Effect of Opioid-Free vs Opioid-Based Anesthesia on Postoperative Pain and Emergence Agitation in Children Undergoing Cleft Surgery

NCT07557576 | Recruiting DMC

• 2 other identifiers: SF 05-PA-2-5/2025KBD 2024/0321-07
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

Orofacial clefts are among the most common congenital malformations, affecting approximately 1 in 700-1500 live births worldwide. They are associated not only with aesthetic concerns but also with functional impairments in feeding, speech, hearing, and dentition, and may be accompanied by other systemic malformations, often requiring multiple surgical procedures and long-term multidisciplinary care. Although cognitive development is preserved, the psychosocial impact on both children and families can be significant. Anesthesia in children with clefts presents specific challenges. Airway management is often more difficult due to anatomical variations, particularly in syndromic patients and those under 1 year of age. Immature organ systems affect drug metabolism, requiring careful dose adjustment. Preoperative anxiety and stress responses are common and may contribute to complications such as laryngospasm and bronchospasm. In the postoperative period, emergence agitation (EA) and emergence delirium (ED) are frequent, with reported incidence up to 80%. These conditions are characterized by restlessness, inconsolability, and disorientation, and may result in self-injury or disruption of surgical repairs. Differentiating agitation from pain is challenging in young children due to limited communication abilities. Validated observational tools such as CHIPPS, PAEDS, and Cravero scales are used for routine clinical assessment of pain and EA/ED, although their subjective nature may limit accuracy. Therefore, evaluation of the perioperative serum cortisol, alpha-amylase, and neuropeptide Y levels will be used. These biomarkers reflect activation of the physiological stress response and indirectly indicate the presence and intensity of pain. Pain management requires a multimodal approach. While opioids remain standard, their use is associated with adverse effects such as respiratory depression, nausea, vomiting, and delayed recovery. Consequently, opioid-free (OF) strategies using different anesthetics, including ketamine and dexmedetomidine have gained attention. This prospective randomized clinical trial will compare opioid-based anesthesia with an opioid-free protocol in children undergoing cleft surgery. A total of 90 patients age of 3 months-7 years will be randomized in a 1:1 ratio. The opioid group will receive fentanyl, while the OF group will receive ketamine and dexmedetomidine; both groups will receive propofol, vecuronium, sevoflurane, and nitrous oxide. Primary outcomes are postoperative pain (CHIPPS) and emergence agitation (PAEDS, Cravero). Pain will be assessed at 5 min, 15 min, 1, 2, 12, and 24 h after extubation, whereas emergence agitation will be evaluated at 5 min, 15 min, 1 h, and 2 h post-extubation. While these scales are routinely used in clinical practice, their subjective nature necessitates additional objective assessment. Therefore, secondary outcomes include evaluation of perioperative stress markers (cortisol, alpha-amylase, neuropeptide Y) and adverse events (nausea, vomiting, pruritus, constipation, respiratory depression, altered consciousness) within 24 h. Procedures will be standardized, with morning surgeries to minimize circadian variations of the biomarkers, performed by the same team. Blood samples will be collected before and after intravenous induction. Postoperative analgesia will include paracetamol and NSAIDs, with fentanyl as rescue therapy. The study hypothesis is that opioid-free anesthesia will provide comparable or superior analgesia, reduce the incidence of emergence agitation, attenuate the stress response, and decrease opioid-related adverse effects, thereby improving overall perioperative safety and recovery in pediatric patients undergoing cleft surgery. The particular value of this study lies in the subgroup of children who will undergo at least two surgical procedures within the observation period. In these patients, each child will be exposed to both anesthetic protocols in separate procedures-once according to the randomly assigned regimen and the second time according to the alternative protocol. In this way, each patient serves as their own control, allowing for a more precise comparison of outcomes with a substantial reduction in inter-individual variability. This approach largely eliminates individual differences such as age, body weight, baseline hemodynamic status, individual sensitivity to anesthetics and analgesics, as well as variability in stress response and pain perception. Such a design enhances the internal validity of the study and enables a more reliable interpretation of the results.

Conditions

Orofacial Cleft; Analgesia Assessment; Analgesia; Pediatric; Cleft Lip Palate; Agitation, Emergence

Keywords

Anesthesia, orofacial clefts, pain control, emergence agitation

Outcome Measures

Primary Outcomes (3)

• Postoperative pain intensity assessed by the Children and Infants Postoperative Pain Scale (CHIPPS)

  Postoperative pain will be assessed using the Children and Infants Postoperative Pain Scale (CHIPPS), a validated observational tool for pain assessment in infants and young children. Scores range from 0 to 10, with higher scores indicating more severe pain. Pain assessments will be performed at predefined time points: 5 minutes ,15 minutes, 30 minutes, 1 hour, 2 hours, 6 hours, 12 hours, and 24 hours after extubation. A CHIPPS score ≥4 is considered indicative of insufficient analgesia.

