p1 - p2) 2 = {2(1.96 + 1.28) 2 *32.5 * 67.5}/ (48 − 17) 2 = 48 per group Assuming a 20% dropout rate, the total sample size will be 116. Randomization and Blinding {16a, 16b} • Sequence Generation : Participants will be randomly assigned to one of two study groups using randomizer.com. The site will generate a random sequence that determines each participant's allocation to either the Bupivacaine plus fentanyl (BF) group or the Bupivacaine plus dexmetomidine (BD) group. This approach ensures that each participant has an equal chance of being selected for either group, thereby minimizing any allocation bias. The researcher responsible for randomization will have no other role in the study, guaranteeing impartiality. • Allocation Concealment : After the site ( http://randomizer.com ) generates a numerical sequence for random allocation, the study will employ the concealment method using sequentially numbered, sealed, and opaque envelopes. These envelopes will contain random participant allocation to study groups BF and BD. They will be securely stored in a locked cabinet with restricted access, ensuring that the researcher in charge of randomization remains unaware of the allocation sequence. At the time of intervention, the independent anesthesia assistant will open the envelopes to identify participants and determine their group assignment. • Blinding {17a} In this study, we'll employ double blinding. Both participants and the researcher conducting assessments will remain unaware of the randomization and intervention processes. Consequently, they won't have any prior knowledge about which intervention (BD vs BF) was assigned to each participant. Drugs will be prepared by an independent anesthesia assistant using a 1 ml syringe containing 50 mcg of Fentanyl and 25 mcg of dexmedetomidine. The anesthesia assistant will blindly code the syringe, which is then administered to the patient during spinal anesthesia. • Procedure for unblinding if needed {17b} Unblinding during the trial will be limited to specific situations, such as medical emergencies. Only one designated researcher will disclose the intervention to participants who require this information for medical or safety reasons. The researcher conducting assessments will not be permitted to unblind participants, and only the researcher responsible for the intervention will possess knowledge of the intrathecal drug specifications. • Data Collection {18a} In the study, data collection methods will include baseline assessments and result collection at various points: before surgery, intraoperatively: during the delivery of the baby, as well as during the exteriorization of the fetus, handling of other intraperitoneal organs such as the bowels and adnexa, suturing of the visceral peritoneum, and placing the uterus back into the abdominal cavity, and post-operatively for baby APGAR score and any adverse events as outlined in the protocol. To ensure the quality of the data, assessment training will be conducted to ensure the accuracy and consistency of the information obtained. The data collection instruments used are renowned for their reliability and validity. The study protocol will provide information on these instruments, including their reliability and validity, as well as guidelines for their correct application. This approach ensures data collection consistency, leading to a reliable and accurate analysis of the results. Timeline: Screening (Day − 0), Intervention (Day 1), Follow-up (6 hours post-op). Data management {19 } Data management will adhere to meticulously crafted plans for data entry, coding, security, and storage. Double entry and range checks will be employed to ensure the data's quality. Daily data collection will be conducted, saved in Excel, and stored on the Google Drive of the principal investigator. He will manage the data himself. With password-protected confidential data, access will be restricted to researchers and registered participants. The qualified team will accurately collect and record the data, ensuring privacy and safeguarding against unauthorized access. Statistical Methods {20a} Statistical analysis will be conducted by a researcher blinded to randomization and assessment, ensuring impartial results. The intention-to-treat approach will be used to analyze the participants initially assigned to each group, irrespective of whether they completed the study. Histograms will be used to determine data distribution and assess normality. Descriptive statistics, including mean ± SD for continuous variables and frequency (%) for categorical variables, will be used. The chi-square test will be employed to compare the primary outcome means between the groups. A mixed linear model will be applied to repeated measures, using compound symmetry in the type of repeated covariance, and Fisher’s exact test will be used to evaluate side effects. The Bonferroni correction with a 95% confidence interval will control for type I errors. Intergroup comparisons will be presented with the mean, standard deviation, difference between means, 95% confidence interval, and effect size calculated using Cohen's d. The interpretation of effect size will adhere to Cohen's criteria, where values less than 0.2 indicate a small effect, 0.5 moderate, 0.8 superior, and 0.8 a large effect. The significance level set for all tests will be 0.05, ensuring the statistical robustness of the conclusions. Statistical analyses will be conducted using IBM® SPSS® Statistics for Mac software, version 30.0, following the standard methodology, thereby guaranteeing the accuracy and reliability of the results obtained. Methods for additional analyses (e.g., subgroup analyses) {20b} In this study, we won't analyze subgroups. Instead, we'll focus on the overall results of all participants, disregarding any differences or subdivisions based on specific traits. Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} The intention-to-treat principle will be employed to analyze non-compliance with the protocol and missing data. All participants will be analyzed in their original groups, irrespective of whether they completed the study or not. In case of discontinuity, the missing data will be analyzed according to this principle to draw statistical conclusions. This approach ensures the validity and reliability of the results obtained. Statistical methods, such as data imputation and specific models, will be applied to analyze the missing information. Composition of the Data monitoring and safety board, its role and reporting structure {21a} The Data Monitoring and Safety Board (DSMB), comprising three members, will be an independent and impartial entity responsible for monitoring the entire trial process in the current study. The DSMB will oversee the trial at all participating sites, including continuous review of participant recruitment, accrual, retention, and withdrawal. It will also provide oversight of participant management, adherence to protocol-specified regimens, and procedures for data management and quality control. The DSMB will ensure the safety and well-being of trial participants by assessing the safety of the interventions during the trial and monitoring the overall progress of the trial. Specifically, the role of the DSMB will be to: Monitor and review participant safety in the trial (including evidence for treatment harm [e.g., adverse effects, safety events) Review participant recruitment, accrual, retention, treatment discontinuation, trial withdrawal, serious breaches, and protocol deviations that require exclusion of the participant from the per-protocol analysis, The DSMB will provide recommendations on continuing, modifying, or stopping the trial. To enhance trial integrity, it may also recommend