Timing of Midazolam in Children Undergoing Adenotonsillectomy: Effects on Stress, Cortisol, and Recovery (TIMING-MIDAZOL)

OPTİMİZATİON OF MİDAZOLAM ADMİNİSTRATİON TİMİNG İN PEDİATRİC ADENOTONSİLLECTOMY: EFFECTS ON CORTİSOL RESPONSE, BEHAVİORAL STRESS, AND RECOVERY QUALİTY

This study is a prospective, randomized, controlled clinical trial designed to evaluate the optimal timing of midazolam administration in children undergoing adenotonsillectomy. The study will be conducted at the Departments of Otorhinolaryngology and Anesthesiology of Erzurum City Hospital.

Midazolam is commonly used in pediatric patients to reduce anxiety and improve perioperative comfort. However, the optimal timing of its administration (before surgery or during anesthesia induction) remains unclear. This study aims to compare the effects of preoperative oral midazolam and intraoperative intravenous midazolam on stress response, behavioral outcomes, and recovery quality.

Participants will be randomly assigned to one of two groups. In Group A, children will receive oral midazolam (0.5 mg/kg) 30 minutes before surgery. In Group B, children will receive intravenous midazolam (0.05-0.1 mg/kg) during anesthesia induction.

The primary outcome of the study is the change in serum cortisol levels, which reflects the physiological stress response. Blood samples will be collected twice: once 10 minutes after anesthesia induction and once 15 minutes after surgery in the post-anesthesia care unit.

In addition to cortisol levels, the study will assess preoperative anxiety using an observational anxiety scale, postoperative pain using a behavioral pain scoring system, and parental satisfaction using a standardized questionnaire. These measures aim to provide a comprehensive evaluation of the child's perioperative experience.

The findings of this study may help determine the most effective timing of midazolam administration to reduce stress, improve recovery, and enhance overall patient and family satisfaction in pediatric surgical care.

Study Overview

• Status: Not yet recruiting
• Conditions: Postoperative Pain; Preoperative Anxiety; Adenotonsillectomy; Surgical Stress Response
• Intervention / Treatment: Drug: Midazolam (Oral); Drug: Midazolam (Intravenous)

Detailed Description

This study is a prospective, randomized, controlled clinical trial designed to evaluate the effects of the timing of midazolam administration on physiological stress response, behavioral anxiety, postoperative pain, recovery quality, and parental satisfaction in pediatric patients undergoing elective adenotonsillectomy.

The primary objective is to compare the effect of midazolam administration timing on physiological stress response, assessed by serum cortisol levels. Secondary objectives include evaluating preoperative anxiety levels, postoperative pain scores, recovery quality, and parental satisfaction between groups receiving midazolam at different time points.

The study will include children aged 3-10 years, classified as ASA physical status I-II, scheduled for elective adenoidectomy, tonsillectomy, or adenotonsillectomy.

Eligible patients will be identified during preoperative anesthesia evaluation. Parents or legal guardians will be informed about the study, and written informed consent will be obtained prior to enrollment.

Participants will be randomly assigned to one of two groups using a computer-generated randomization sequence with sealed envelope allocation:

Group A (Preoperative Midazolam Group): Patients will receive oral midazolam (0.5 mg/kg) 30 minutes before surgery, administered with a small volume of apple juice under clinical supervision.

Group B (Intraoperative Midazolam Group): Patients will receive intravenous midazolam (0.05-0.1 mg/kg) during anesthesia induction.

Anesthesia Protocol

To ensure comparability between groups, all patients will undergo a standardized anesthesia protocol. Vascular access will be established after inhalational induction using sevoflurane in oxygen, minimizing stress associated with intravenous cannulation.

Lidocaine (0.5-1 mg/kg) will be administered prior to propofol injection to reduce injection pain Propofol (2-3 mg/kg) will be used for induction Rocuronium (0.6 mg/kg) will be administered for neuromuscular blockade Fentanyl (1-2 µg/kg) will be used for analgesia

Anesthesia maintenance will be achieved with sevoflurane (2-3%) in a mixture of oxygen and air, targeting an age-adjusted MAC ≥1.3. Mechanical ventilation will be standardized with volume-controlled settings appropriate for age.

Intraoperative fluid management will be based on body weight using standard pediatric maintenance formulas and isotonic saline solution.

Neuromuscular blockade will be reversed with sugammadex (2 mg/kg) Extubation will be performed based on clinical recovery criteria, including adequate spontaneous respiration and responsiveness

All patients will receive intravenous paracetamol (10-15 mg/kg) for postoperative analgesia and ondansetron (0.1 mg/kg) for prophylaxis of nausea and vomiting.

Serum cortisol levels will be measured at two time points:

Intraoperative period (10 minutes after anesthesia induction) Early postoperative period (15 minutes after admission to the post-anesthesia care unit)

Cortisol levels will be analyzed using an electrochemiluminescence immunoassay method.

