An Observational Study Measuring in a Non-invasive Approach the Nociception Level Index and Its Association With Pain and Anxieiy Perception Evaluated by Questionnaires, in Awake Women During Elective Cesarean Delivery Under Spinal Anesthesiaanxiety

Official title

A Prospective Observational Study Evaluating the Nociception Level Index and Its Association With Pain Perception, Anxiety, Uterine Activity, and Autonomic Responses During Elective Cesarean Delivery Under Spinal Anesthesia

Overview

The Nociception Level (NOL) Index is a multiparametric, non-invasive monitor that objectively assesses nociception by integrating several autonomic physiological signals. Although the NOL Index has been extensively validated during general anesthesia, its performance in awake patients undergoing regional anesthesia remains poorly understood. During cesarean delivery (CD) under spinal anesthesia, autonomic responses may be influenced not only by nociceptive stimulation but also by anxiety, uterine contractions, hemodynamic changes, uterotonic medications, and other non-nociceptive factors. Understanding the relative contribution of these factors is essential before the NOL Index can be reliably applied in awake surgical patients. This prospective observational study aims to characterize the behavior of the NOL Index throughout elective CD performed under spinal anesthesia and to evaluate its relationship with subjective pain intensity, anxiety, uterine activity, perioperative autonomic responses, and routine physiological variables. Approximately 100 women undergoing elective CD under spinal anesthesia will be enrolled at Carmel Medical Center. Continuous NOL monitoring using the PMD-200 system will be performed from before spinal anesthesia until the early postoperative period. Subjective pain (Visual Analog Scale), anxiety (Visual Analog Scale for Anxiety), uterine activity, hemodynamic variables, perioperative medications, and predefined surgical events will be prospectively recorded and synchronized with continuous NOL measurements. Potential confounding factors, including vasopressor administration, uterotonic drugs, nausea, shivering, patient movement, and supplemental analgesia, will also be documented. This study will provide one of the first comprehensive evaluations of continuous NOL monitoring during CD under spinal anesthesia. The results are expected to improve the understanding of objective nociception monitoring in awake patients, clarify the influence of non-nociceptive autonomic activation on the NOL Index, and help define the clinical role and limitations of NOL monitoring during regional anesthesia, and may contribute to the future development of objective pain assessment strategies in obstetric anesthesia and other clinical settings involving awake patients.

Detailed description

Elective cesarean delivery performed under spinal anesthesia provides a unique and highly reproducible clinical model for investigating objective nociception monitoring in awake patients. Unlike patients undergoing general anesthesia, women receiving spinal anesthesia remain conscious throughout surgery, allowing simultaneous assessment of subjective pain perception, anxiety, autonomic physiological responses, and objective nociception monitoring under standardized surgical conditions.

The Nociception Level (NOL) Index is a multiparametric physiological monitoring system that integrates several autonomic variables, including heart rate variability, skin conductance, photoplethysmographic waveform characteristics, and additional physiological parameters using a proprietary machine-learning algorithm. The NOL Index has been extensively validated during general anesthesia and has demonstrated good correlation with surgical stimulation and analgesic adequacy. However, its performance during regional anesthesia, particularly in awake obstetric patients, remains insufficiently characterized.

During cesarean delivery under spinal anesthesia, multiple physiological and psychological factors may influence autonomic nervous system activity independently of nociceptive stimulation. These include preoperative and intraoperative anxiety, emotional stress, patient communication, uterine manipulation, uterine contractions following administration of uterotonic agents, hemodynamic changes associated with neuraxial anesthesia, vasopressor administration, nausea, shivering, and patient movement. Consequently, interpretation of the NOL Index in this setting requires further clinical investigation.

This prospective, single-center observational study will enroll approximately 100 women undergoing elective cesarean delivery under spinal anesthesia at Carmel Medical Center, Haifa, Israel. Standard perioperative management will not be modified for study purposes. Continuous NOL monitoring will begin before initiation of spinal anesthesia and continue throughout surgery and the early postoperative recovery period.

Simultaneously, subjective pain intensity will be assessed using the Visual Analog Scale (VAS), anxiety will be evaluated using the Visual Analog Scale for Anxiety (VAS-A), and routine physiological variables including heart rate, blood pressure, mean arterial pressure, and oxygen saturation will be recorded. Surgical milestones, administration of intrathecal medications, uterotonic agents, vasopressors, rescue analgesia, and other clinically relevant medications will be prospectively documented and synchronized with continuous NOL recordings.

The primary objective of the study is to characterize the intraoperative behavior of the NOL Index and determine the percentage of monitoring time during which NOL values remain outside the predefined target range of 10-25. Secondary objectives include evaluation of the relationships between the NOL Index and subjective pain intensity, anxiety, uterine activity, surgical phases, rescue analgesia requirements, and perioperative autonomic responses.