participant selection, recruitment, retention, management, protocol adherence, data management, and quality control. The DSMB will differentiate reported safety events associated with trial interventions from those with other causes using clinical data. Reported safety data must indicate the likelihood of causality. Interim analyses {21b} Interim analyses will not be conducted. The protocol explicitly determines that no provisional analysis will be carried out. If any discontinuity occurs during the trial, the intention-to-treat principle will be applied to handle the missing data. Adverse event reporting and harms {22} The study will adhere to a strict protocol for monitoring and managing adverse events and intervention-related harm. Detailed information, including the occurrence, severity, and relationship with the intervention, will be recorded on notification charts for all events. The research team will be trained to identify and document these events, and participants will be informed about how to report any discomfort during the study. If any treatment-related harm or complication arises, appropriate measures will be taken to ensure participant safety. All relevant information will be documented and reported to the DSMB, NHRC, and the hospital administration authorities, complying with applicable legal and ethical guidelines. Frequency and plans for auditing trial conduct {23} In the present study, trial conduct will not be audited since it does not apply to the specific circumstances of the study. Declarations Ethical Considerations {24} Approval: NHRC Nepal (Protocol ID: 98_2024). Informed Consent: Bilingual forms (English and Nepali) with witness signatures. Confidentiality: Encrypted databases; anonymized data sharing. Adverse Events: Reported to DSMB, Hospital administration, and NHRC within 24 hours. Plans for communicating important protocol amendments to relevant parties (e.g. , trial participants, ethical committees) {25} This study protocol was approved by the Nepal Health Research Council and registered on Clinicaltrial.gov under the registration number NCT06367660. Any significant modifications to the protocol, such as changes in eligibility criteria, results, or analyses, were meticulously documented and submitted to the relevant centers and the NHRC ethics committee, adhering strictly to SPIRIT guidelines. All pertinent parties, including investigators, DSMB members, research ethics committees, and trial regulators, will be promptly informed of any changes, ensuring the utmost transparency and integrity of the study. Dissemination Plan {31a} Publications : peer-reviewed scientific journals, Open-access journals Data Sharing : De-identified data available upon request post-publication. Funding {4}: The researchers themselves will completely fund this study. Author Details {5a}: Dr. Sujan Dhakal : Principal Investigator, Department of Anaesthesiology, Om Sai Pathibhara Hospital. Dr. Elija Gautam : Co-Investigator, Department of Gynecology, Om Sai Pathibhara Hospital. Dr. Muskaan Shrestha : Co-Investigator, Department of Anaesthesiology, Om Sai Pathibhara Hospital. Dr. Allen Suwal : Co-Investigator, Department of Anaesthesiology, Patan Hospital. Dr Salin Dhakal : Co-Investigator, National Medical College. Mrs. Sita Dhakal, Clinical Pharmacist, Tribhuwan University Sponsor {5b}: This study has no sponsors. Role of Sponsor {5c}: Not Applicable References Fassoulaki A, Staikou C, Melemeni A, Kottis G, Petropoulos G (2010) Anaesthesia preference, neuraxial vs general, and outcome after cesarean section. J Obstet Gynaecol 30(8):818–821 Pedersen H, Santos AC, Steinberg ES, Schapiro HM, Harmon TW, Finster M (1989) Incidence of visceral pain during cesarean section: the effect of varying doses of spinal bupivacaine. 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Philadelphia: Churchill Livingstone; pp. 29–34 Biswas BN, Rudra A, Bose BK, Nath S, Chakrabarty S, Bhattacharjee S (2002) Intrathecal fentanyl with hyperbaric bupivacaine improves analgesia during cesarean delivery and in the early postoperative period. Indian J Anaesth 46(6):469 Additional Declarations The authors declare potential competing interests as follows: No, I declare that authors have no interests, affiliations, or associations that might be perceived to influence the results and/or discussion reported in this preprint submission Supplementary Files Appendices.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6337531","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":435874156,"identity":"ea9aca1e-74fc-49b5-b418-a8bb495787b4","order_by":0,"name":"Dr Sujan Dhakal","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0ElEQVRIiWNgGAWjYJACyYYCNmZ+ECuhgGgtBnzskg0gLQbEa5HjNzgAYhKjRb7/7MGbMwzMpI3Pr0788MCAQZ5f7AB+LQYHziVbbjBIMza78XazBNBhhjNnJxDQwthjJvnA4Fiy2Y2zG0BaEgxuE9Ai38wD0vK/fvOMs5t/EKWF4RhQywYDNmYD/t5txNlicIbH2HIGUIvEDd5tFgkGEoT9It9/xvBmTwUwKvvPbr75o8JGnl+akMPgQAKsUoJY5SDAf4AU1aNgFIyCUTCSAADiQUEBZP8XNAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-6422-4810","institution":"Om Sai Pathibhara Hospital","correspondingAuthor":true,"prefix":"Dr","firstName":"Sujan","middleName":"","lastName":"Dhakal","suffix":""},{"id":435874157,"identity":"0b1f3554-cc43-4b88-a568-da76a446088d","order_by":1,"name":"Dr Elija Gautam","email":"","orcid":"","institution":"Om Sai Pathibhara Hospital","correspondingAuthor":false,"prefix":"Dr","firstName":"Elija","middleName":"","lastName":"Gautam","suffix":""},{"id":435874158,"identity":"553e4671-dd2a-4193-85bf-30a6f752952e","order_by":2,"name":"Dr Allen Suwal","email":"","orcid":"","institution":"Patan Academy of Health Science","correspondingAuthor":false,"prefix":"Dr","firstName":"Allen","middleName":"","lastName":"Suwal","suffix":""},{"id":435874159,"identity":"ba5e26c0-90f4-4aab-a462-9c9c3af4a553","order_by":3,"name":"Dr Salin Dhakal","email":"","orcid":"","institution":"National Medical College","correspondingAuthor":false,"prefix":"Dr","firstName":"Salin","middleName":"","lastName":"Dhakal","suffix":""},{"id":435874160,"identity":"92300e04-49e4-49ca-83ea-d99f92b7ade0","order_by":4,"name":"Sita Dhakal","email":"","orcid":"","institution":"Tribhuwan University","correspondingAuthor":false,"prefix":"","firstName":"Sita","middleName":"","lastName":"Dhakal","suffix":""},{"id":435874161,"identity":"9302c47d-a5b0-4df6-a4f3-6cb8af358b1d","order_by":5,"name":"Dr Muskaan Shrestha","email":"","orcid":"","institution":"Om Sai Pathibhara Hospital","correspondingAuthor":false,"prefix":"Dr","firstName":"Muskaan","middleName":"","lastName":"Shrestha","suffix":""}],"badges":[],"createdAt":"2025-03-30 08:42:18","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":true,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":true,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6337531/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6337531/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":79651830,"identity":"c3f1fd50-ab4d-483a-ae4f-d832cb9ef356","added_by":"auto","created_at":"2025-04-01 08:06:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1241324,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6337531/v1/3e553f55-b7a3-4758-8ff7-4db16556e8b6.pdf"},{"id":79650498,"identity":"132050f4-4002-4b5e-9fb3-913cb01a6855","added_by":"auto","created_at":"2025-04-01 07:50:47","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":65898,"visible":true,"origin":"","legend":"","description":"","filename":"Appendices.docx","url":"https://assets-eu.researchsquare.com/files/rs-6337531/v1/87682c889d75ba10f657f853.docx"}],"financialInterests":"The authors declare potential competing interests as follows: No, I declare that authors have no interests, affiliations, or associations that might be perceived to influence the results and/or