  Scores will be estimated 5 minutes ,15 minutes, 30 minutes, 1 hour, 2 hours, 6 hours, 12 hours, and 24 hours after extubation.

• Emergence agitation assessed by the Pediatric Anesthesia Emergence Delirium Scale (PAEDS)

  Emergence agitation will be assessed using the Pediatric Anesthesia Emergence Delirium Scale (PAEDS), a validated observational tool based on behavioral observation and consisting of five items: eye contact, purposeful actions, awareness of surroundings, restlessness, and inconsolability. Each item is scored from 0 to 4, with total scores ranging from 0 to 20. Higher scores indicate severe emergence delirium. Values ≥10 are commonly considered clinically significant.

  Scores will be estimated 5 minutes ,15 minutes, 30 minutes, 1 hour and 2 hours after extubation.

• Emergence agitation assessed by the Cravero Agitation Scale

  Emergence agitation will also be assessed using the Cravero scale, an observational scale used for evaluation of postoperative agitation in pediatric patients. Agitation will be recorded at extubation and during the early postoperative recovery period at predefined intervals of 5 minutes ,15 minutes, 30 minutes, 1 hour and 2 hours after extubation. Higher scores indicate more pronounced agitation.

  Scores will be estimated 5 minutes ,15 minutes, 30 minutes, 1 hour and 2 hours after extubation.

Secondary Outcomes (4)

• Perioperative stress response assessed by serum cortisol levels

  Before intravenous anesthesia induction and before emergence from anesthesia

• Perioperative stress response assessed by serum alpha-amylase levels

  Before intravenous anesthesia induction and before emergence from anesthesia

• Perioperative stress response assessed by serum neuropeptide Y levels

  Before intravenous anesthesia induction and before emergence from anesthesia

• Incidence of postoperative adverse events

  From anesthesia emergence until 24 hours postoperatively

Study Arms (2)

Opioid-Free Anesthesia

EXPERIMENTAL

Participants receive opioid-free anesthesia using a combination of ketamine and dexmedetomidine, along with standard anesthetic agents (propofol, sevoflurane, nitrous oxide, and muscle relaxant) during cleft lip and/or palate surgery.

Drug: Ketamine (1 mg/kg); Drug: Dexmedetomidine (1-0,8-0,6-0,4 mcg/kg/h); Drug: Propofol (IV) 3-4 mg/kg; Drug: Sevoflurane (Volatile Anesthetic); Drug: Nitrous Oxide/Oxygen; Drug: Vecuronium (0.1 mg/kg)

Opioid-Based Anesthesia

ACTIVE COMPARATOR

Participants receive opioid-based anesthesia using fentanyl in combination with standard anesthetic agents (propofol, sevoflurane, nitrous oxide, and muscle relaxant) during cleft lip and/or palate surgery.

Drug: Fentanyl 5 mcg/kg; Drug: Propofol (IV) 3-4 mg/kg; Drug: Sevoflurane (Volatile Anesthetic); Drug: Nitrous Oxide/Oxygen; Drug: Vecuronium (0.1 mg/kg)

Interventions

Ketamine (1 mg/kg) DRUG

Ketamine administered as part of an opioid-free anesthesia protocol during pediatric cleft surgery.

Opioid-Free Anesthesia

Dexmedetomidine (1-0,8-0,6-0,4 mcg/kg/h) DRUG

Dexmedetomidine administered as part of an opioid-free anesthesia protocol during pediatric cleft surgery.

Opioid-Free Anesthesia

Fentanyl 5 mcg/kg DRUG

Fentanyl administered as part of an opioid-based anesthesia protocol during pediatric cleft surgery.

Opioid-Based Anesthesia

Propofol (IV) 3-4 mg/kg DRUG

Propofol used for induction and/or maintenance of general anesthesia.

Opioid-Based Anesthesia; Opioid-Free Anesthesia

Sevoflurane (Volatile Anesthetic) DRUG

Sevoflurane used for maintenance of general anesthesia

Opioid-Based Anesthesia; Opioid-Free Anesthesia

Nitrous Oxide/Oxygen DRUG

Nitrous oxide used as an adjunct to general anesthesia.

