Use of Nitrous Oxide During Office Hysteroscopy

Office hysteroscopy offers a convenient alternative to operating room-based procedures, yet many patients experience pain and anxiety significant enough to interfere with procedural completion. Nitrous oxide is a fast-acting inhaled agent with both analgesic and anxiolytic properties, widely used in outpatient settings across various medical specialties.

This study will investigate the role of nitrous oxide in improving patient tolerability and comfort during office hysteroscopy. Participants will undergo a standardized procedural protocol with either nitrous oxide or ambient air administered via a demand-valve mask system. Comprehensive data on patient responses during the procedure will be collected and analyzed.

The study will also examine variability in patient responses across different subgroups and procedural types. All procedures will adhere to ethical standards, and patient confidentiality will be maintained throughout.

• Inhalation of Nitrous Oxide (N₂O) during Office Operative Hysteroscopy (Procedure): Inhaled nitrous oxide
• inhalation of ambient air during office hysteroscopy (Procedure): inhalation of ambient air

Primary outcomes

• Comparison of Pain During Office Hysteroscopy Between Inhaled Nitrous Oxide (Treatment Group) and Ambient Air (Placebo Group) [Periprocedural (start to end of the hysteroscopy procedure)]: The difference in pain between the two groups will be assessed using the Visual Analog Scale (VAS), ranging from 0 to 10, where 0 indicates no pain and 10 represents the worst imaginable pain. Pain scores will be collected at three time points throughout the procedure : uterine entry, during the procedure, and immediately after its completion.

Secondary outcomes

• Incidence of side effects related to inhaled substance [Periprocedural (start to end of the hysteroscopy procedure)]: The number and type of side effects reported during the procedure following administration of the inhaled agent (nitrous oxide or ambient air), including nausea, dizziness and presyncope. Adverse events will be recorded and categorized.
• Procedure completion [Periprocedural]: Success is defined as the completion of the planned hysteroscopy procedure without the need for an additional intervention - either a repeat hysteroscopy or transfer to the operating room. The outcome will be measured as the percentage of participants for whom the procedure was successfully completed as planned.
• Patient satisfaction with the procedure [Immediately post-procedure]: Assessed after the procedure by a binary question: "Would you be willing to undergo the same procedure again with the same inhaled agent?" (Yes/No)

Other outcomes

• Subgroup differences in pain reduction associated with nitrous oxide during office hysteroscopy [Periprocedural (start to end of the hysteroscopy procedure)]: To evaluate whether specific patient characteristics are associated with greater pain reduction from nitrous oxide use during office hysteroscopy. Subgroups include nulliparity, prior surgeries, prolonged procedure duration, type of procedure, and type of hysteroscopic device. Pain will be measured using visual analogue scale (VAS) ranging from 0 to 10, where 0 indicates no pain and 10 represents the worst imaginable pain. Assessments will be performed at three points: uterine entry, during the procedure and immediately after.
• Pre-procedural anxiety level assessed using modified State-Trait Anxiety Inventory (STAI) [Immediately before the procedure]: Anxiety levels will be assessed prior to the start of the hysteroscopy using a modified version of the State-Trait Anxiety Inventory (STAI) questionnaire. This tool evaluates both: State anxiety (temporary emotional state) Trait anxiety (long-term anxiety disposition) The state subscale includes 5 items, and the trait subscale includes 4 items. Each item is scored on a 5-point Likert scale (1 to 5), where: 1 = lowest anxiety 5 = highest anxiety Total scores are calculated separately for state and trait components. Higher scores indicate greater anxiety.

Sex: Female, ages: 18 Years to any

Inclusion Criteria:

Women aged ≥18 years Scheduled to undergo operative office hysteroscopy for clinical indications

Exclusion Criteria:

Any contraindications to N₂O, including:

Pneumothorax Significant chronic obstructive pulmonary disease (COPD) Upper airway obstruction Bowel obstruction Middle ear pathology (e.g., recent ear surgery or active ear infection) Severe recent intraocular gas injection Severe vitamin B12 deficiency Known hypersensitivity to N₂O

Women who will decline randomization or unable to provide informed consent.

• Results publication: Likis FE, Andrews JC, Collins MR, Lewis RM, Seroogy JJ, Starr SA, Walden RR, McPheeters ML. Nitrous oxide for the management of labor pain: a systematic review. Anesth Analg. 2014 Jan;118(1):153-67. doi: 10.1213/ANE.0b013e3182a7f73c. PMID 24356165
• Results publication: Buhre W, Disma N, Hendrickx J, DeHert S, Hollmann MW, Huhn R, Jakobsson J, Nagele P, Peyton P, Vutskits L. European Society of Anaesthesiology Task Force on Nitrous Oxide: a narrative review of its role in clinical practice. Br J Anaesth. 2019 May;122(5):587-604. doi: 10.1016/j.bja.2019.01.023. Epub 2019 Feb 22. PMID 30916011
• Results publication: Razdolsky S, Yaniv-Tamir R, Raz M, Kolp-Asis S, Katz T, Elbaz L, Tzur T. Nitrous Oxide for Pain Management in Office Hysteroscopy: A Randomized Placebo-Controlled Trial. Obstet Gynecol. 2026 Jul 1;148(1):71-79. doi: 10.1097/AOG.0000000000006282. Epub 2026 Apr 9. PMID 41955620

• Tamar Tzur, MD, Principal investigator, Mayanei Hayeshua Medical Center