discussion reported in this preprint submission","formattedTitle":"\u003cp\u003eComparison Between Hyperbaric Bupivacaine with Fentanyl vs. Hyperbaric Bupivacaine with Dexmedetomidine in Reducing Visceral Pain During Cesarean Delivery Under Spinal Anesthesia, A Prospective Randomized Double-Blind Comparative Study; Clinical Trial Protocol\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003ch2\u003eBackground and Rationale {6a}:\u003c/h2\u003e\u003cp\u003eThe subarachnoid block is the most commonly employed anesthetic technique for cesarean delivery. Subarachnoid block in cesarean section is associated with better outcomes in terms of postoperative pain, duration of stay in the hospital, and patient satisfaction when compared with general anesthesia. \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Hyperbaric Bupivacaine is most commonly employed for a subarachnoid block at different doses. Visceral pain during cesarean delivery under spinal anesthesia originates from mechanical traction on the peritoneum and intra-abdominal organs, mediated by unmyelinated C-fibers and poorly localized nociceptive pathways. This pain is particularly intense when the surgeon is handling different intraabdominal organs during cesarean delivery under subarachnoid block. The incidence of visceral pain during cesarean section is estimated to be 71% under spinal anesthesia with 7.5–10 mg and 50% with 10-12.5 mg of hyperbaric 0.5% bupivacaine, respectively. \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e With higher doses of hyperbaric bupivacaine, the incidence of intraoperative visceral pain is reduced, but increasing the dose of bupivacaine increases the risk of high block. \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e To mitigate this problem, benzodiazepines, opioids (e.g. morphine, fentanyl, and sufentanil), α-adrenergic agonists (e.g. epinephrine or phenylephrine), ketamine, and α2-adrenergic receptor agonists (e.g. clonidine or dexmedetomidine) are adjuvants of common use. \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Adjuvants like fentanyl (a µ-opioid receptor agonist) and dexmedetomidine (a selective α2-adrenergic agonist) enhance analgesia through distinct mechanisms:\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eFentanyl\u003c/b\u003e binds spinal opioid receptors, inhibiting nociceptive transmission.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eDexmedetomidine\u003c/b\u003e modulates pain via α2 receptors in the dorsal horn, reducing sympathetic outflow and prolonging sensory blockade.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eThe rationale for Comparison:\u003c/h3\u003e\n\u003cp\u003eVisceral pain is poorly controlled with the standard dose of hyperbaric bupivacaine. However, higher doses of hyperbaric bupivacaine may reduce the incidence of intraoperative visceral pain, but increasing the dose of bupivacaine increases the risk of high block. To address this issue, opioids such as fentanyl are being widely used with varying success, and the newer adjuvant dexmedetomidine may be more promising in alleviating visceral pain during cesarean section. This trial builds on preliminary evidence (Gautam et al., 2023)\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e suggesting dexmedetomidine's superiority in reducing visceral pain. The rationale for comparing these adjuvants lies in their contrasting safety profiles: Dexmedetomidine may offer hemodynamic stability, while fentanyl poses risks of respiratory depression and pruritus.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eObjectives {7}\u003c/h2\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003ch2\u003eHypotheses:\u003c/h2\u003e \u003cp\u003eNull hypothesis (H\u003csub\u003e0\u003c/sub\u003e): Intrathecal bupivacaine with dexmedetomidine will not reduce the incidence of visceral pain during cesarean delivery as compared to hyperbaric bupivacaine with fentanyl in spinal anesthesia.\u003c/p\u003e \u003cp\u003eAlternative hypothesis (H\u003csub\u003e1\u003c/sub\u003e): Intrathecal bupivacaine with dexmedetomidine will reduce the incidence of visceral pain during cesarean delivery compared to hyperbaric bupivacaine with fentanyl in spinal anesthesia.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e\n\u003ch3\u003ePrimary\u003c/h3\u003e\n\u003cp\u003eCompare the incidence of intraoperative visceral pain between Group BF and Group BD.\u003c/p\u003e\n\u003ch3\u003eSecondary Objectives:\u003c/h3\u003e\n\u003cp\u003eTo compare the occurrence of intraoperative shivering between two groups.\u003c/p\u003e \u003cp\u003eTo compare the intraoperative systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate between two groups.\u003c/p\u003e \u003cp\u003eTo compare the incidence of side effects like nausea, vomiting, respiratory depression, and pruritus, between two groups\u003c/p\u003e \u003cp\u003eTo compare the neonatal APGAR score between two groups\u003c/p\u003e\n\u003ch3\u003eTrial Design {8}\u003c/h3\u003e\n\u003cp\u003eThis prospective, randomized, double-blind, parallel-group, and active-controlled trial aims to assess the effects of adjuvants to hyperbaric bupivacaine on visceral pain alleviation. The study will adhere to Consolidated Standards of Trial Reporting (CONSORT) guidelines \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e and be developed based on Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT)\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Participants will be randomly allocated to two groups: BF (bupivacaine-fentanyl) and BD (bupivacaine-dexmedetomidine), at a 1:1 ratio. Intention-to-treat analysis will be employed to ensure the inclusion of all participants from the original groups, regardless of their adherence to the study protocol. Allocation concealment and participant and clinician blinding will be implemented to minimize bias and enhance internal study validity. This methodology seeks to ensure the quality and reliability of the results obtained in evaluating the impact of these adjuvants on visceral pain relief.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Methods","content":"\u003ch2\u003eStudy Setting {9}\u003c/h2\u003e\u003cp\u003e The study will be conducted at Om Sai Pathibhara Hospital, a tertiary care teaching hospital in Nepal that provides comprehensive obstetric and anesthetic services. The facility is well equipped for the conduct of clinical research, with dedicated operating theaters, an experienced anesthesia team, and a postoperative recovery unit that meets the monitoring and safety requirements for this trial.\u003c/p\u003e\n\u003ch3\u003eEligibility criteria {10}\u003c/h3\u003e\n\u003cp\u003eThe eligibility criteria to participate in the study are established based on non-emergent operative delivery, term pregnancy, and cesarean section under subarachnoid block.\u003c/p\u003e \u003cp\u003eThese eligibility criteria are important to ensure patient education regarding visceral pain, participant homogeneity, and result validity, in addition to guaranteeing patient safety during the intraoperative and postoperative period.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eInclusion Criteria:\u003c/h2\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eElective cesarean under spinal anesthesia.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eASA PS II-III.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAge ≥ 18 years.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eSingleton term pregnancy (≥ 37 weeks).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eHeight ≥ 150 cm (to standardize spinal drug spread).\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003cp\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eExclusion Criteria:\u003c/h2\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eContraindications to spinal anesthesia (coagulopathy, infection).