Opioid-Based Anesthesia; Opioid-Free Anesthesia

Vecuronium (0.1 mg/kg) DRUG

Neuromuscular blocking agent used to facilitate tracheal intubation and surgical conditions.

Opioid-Based Anesthesia; Opioid-Free Anesthesia

Eligibility Criteria

• Age: 3 Months - 7 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• ASA physical status I-II
• Body weight \>5 kg
• Age ≥3 months for cleft lip repair and ≥9 months for cleft palate repair
• Hemoglobin \>100 g/L

You may not qualify if:

• ASA physical status III-IV
• Body weight \<5 kg
• Age \<3 months for cleft lip repair or \<9 months for cleft palate repair
• Hemoglobin \<100 g/L
• Acute illness
• Respiratory infection or vaccination within 2 weeks prior to surgery
• Requirement for perioperative intensive care

Sponsors & Collaborators

• Iva Smiljanić: lead
• University of Zagreb: collaborator
• University Hospital Dubrava: collaborator

Study Sites (1)

University Hospital Dubrava

Zagreb, 10000, Croatia

RECRUITING

Related Publications (24)

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  BACKGROUND

• Disma N, Virag K, Riva T, Kaufmann J, Engelhardt T, Habre W; NECTARINE Group of the European Society of Anaesthesiology Clinical Trial Network; AUSTRIA (Maria Vittinghoff); BELGIUM (Francis Veyckemans); CROATIA (Sandra Kralik); CZECH REPUBLIC (Jiri Zurek); DENMARK (Tom Hansen); ESTONIA (Reet Kikas); FINLAND (Tuula Manner); FRANCE (Christophe Dadure, Anne Lafargue); GERMANY (Karin Becke, Claudia Hoehne); GREECE (Anna Malisiova); HUNGARY (Andrea Szekely); IRELAND (Brendan O'Hare); ITALY (Nicola Disma); LATVIA (Zane Straume); LITHUANIA (Laura Lukosiene); LUXEMBOURG (Bernd Schmitz); MALTA (Francis Borg); NETHERLANDS (Jurgen de Graaff); NORWAY (Wenche B Boerke); POLAND (Marzena Zielinska); PORTUGAL (Maria Domingas Patuleia); ROMANIA (Radu Tabacaru); SERBIA (Dusica Simic); SLOVAKIA (Miloslav Hanula); SLOVENIA (Jelena Berger); SPAIN (Ignacio Galvez Escalera); SWEDEN (Albert Castellheim); SWITZERLAND (Walid Habre); TURKEY (Dilek Ozcengiz - Zehra Hatipoglu); UKRAINE (Dmytro Dmytriiev); UNITED KINGDOM (Thomas Engelhardt, Suellen Walker); Management Team. Difficult tracheal intubation in neonates and infants. NEonate and Children audiT of Anaesthesia pRactice IN Europe (NECTARINE): a prospective European multicentre observational study. Br J Anaesth. 2021 Jun;126(6):1173-1181. doi: 10.1016/j.bja.2021.02.021. Epub 2021 Apr 1. Erratum In: Br J Anaesth. 2021 Aug;127(2):326. doi: 10.1016/j.bja.2021.05.015.

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MeSH Terms

Conditions

Emergence Delirium; Agnosia

Interventions

Ketamine; Dexmedetomidine; Fentanyl; Propofol; Sevoflurane; Nitrous Oxide; Oxygen; Vecuronium Bromide

Condition Hierarchy (Ancestors)

Delirium; Confusion; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Neurocognitive Disorders; Mental Disorders; Perceptual Disorders

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperidines; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Methyl Ethers; Ethers; Hydrocarbons, Fluorinated; Hydrocarbons, Halogenated; Nitrogen Oxides; Gases; Inorganic Chemicals; Nitrogen Compounds; Oxides; Oxygen Compounds; Chalcogens; Elements; Androstanols; Androstanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Iva Smiljanic, MD, MSc

  University Hospital Dubrava, Zagreb

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Iva SMILJANIĆ, MD, MSc

CONTACT

+385915406518; iva.smiljanic@yahoo.com

Predrag Knežević, MD, Professor

CONTACT

+385 91 539 5202; pknezev@kbd.hr

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD, MSc

Study Record Dates

• First Submitted: April 22, 2026
• First Posted: April 29, 2026
• Study Start: May 16, 2024
• Primary Completion (Estimated): August 30, 2026
• Study Completion (Estimated): September 30, 2026
• Last Updated: April 29, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

CR (1)