Preoperative anxiety will be assessed using a modified observational anxiety scale. Postoperative pain will be evaluated using a validated behavioral pain scoring system, and recovery status will be assessed using standard recovery criteria.

Parental satisfaction will be evaluated within the first 30 minutes after surgery using a structured questionnaire assessing overall perioperative experience.

All perioperative data will be recorded by the anesthesia team and post-anesthesia care unit staff. Collected data will be analyzed statistically to compare outcomes between the two groups.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Mehmet Sercan Orbak, MD; Phone Number: + 90 (506) 288 35 34; Email: sercanorbak@gmail.com
• Study Contact Backup: Name: Ahmet Ergün, MD; Email: draergn@gmail.com

Study Locations

• Turkey (Türkiye)
  • Yakutiye
    • Erzurum, Yakutiye, Turkey (Türkiye), 25240
      • Erzurum City Hospital
      • Sub-Investigator: Ahmet Ergün, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Children aged 3-10 years,
• Scheduled for elective adenoidectomy, tonsillectomy, or adenotonsillectomy,
• American Society of Anesthesiologists (ASA) physical status I-II,
• Written informed consent obtained from parents or legal guardians

Exclusion Criteria:

• Children younger than 3 years or older than 10 years,
• American Society of Anesthesiologists (ASA) physical status greater than II,
• Known allergy to apple or apple-derived products,
• Known allergy or hypersensitivity to benzodiazepines,
• Presence of developmental delay,
• History of neuropsychiatric disorders,
• Current or recent use of corticosteroids,
• Expected or actual surgical duration longer than 90 minutes,
• Refusal of participation by parents or legal guardians

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Preoperative Oral Midazolam; Participants in this group will receive oral midazolam at a dose of 0.5 mg/kg, administered 30 minutes before surgery. The medication will be mixed with a small volume of apple juice to facilitate administration and improve tolerance.	Drug: Midazolam (Oral); Oral midazolam will be administered at a dose of 0.5 mg/kg, 30 minutes before surgery. The medication will be mixed with a small volume of apple juice to facilitate administration.
Experimental: Intraoperative Intravenous Midazolam; Participants in this group will receive intravenous midazolam at a dose of 0.05-0.1 mg/kg during anesthesia induction.	Drug: Midazolam (Intravenous); Intravenous midazolam will be administered at a dose of 0.05-0.1 mg/kg during anesthesia induction.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Serum Cortisol Levels	Serum cortisol levels will be measured to assess physiological stress response.	At 10 minutes after anesthesia induction and at 15 minutes postoperatively in the post-anesthesia care unit (PACU)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Preoperative Anxiety Level (mYPAS Score)	Preoperative anxiety will be assessed using the modified Yale Preoperative Anxiety Scale (mYPAS), an observational tool evaluating behavioral anxiety in children across multiple domains. Scores will be normalized to a 0-100 scale, with higher scores indicating greater anxiety.	During the preoperative period before anesthesia induction
Postoperative Pain Score (FLACC Score)	Postoperative pain will be evaluated using the FLACC (Face, Legs, Activity, Cry, Consolability) scale, a validated behavioral pain assessment tool for pediatric patients. Each category is scored from 0 to 2, with a total score ranging from 0 to 10, where higher scores indicate more severe pain.	At 15 minutes postoperatively in the post-anesthesia care unit (PACU)
Recovery Status (Modified Aldrete Score)	Recovery status will be assessed using the Modified Aldrete Score, which evaluates activity, respiration, circulation, consciousness, and oxygen saturation. Higher scores indicate better recovery and readiness for discharge from the PACU.	Within the first 30 minutes postoperatively in the PACU
Parental Satisfaction (PAPS Survey)	Parental satisfaction will be evaluated using the Pediatric Anesthesia Parent Satisfaction (PAPS) survey, a structured questionnaire assessing satisfaction with perioperative care, including communication, pain management, and overall experience. Scores range from 5 to 25, with higher scores indicating greater satisfaction.	Within 30 minutes after the child becomes clinically stable in the postoperative period

Collaborators and Investigators

• Sponsor: Erzurum City Hospital
• Investigators: Principal Investigator: Mehmet Sercan Orbak, MD, Erzurum City Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): September 1, 2027

Study Registration Dates

• First Submitted: May 28, 2026
• First Submitted That Met QC Criteria: May 28, 2026
• First Posted (Actual): June 3, 2026

Study Record Updates

• Last Update Posted (Actual): June 3, 2026
• Last Update Submitted That Met QC Criteria: May 28, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Postoperative Pain; Midazolam; Adenotonsillectomy; Preoperative Anxiety; Pediatric Anesthesia; Recovery Quality; Premedication Timing; Cortisol Response
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Pain, Postoperative; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Benzazepines; Benzodiazepines; Midazolam
• Other Study ID Numbers: ECH-AR-MSO-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data (IPD) will not be publicly available due to institutional and ethical restrictions.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No