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eChronic pain disorders or opioid use.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAllergy to study drugs.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePatients with communication problems\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eFetal anomalies or placental abnormalities.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003cp\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eInterventions {11a}\u003c/h2\u003e \u003cp\u003e \u003cb\u003ePreoperative\u003c/b\u003e \u003c/p\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003ePatients will undergo screening to determine their potential eligibility for the study.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAll the patients participating in the study will receive a comprehensive explanation of the study's purpose, their needs, the potential benefits and risks of the procedure, and any other relevant information.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThey will be taught the method for sensory and motor assessments.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIn addition, they will be explained about the numerical rating scale of pain, its usage, and how to rate it. They will also be informed about the symptoms of visceral pain (if any) that may occur during SAB during the intraoperative period.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eWritten informed consent will be obtained during pre-anesthetic check-up.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eA fasting period will be ensured before taking to the pre-operative room.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePremedication will be done with Tab. Ranitidine 150mg and Tab. Metoclopramide 10 mg at 10 pm the day before surgery and 6 am on the morning of surgery will be ensured.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003cp\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eBefore surgery\u003c/b\u003e \u003c/p\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eIn the pre-operative room, a peripheral intravenous (IV) line will be established with an 18-G IV cannula.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePreloading will be done with 10 ml/kg of Lactated Ringer’s solution.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eBaseline blood pressure, mean arterial pressure, heart rate, respiratory rate, SpO2, and fetal heart rate will be recorded in the pre-delivery room.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003cp\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eIn the operation theater\u003c/b\u003e:\u003c/p\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eStandard monitors including electrocardiography, non-invasive blood pressure monitoring, and pulse oximetry will be attached.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThe patient will be positioned in a sitting position.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePainting of the patient’s back with 10% Povidone Iodine and draping with sterile drapes will be done.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIdentification of intervertebral space will be done by noting the location of the L\u003csub\u003e4\u003c/sub\u003e spinous process on Tuffier's line (the line connecting the highest point of the iliac crests).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eUnder all aseptic precautions, the skin will be infiltrated with lidocaine 2%, then a 25-gauge Quincke’s spinal needle (Spinocan, B Braun Medical Industries, Malaysia) will be introduced at L3-L4 or L4-L5 intervertebral space using a midline approach in sitting position.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAfter ensuring the free flow of cerebrospinal fluid, the study drug will be given over 12–15 sec.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eStudy drugs would be prepared as:\u003c/p\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eIn group BD, Inj 0.5% hyperbaric bupivacaine (ANAWIN heavy, Neon Laboratories, India) 10mg (2ml) with the addition of 5 mcg (0.2ml) Dexmedetomidine (DEXTOMID, Neon Laboratories, India) with a total volume of 2.2 ml will be prepared.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIn group BF, Inj 0.5% hyperbaric bupivacaine (ANAWIN heavy, Neon Laboratories, India) 10 mg (2ml) with the addition of 10mcg (0.2ml) fentanyl (TROFENTYL, Troikaa pharmaceuticals, India) with a total volume of 2.2 ml will be prepared.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003cp\u003e\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003cp\u003e\u003c/p\u003e \u003cp\u003e- Immediately after the administration of spinal anesthesia, the patient will be positioned supine with a wedge under the right hip and the time will be recorded as “time-zero”.\u003c/p\u003e\u003cul\u003e \u003cli\u003e \u003cp\u003eFetal heart rates will be noted for any bradycardia.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePatients will receive oxygen 3L/min via nasal cannula if SpO2 decreases to \u0026lt; 95%\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eNIBP and HR will be assessed every 3 minutes following SAB for 15 minutes or until delivery of the baby and thereafter every 5 minutes till the end of surgery.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eSpO2 and ECG were monitored continuously throughout the study period.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eHypotension will be promptly treated with intravenous fluid bolus (200 ml) and Inj. Mephentermine 6mg IV boluses, which will be repeated if necessary.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIf the bolus dose of Mephentermine exceeds 30mg then Inj. Phenylephrine 50 mcg IV will be given.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eInj. Atropine 0.6mg will be given if bradycardia occurs.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIf respiratory depression occurs, it will be recorded and managed as:\u003c/p\u003e\u003cul\u003e \u003cli\u003e \u003cp\u003eRR \u003cb\u003e≤\u003c/b\u003e 10 breaths /min physical stimulus will be given (tapping a patient’s shoulder with calling her name)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIf RR is still not increased or RR \u003cb\u003e≤\u003c/b\u003e 8 breaths /min Inj Naloxone\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003cp\u003e\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003cp\u003e\u003c/p\u003e \u003cp\u003e0.4 mg IV will be given and will be repeated after 2–3 min if necessary.\u003c/p\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eThe dose of Naloxone will not exceed 10mg/ day.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThe sensory level will be assessed bilaterally along the midclavicular line using spirit-soaked cotton until the block reaches up to the T6 dermatome and time will be noted.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThe motor block will be assessed based on the Modified Bromage Scale\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e and time will be noted.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eSurgery will be allowed as soon as the upper sensory level reaches T\u003csub\u003e6\u003c/sub\u003e and the Bromage scale of M3.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThereafter, the level will be checked every 2 min until the maximal sensory block level is confirmed.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIntraoperative pain will be assessed whenever the patient complains of pain or discomfort during surgery.