Potential confounding factors known to influence autonomic nervous system activity-including maternal anxiety, hypotension, vasopressor administration, uterotonic medications, nausea, shivering, supplemental analgesia, sedation, and patient movement-will be prospectively documented and considered during statistical analyses. Continuous NOL data will be automatically recorded according to the device sampling frequency and exported for offline analysis following predefined quality-control procedures.

The findings of this study are expected to improve understanding of objective nociception monitoring in awake patients undergoing regional anesthesia and to define the clinical utility and limitations of the NOL Index in obstetric anesthesia. The results may contribute to optimizing intraoperative pain assessment, improving interpretation of physiological monitoring during regional anesthesia, and guiding future research on objective nociception monitoring in conscious surgical patients.

Primary outcome measures

• Percentage of intraoperative monitoring time during which the Nociception Level Index remains outside the predefined target range (10-25) during elective cesarean delivery under spinal anesthesia [Time frame: Intraoperative period up to 3 hours]

Secondary outcome measures (6)

• Duration of Nociception Level Index (>25) [Time frame: Intraoperative period and approximately 1 hour postoperatively, up to 5 hours]
• Correlation between Nociception Level Index and Visual Analog Scale [Time frame: : Intraoperative period and approximately 1 hour postoperatively up to 5 hours]
• Correlation between Nociception Level Index and Visual Analogue Scale- anxiety [Time frame: Intraoperative period and approximately 1 hour postoperatively up to 5 hours]
• Surgical phase analysis [Time frame: Intraoperative period and approximately 1 hour postoperatively]
• Association of Nociception Level Index with uterine activity [Time frame: Intraoperative period and approximately 1 hour postoperatively up to 5 hours]
• Rescue analgesia requirements [Time frame: Intraoperative period and approximately 1 hour postoperatively up to 5 hours]

Eligibility criteria

Inclusion criteria

• Women ≥18 years
• Scheduled to elective cesarean delivery under spinal anesthesia
• ASA I-III
• Able to provide informed consent

Exclusion criteria

• Women Age <18 years
• BMI >35 kg/m²
• Major psychiatric illness
• Chronic psychotropic/anxiolytic therapy
• Substance abuse
• Inability to communicate
• Contraindication to spinal anesthesia
• Any pre condition interfering with study participation

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Israel · 1 center

• Carmel medical center — Haifa

Publications

• Okur, N., Yıldırım, D., & Aydın, E. (2020). Evaluation of preoperative anxiety in pregnant women before elective cesarean section: Comparison of VAS and STAI scales. Journal of Obstetrics and Gynaecology Research, 46(1), 5-10. https://doi.org/10.1111/jog.14126
• Abend, R., Dan, O., Maoz, K., Raz, S., & Bar-Haim, Y. (2014). Reliability, validity and sensitivity of a computerized visual analog scale for anxiety. Cognition and Emotion, 28(8), 1434-1441. https://doi.org/10.1080/02699931.2014.881326
• Andersen T, Sandnes A, Hilland M, Halvorsen T, Fondenes O, Heimdal JH, Tysnes OB, Roksund OD. Laryngeal response patterns to mechanical insufflation-exsufflation in healthy subjects. Am J Phys Med Rehabil. 2013 Oct;92(10):920-9. doi: 10.1097/PHM.0b013e3182a4708f. PMID 24051994
• Witteveen, A. B. et al. (2019). "Postpartum PTSD and its risk factors following emergency cesarean delivery." Arch Womens Ment Health, 22, 229-237. https://doi.org/10.1007/s00737-018-0918-5
• Fentie Y, Yetneberk T, Gelaw M. Preoperative anxiety and its associated factors among women undergoing elective caesarean delivery: a cross-sectional study. BMC Pregnancy Childbirth. 2022 Aug 17;22(1):648. doi: 10.1186/s12884-022-04979-3. PMID 35978308
• 8. Sessler, D. I., & Devereaux, P. J. (2021).*Perioperative anesthetic management and long-term outcomes*. Anesthesiology, 134(5), 698-713. https://doi.org/10.1097/ALN.0000000000003707
• 7. Edry, R., Recea, V., Dikust, Y., Sessler, D. I., & Ezri, T. (2016). *Preliminary intraoperative evaluation of a novel nociception monitor in patients undergoing abdominal surgery*. British Journal of Anaesthesia, 117(4), 477-483. https://doi.org/10.1093/bja/aew223
• Meijer, F., Honing, M., Bom, A., Kalmar, A., Martini, C., & Struys, M. (2020). *Nociception-guided versus standard opioid administration during general anaesthesia: A meta-analysis of randomized controlled trials*. British Journal of Anaesthesia, 124(4), 474-483. https://doi.org/10.1016/j.bja.2019.12.034

Identifiers

NCT: NCT07726316 · 0005-26-CMC

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