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIf somatic pain occurs (at the time of incision to skin or subcutaneous tissue), spinal anesthesia will be converted to general anesthesia and excluded from the study.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eWhenever visceral pain occurred, participants were encouraged to self-report such experience and were enquired every five-minute interval during surgery. For analysis, visceral pain outcome was categorized as follows: \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003e1 = Excellent, no complaints,\u003c/p\u003e \u003cp\u003e2 = Mild discomfort, requiring no analgesia,\u003c/p\u003e \u003cp\u003e3 = Intermediate discomfort accompanied by nausea requiring anti-emetic,\u003c/p\u003e \u003cp\u003e4 = Severe discomfort accompanied by pain requiring analgesic, and\u003c/p\u003e \u003cp\u003e5 = Failed SA, requiring GA.\u003c/p\u003e \u003c/div\u003e \u003cp\u003e\u003c/p\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eAssessment of visceral pain will be mainly done during;\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003cp\u003e\u003c/p\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eDelivery of baby with fundal pressure application: When pulling out the head of the baby from the uterus\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eExteriorization of the uterus: Temporary extraction of the uterus outside the abdominal cavity to facilitate uterine incision repair\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eHandling of other intraperitoneal organs like bowels and adnexa to clear off the secretions and blood\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSuturing of visceral peritoneum\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePlacement of the uterus back to the abdominal cavity after repair\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003cp\u003e\u003c/p\u003e \u003cp\u003eThe occurrence of nausea will be correlated with the decrement of SBP and/or HR will be addressed first.\u003c/p\u003e\u003cul\u003e \u003cli\u003e \u003cp\u003eNausea-vomiting occurring otherwise was treated with Ondansetron, Metoclopramide, and Dexamethasone as needed.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAnxiety was addressed with Midazolam (maximum three mg).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eEach time NRS is 4 or more it will be considered as inadequate analgesia\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, and inj. Fentanyl 25 mcg will be given IV bolus.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eWe will wait for 3 min for its adequate effect.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIf still pain persists, then the dose of fentanyl will be increased to 1 mcg/kg.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAfter 2 doses of fentanyl, if pain persists then Inj. Ketamine 0.5mcg/kg IV will be given.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIf pain is still unbearable, general anesthesia will be administered.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThe need to convert to GA will be noted.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThe level of consciousness will be measured using the sedation scale (POSS scale)\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThe incidence of shivering will be noted during the intraoperative period, where the temperature of OR will be kept between 18–21 degrees Celsius.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eOccurrences of side effects such as nausea, vomiting, dizziness, pruritus, bradycardia, decrease in SPO2, and respiratory rate will be recorded and treated according to severity.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAny patients who will have these signs and symptoms will be assessed every 15 min in the OR and recovery room.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eFollowing the delivery of the baby, Inj. Oxytocin 3 IU will be administered bolus.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eContinuous infusion of oxytocin drip will be given as needed after communicating with an obstetrician.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThe APGAR score\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e of the neonate will be evaluated at 1 minute and 5 minutes.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThe weight of the baby will be noted.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePostoperatively, patients will be monitored hourly for hemodynamic changes and any side effects of study drugs up to 6 hours.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003cp\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes {12}\u003c/h2\u003e \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e \u003ch2\u003ePrimary Outcome:\u003c/h2\u003e \u003cp\u003eThe primary outcome will be the occurrence of Visceral pain, assessed using the Numerical Pain Scale (NPS) at five different stages of cesarean section as mentioned above.\u003c/p\u003e \u003cp\u003eFor analysis, visceral pain outcome was categorized as follows:\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e1 = Excellent, no complaints,\u003c/p\u003e \u003cp\u003e2 = Mild discomfort, requiring no analgesia,\u003c/p\u003e \u003cp\u003e3 = Intermediate discomfort accompanied by nausea requiring anti-emetic,\u003c/p\u003e \u003cp\u003e4 = Severe discomfort accompanied by pain requiring analgesic, and\u003c/p\u003e \u003cp\u003e5 = Failed SA, requiring GA.\u003c/p\u003e \u003cp\u003eNRS (Numerical Pain Rating Scale):\u003c/p\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eA subjective measure of pain assessment in which individual verbally rate their pain on an eleven-point numerical scale.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eScale composed of 0 (no pain at all) − 10 (worst imaginable pain). \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cimg 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\" style=\"width: 599px;\"\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eSecondary Outcomes\u003c/b\u003e:\u003c/p\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eHemodynamic parameters (SBP, DBP, HR).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eNeonatal APGAR scores (1/5 minutes).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIncidence of shivering, pruritus, nausea, vomiting.\u003c/p\u003e\u003cul\u003e \u003cli\u003e \u003cp\u003eAssessment of sedation :\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003cp\u003e\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003ePasero Opioid-Induced Sedation Scale (POSS)\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cp\u003e\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e\u003ccolgroup cols=\"2\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePOSS score\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFeatures\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eS\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSleepy, easy to arouse\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAwake and alert\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSlightly drowsy, easily arousable\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFrequently drowsy, arousable, drift off to sleep during conversation\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSomnolent, minimal or no response to verbal or physical stimulation\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e \u003cp\u003e\u003c/p\u003e \u003cp\u003eA POSS score of S, 1, or 2 indicates an acceptable level of sedation, whereas a score of 3 or 4 indicates over-sedation and the need for a reversal agent.\u003c/p\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003ePruritus: Scratch or itching complained by the patient and its Intensity will be assessed as: \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eMild – itching will be only a minor concern\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eModerate- itching will be a primary concern, although bearable\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eSevere- unbearable, patients requiring treatment\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eSecondary Outcomes:\u003c/h2\u003e\u003cul\u003e \u003cli\u003e \u003cp\u003eHemodynamic parameters (SBP, DBP, HR).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eNeonatal APGAR scores (1/5 minutes).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIncidence of shivering, pruritus, nausea, vomiting.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003cp\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eParticipant timeline {13}\u003c/h2\u003e\u003cul\u003e \u003cli\u003e \u003cp\u003ePatients will be randomly distributed in the two groups using computed generated numbers that will be concealed in sequentially numbered opaque sealed envelopes.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThe envelopes will be opened by an anesthesia assistant not involved in the study.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThe proforma will be filled by the investigating anesthesist.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003cp\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eSample Size {14}\u003c/h2\u003e \u003cp\u003eFrom the study conducted by Gautam B et al.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003ePain in Group BF- 48%\u003c/p\u003e \u003cp\u003ePain in Group BD-17%\u003c/p\u003e \u003cp\u003eSo, comparing this % of the incidence of pain in each group\u003c/p\u003e \u003cp\u003e{2(z\u003cem\u003eα\u003c/em\u003e + z\u003cem\u003eβ\u003c/em\u003e)\u003csup\u003e2\u003c/sup\u003e pq}/(p1 - p2) \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e= {2(1.96 + 1.28) \u003csup\u003e2\u003c/sup\u003e *32.5 * 67.5}/ (48 − 17) \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e\u003c/h2\u003e\u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003e= 48 per group\u003c/p\u003e \u003cp\u003eAssuming a 20% dropout rate, the total sample size will be 116.\u003c/p\u003e \u003c/div\u003e \u003cp\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eRandomization and Blinding {16a, 16b}\u003c/h2\u003e \u003cdiv id=\"Sec21\" class=\"Section3\"\u003e \u003ch2\u003e• \u003cb\u003eSequence Generation\u003c/b\u003e:\u003c/h2\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eParticipants will be randomly assigned to one of two study groups using randomizer.com. The site will generate a random sequence that determines each participant's allocation to either the Bupivacaine plus fentanyl (BF) group or the Bupivacaine plus dexmetomidine (BD) group. This approach ensures that each participant has an equal chance of being selected for either group, thereby minimizing any allocation bias. The researcher responsible for randomization will have no other role in the study, guaranteeing impartiality.\u003c/p\u003e \u003c/div\u003e \u003cp\u003e\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003e• \u003cb\u003eAllocation Concealment\u003c/b\u003e:\u003c/h2\u003e \u003cp\u003eAfter the site (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://randomizer.com\u003c/span\u003e\u003cspan address=\"http://randomizer.com\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) generates a numerical sequence for random allocation, the study will employ the concealment method using sequentially numbered, sealed, and opaque envelopes. These envelopes will contain random participant allocation to study groups BF and BD. They will be securely stored in a locked cabinet with restricted access, ensuring that the researcher in charge of randomization remains unaware of the allocation sequence. At the time of intervention, the independent anesthesia assistant will open the envelopes to identify participants and determine their group assignment.\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003e• Blinding {17a}\u003c/h2\u003e \u003cp\u003eIn this study, we'll employ double blinding. Both participants and the researcher conducting assessments will remain unaware of the randomization and intervention processes. Consequently, they won't have any prior knowledge about which intervention (BD vs BF) was assigned to each participant.\u003c/p\u003e \u003cp\u003eDrugs will be prepared by an independent anesthesia assistant using a 1 ml syringe containing 50 mcg of Fentanyl and 25 mcg of dexmedetomidine. The anesthesia assistant will blindly code the syringe, which is then administered to the patient during spinal anesthesia.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003e• Procedure for unblinding if needed {17b}\u003c/h2\u003e \u003cp\u003eUnblinding during the trial will be limited to specific situations, such as medical emergencies. Only one designated researcher will disclose the intervention to participants who require this information for medical or safety reasons. The researcher conducting assessments will not be permitted to unblind participants, and only the researcher responsible for the intervention will possess knowledge of the intrathecal drug specifications.\u003c/p\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003e• Data Collection {18a}\u003c/h2\u003e \u003cp\u003eIn the study, data collection methods will include baseline assessments and result collection at various points: before surgery, intraoperatively: during the delivery of the baby, as well as during the exteriorization of the fetus, handling of other intraperitoneal organs such as the bowels and adnexa, suturing of the visceral peritoneum, and placing the uterus back into the abdominal cavity, and post-operatively for baby APGAR score and any adverse events as outlined in the protocol. To ensure the quality of the data, assessment training will be conducted to ensure the accuracy and consistency of the information obtained.\u003c/p\u003e \u003cp\u003eThe data collection instruments used are renowned for their reliability and validity. The study protocol will provide information on these instruments, including their reliability and validity, as well as guidelines for their correct application. This approach ensures data collection consistency, leading to a reliable and accurate analysis of the results.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec26\" class=\"Section3\"\u003e \u003ch2\u003eTimeline:\u003c/h2\u003e \u003cp\u003eScreening (Day − 0), Intervention (Day 1), Follow-up (6 hours post-op).\u003c/p\u003e\u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eData management {19\u003c/b\u003e}\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003cp\u003e\u003c/p\u003e \u003cp\u003eData management will adhere to meticulously crafted plans for data entry, coding, security, and storage. Double entry and range checks will be employed to ensure the data's quality. Daily data collection will be conducted, saved in Excel, and stored on the Google Drive of the principal investigator. He will manage the data himself. With password-protected confidential data, access will be restricted to researchers and registered participants. The qualified team will accurately collect and record the data, ensuring privacy and safeguarding against unauthorized access.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec27\" class=\"Section3\"\u003e \u003ch2\u003eStatistical Methods {20a}\u003c/h2\u003e \u003cp\u003eStatistical analysis will be conducted by a researcher blinded to randomization and assessment, ensuring impartial results. The intention-to-treat approach will be used to analyze the participants initially assigned to each group, irrespective of whether they completed the study. Histograms will be used to determine data distribution and assess normality. Descriptive statistics, including mean ± SD for continuous variables and frequency (%) for categorical variables, will be used. The chi-square test will be employed to compare the primary outcome means between the groups. A mixed linear model will be applied to repeated measures, using compound symmetry in the type of repeated covariance, and Fisher’s exact test will be used to evaluate side effects.\u003c/p\u003e \u003cp\u003eThe Bonferroni correction with a 95% confidence interval will control for type I errors. Intergroup comparisons will be presented with the mean, standard deviation, difference between means, 95% confidence interval, and effect size calculated using Cohen's d. The interpretation of effect size will adhere to Cohen's criteria, where values less than 0.2 indicate a small effect, 0.5 moderate, 0.8 superior, and 0.8 a large effect. The significance level set for all tests will be 0.05, ensuring the statistical robustness of the conclusions. Statistical analyses will be conducted using IBM® SPSS® Statistics for Mac software, version 30.0, following the standard methodology, thereby guaranteeing the accuracy and reliability of the results obtained.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec28\" class=\"Section2\"\u003e \u003ch2\u003eMethods for additional analyses (e.g., subgroup analyses) {20b}\u003c/h2\u003e \u003cp\u003eIn this study, we won't analyze subgroups. Instead, we'll focus on the overall results of all participants, disregarding any differences or subdivisions based on specific traits.\u003c/p\u003e \u003cp\u003e \u003cb\u003eMethods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe intention-to-treat principle will be employed to analyze non-compliance with the protocol and missing data. All participants will be analyzed in their original groups, irrespective of whether they completed the study or not. In case of discontinuity, the missing data will be analyzed according to this principle to draw statistical conclusions. This approach ensures the validity and reliability of the results obtained. Statistical methods, such as data imputation and specific models, will be applied to analyze the missing information.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec29\" class=\"Section2\"\u003e \u003ch2\u003eComposition of the Data monitoring and safety board, its role and reporting structure {21a}\u003c/h2\u003e \u003cp\u003eThe Data Monitoring and Safety Board (DSMB), comprising three members, will be an independent and impartial entity responsible for monitoring the entire trial process in the current study. The DSMB will oversee the trial at all participating sites, including continuous review of participant recruitment, accrual, retention, and withdrawal. It will also provide oversight of participant management, adherence to protocol-specified regimens, and procedures for data management and quality control.\u003c/p\u003e \u003cp\u003eThe DSMB will ensure the safety and well-being of trial participants by assessing the safety of the interventions during the trial and monitoring the overall progress of the trial.\u003c/p\u003e \u003cp\u003eSpecifically, the role of the DSMB will be to:\u003c/p\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eMonitor and review participant safety in the trial (including evidence for treatment harm [e.g., adverse effects, safety events)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eReview participant recruitment, accrual, retention, treatment discontinuation, trial withdrawal, serious breaches, and protocol deviations that require exclusion of the participant from the per-protocol analysis,\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003cp\u003e\u003c/p\u003e \u003cp\u003eThe DSMB will provide recommendations on continuing, modifying, or stopping the trial. To enhance trial integrity, it may also recommend participant selection, recruitment, retention, management, protocol adherence, data management, and quality control.\u003c/p\u003e \u003cp\u003eThe DSMB will differentiate reported safety events associated with trial interventions from those with other causes using clinical data. Reported safety data must indicate the likelihood of causality.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eInterim analyses {21b}\u003c/h3\u003e\n\u003cp\u003eInterim analyses will not be conducted. The protocol explicitly determines that no provisional analysis will be carried out. If any discontinuity occurs during the trial, the intention-to-treat principle will be applied to handle the missing data.\u003c/p\u003e \u003cdiv id=\"Sec31\" class=\"Section2\"\u003e \u003ch2\u003eAdverse event reporting and harms {22}\u003c/h2\u003e \u003cp\u003eThe study will adhere to a strict protocol for monitoring and managing adverse events and intervention-related harm. Detailed information, including the occurrence, severity, and relationship with the intervention, will be recorded on notification charts for all events. The research team will be trained to identify and document these events, and participants will be informed about how to report any discomfort during the study. If any treatment-related harm or complication arises, appropriate measures will be taken to ensure participant safety. All relevant information will be documented and reported to the DSMB, NHRC, and the hospital administration authorities, complying with applicable legal and ethical guidelines.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec32\" class=\"Section2\"\u003e \u003ch2\u003eFrequency and plans for auditing trial conduct {23}\u003c/h2\u003e \u003cp\u003eIn the present study, trial conduct will not be audited since it does not apply to the specific circumstances of the study.\u003c/p\u003e \u003cdiv id=\"Sec33\" class=\"Section3\"\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Considerations {24}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eApproval:\u003c/strong\u003e NHRC Nepal (Protocol ID: 98_2024).\u003cbr\u003e\u003cstrong\u003eInformed Consent:\u003c/strong\u003e Bilingual forms (English and Nepali) with witness signatures.\u003cbr\u003e\u003cstrong\u003eConfidentiality:\u003c/strong\u003e Encrypted databases; anonymized data sharing.\u003cbr\u003e\u003cstrong\u003eAdverse Events:\u003c/strong\u003e Reported to DSMB, Hospital administration, and NHRC within 24 hours.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for communicating important protocol amendments to relevant parties (e.g.\u003c/strong\u003e\u003cstrong\u003e,\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;trial participants,\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eethical committees) {25}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study protocol was approved by the Nepal Health Research Council and registered on Clinicaltrial.gov under the registration number NCT06367660. Any significant modifications to the protocol, such as changes in eligibility criteria, results, or analyses, were meticulously documented and submitted to the relevant centers and the NHRC ethics committee, adhering strictly to SPIRIT guidelines. All pertinent parties, including investigators, DSMB members, research ethics committees, and trial regulators, will be promptly informed of any changes, ensuring the utmost transparency and integrity of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDissemination Plan {31a}\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003ePublications\u003c/strong\u003e: peer-reviewed scientific journals, Open-access journals\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eData Sharing\u003c/strong\u003e: De-identified data available upon request post-publication.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eFunding {4}:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe researchers themselves will completely fund this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Details {5a}:\u003c/strong\u003e\u003c/p\u003e\n\u003col start=\"1\" type=\"1\"\u003e\n \u003cli\u003e\u003cstrong\u003eDr. Sujan Dhakal\u003c/strong\u003e: Principal Investigator, Department of Anaesthesiology, Om Sai Pathibhara Hospital.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eDr. Elija Gautam\u003c/strong\u003e: Co-Investigator, Department of Gynecology, Om Sai Pathibhara Hospital.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eDr. Muskaan Shrestha\u003c/strong\u003e: Co-Investigator, Department of Anaesthesiology, Om Sai Pathibhara Hospital.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eDr. Allen Suwal\u003c/strong\u003e: Co-Investigator, Department of Anaesthesiology, Patan Hospital.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eDr Salin Dhakal\u003c/strong\u003e:\u0026nbsp;Co-Investigator,\u0026nbsp;National Medical College.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eMrs. Sita Dhakal,\u0026nbsp;\u003c/strong\u003eClinical Pharmacist, Tribhuwan University\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eSponsor {5b}:\u003c/strong\u003e This study has no sponsors.\u003cbr\u003e\u003cstrong\u003eRole of Sponsor {5c}:\u003c/strong\u003e Not Applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eFassoulaki A, Staikou C, Melemeni A, Kottis G, Petropoulos G (2010) Anaesthesia preference, neuraxial vs general, and outcome after cesarean section. J Obstet Gynaecol 30(8):818\u0026ndash;821\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePedersen H, Santos AC, Steinberg ES, Schapiro HM, Harmon TW, Finster M (1989) Incidence of visceral pain during cesarean section: the effect of varying doses of spinal bupivacaine. Anesth Analg 69(1):46\u0026ndash;49\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlahuht S (1990) Visceral pain during cesarean section under spinal and epidural anesthesia with bupivacaine. Actu Anuesthesiol Scand 34:95\u0026ndash;98\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBogra J, Arora N, Srivastava P (2005) Synergistic effect of intrathecal fentanyl and bupivacaine in spinal anesthesia for cesarean section. BMC Anesthesiol 5(1):5\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSolanki SL, Goyal VK (2015) Neuraxial Dexmedetomidine: Wonder Drug or Simply Harmful. Anesth Pain Med. Apr 20 [cited 2023 Nov 19];5(2)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGautam B, Tabdar S, Shrestha U (2018) Comparison of Fentanyl and Dexmedetomidine as Intrathecal Adjuvants to Spinal Anaesthesia for Abdominal Hysterectomy. J Nepal Med Assoc 56(213):848\u0026ndash;855\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchulz KF, Altman DG, Moher D, Group CONSORT (2010) CONSORT 2010 Statement: updated guidelines for reporting parallel group randomized trials. BMC Med 8:18\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChan AW, Tetzlaff JM, Altman DG, Laupacis A, G\u0026oslash;tzsche PC, Krleža-Jerić K et al (2013) SPIRIT 2013 Statement: Defining Standard Protocol Items for Clinical Trials. Ann Intern Med. Feb 5\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBreen TW, Shapiro T, Glass B, Foster-Payne D, Oriol NE (1993) Epidural anesthesia for labor in an ambulatory patient. Anesth Analg 77(5):919\u0026ndash;924\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAli MA, Ismail S, Sohaib M, Aman A (2018) A double-blind randomized control trial to compare the effect of varying doses of intrathecal fentanyl on clinical efficacy and side effects in parturients undergoing cesarean section. J Anaesthesiol Clin Pharmacol [Internet] 34(2):221\u0026ndash;226\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNisbet AT, Mooney-Cotter F (2009) Comparison of selected sedation scales for reporting opioid-induced sedation assessment. Pain Manag Nurs 10(3):154\u0026ndash;164\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eApgar V (1953) A proposal for a new method of evaluation of the newborn infant. Curr Res Anesth Analg 32(4):260\u0026ndash;267\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEdwards RR (2005) Chapter 5 - Pain Assessment. In: Benzon HT, Raja SS, Molloy RE, Liu SS, Fishman SM, editors. Essentials of Pain Medicine and Regional Anesthesia (Second Edition). Philadelphia: Churchill Livingstone; pp. 29\u0026ndash;34\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBiswas BN, Rudra A, Bose BK, Nath S, Chakrabarty S, Bhattacharjee S (2002) Intrathecal fentanyl with hyperbaric bupivacaine improves analgesia during cesarean delivery and in the early postoperative period. Indian J Anaesth 46(6):469\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Visceral Pain, Dexmedetomidine , Fentanyl, Cesarean Section, Spinal Anaesthesia","lastPublishedDoi":"10.21203/rs.3.rs-6337531/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6337531/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eVisceral pain during cesarean delivery under spinal anesthesia continues to pose a significant clinical challenge. This study aims to compare the effectiveness of intrathecal hyperbaric bupivacaine combined with fentanyl (Group BF) versus dexmedetomidine (Group BD) in mitigating intraoperative visceral pain.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA prospective, randomized, double-blind trial will enroll 116 ASA PS II \u0026amp; III parturients undergoing elective cesarean delivery. Participants will receive either 10mg hyperbaric bupivacaine\u0026thinsp;+\u0026thinsp;10\u0026micro;g fentanyl (Group BF) or 10mg hyperbaric bupivacaine\u0026thinsp;+\u0026thinsp;5\u0026micro;g dexmedetomidine (Group BD). Primary outcome: the frequency of intraoperative visceral pain during various stages of cesarean section. Secondary outcomes include hemodynamic stability, shivering, neonatal APGAR scores, and side effects such as nausea, vomiting, and pruritus.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003eThis study's findings will offer crucial insights into the impact of dexmedetomidine as the preferred adjuvant for spinal anesthesia during cesarean delivery. Potentially replacing opioids, it could reduce the incidence of opioid-related complications such as respiratory depression and pruritus, thereby enhancing recovery. This aligns with global initiatives aimed at optimizing perioperative outcomes through the adoption of non-opioid analgesia.\u003c/p\u003e\u003ch2\u003eTrial Registration:\u003c/h2\u003e \u003cp\u003eRegistered at ClinicalTrials.gov (ID: \u003cb\u003eNCT06367660\u003c/b\u003e\u003c/p\u003e\u003ch2\u003eTrial Registration:\u003c/h2\u003e \u003cp\u003eClinicalTrials.gov ID: \u003cb\u003eNCT06367660\u003c/b\u003e\u003c/p\u003e","manuscriptTitle":"Comparison Between Hyperbaric Bupivacaine with Fentanyl vs. Hyperbaric Bupivacaine with Dexmedetomidine in Reducing Visceral Pain During Cesarean Delivery Under Spinal Anesthesia, A Prospective Randomized Double-Blind Comparative Study; Clinical Trial Protocol","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-01 07:50:42","doi":"10.21203/rs.3.rs-6337531/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a7495938-361a-4105-814c-f76d9c090d8a","owner":[],"postedDate":"April 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":46408732,"name":"Anesthesiology \u0026 Pain Medicine"}],"tags":[],"updatedAt":"2025-04-01T07:50:42+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-01 07:50:42","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6337531","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6337531","identity":"rs-6337531","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}