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.

Introduction to the problem of orofacial clefts

According to studies, worldwide one child with an orofacial cleft (lip, palate or both) is born per 700 to 1500 live births annually, making clefts the most common congenital malformations. The causes are not fully defined and are considered to result from multifactorial influences including heredity, mutations, and teratogens, as well as various chromosomal aberrations. To date, at least 275 such syndromes have been described, most commonly Treacher Collins, Goldenhar, DiGeorge, and Van der Woude syndromes.

Clefts do not imply only a cosmetic defect, but also disturbances in speech, hearing, dentition, feeding, and sometimes additional malformations. Cognitive abilities are not impaired, but psychosocial implications significantly affect quality of life, particularly because cleft treatment is multidisciplinary, long-term, and costly.

The diagnostic and treatment process involves gynecologists, geneticists, and maxillofacial surgeons already prenatally, and after birth neonatologists, anesthesiologists, and numerous other specialists. Anesthesia in children with orofacial clefts requires additional caution due to anatomical and physiological specificities. Due to organ immaturity, pharmacodynamics and pharmacokinetics differ, drugs are metabolized differently, and doses must be individually adjusted according to age and body weight.

Airway assessment is often difficult due to lack of cooperation, but a higher incidence of difficult intubation must be expected in cleft patients, especially in syndromic children. Risk factors include age under 1 year, low body weight, high ASA and Mallampati scores, and Pierre Robin sequence. Syndromic clefts are associated with cardiomyopathies in 5-80% of cases, significantly increasing anesthetic risk.

Children's reactions are often accompanied by stress and crying, which increases the risk of laryngospasm and bronchospasm. Preparation of the child, parental presence, and effective premedication are key factors for safety and reduction of complications in pediatric patients.

Following two issues represent two major challenges in pediatric anesthesia, and the present study specifically addresses both of them.

1. Postoperative agitation and emergence delirium

   After emergence from anesthesia, children may develop emergence agitation (EA) or emergence delirium (ED), characterized by restlessness, crying, and disorientation. ED is more intense and may include hallucinations, while EA can also result in unintentional self-injury. Long-term consequences may include behavioral disturbances such as nightmares, enuresis, and separation anxiety.

   The incidence of EA/ED in children may reach up to 80%, particularly in preschool children, boys, and in maxillofacial and ENT procedures. Risk factors include preoperative anxiety and the use of inhalational anesthetics.

   Agitation may overlap with the presence of pain and can serve as its indirect indicator, just as pain may trigger EA. Differentiation between these two entities is often difficult due to lack of clear feedback. If the cause is unclear, the child should be treated as if pain is the underlying cause of agitation .

   For the diagnosis of EA/ED, there are several clinical assessment scales for pediatric (PAEDS, Cravero, Watcha scale..). Unfortunatelly, there is no specific therapy for EA/ED. In clinical practice, treatment mainly includes analgesia with nonsteroidal analgesics and non-pharmacological measures such as preparation, communication, and distraction, while pharmacological interventions are mainly applied in intensive care units.

   Since there is no etiological therapy, emphasis is placed on prevention. The goal is early identification of high-risk children and planning total intravenous anesthesia with preference for propofol over inhalational anesthesia.

   Recent studies have shown ketamine and dexmedetomidine to be effective. Over the past years, various doses, combinations, and timing of administration have been investigated. Results are contradictory: some studies confirm a reduction in EA, while others show no clear advantage over other anesthetics.

2. Pediatric postoperative pain and pain management

Pain management in children is complex due to communication limitations, and lack of feedback complicates both assessment and treatment. In younger children, observational scales such as FLACC and CHIPPS are used, while in older children self-report scales (Wong-Baker, VAS) can be applied. FLACC includes five categories, while CHIPPS includes additional motor parameters. Both scales are proven to be more reliable than physiological indicators for pain assessment.

As with EA/ED, both non-pharmacological and pharmacological methods are used. Non-pharmacological methods are recommended in both editions of ESPA guidelines and include distraction, music, and parental education.

Pharmacological treatment should follow a multimodal approach: paracetamol and nonsteroidal anti-inflammatory drugs are the basis for mild to moderate pain, while opioids are reserved for severe pain. Although effective, opioids are associated with risks such as respiratory depression, nausea, and dependence, and are therefore increasingly used postoperatively only as rescue therapy. Studies on their use in cleft surgery are inconclusive, with emphasis on regional blocks (palatal, infraorbital) to reduce opioid requirements.

Adequate intraoperative analgesia plays a key role in postoperative pain, as the choice and quality of anesthesia directly influence pain outcomes, with opioid-based protocols traditionally representing the cornerstone of anesthetic management in this context.

With the development of regional techniques, opioid-free protocols have emerged, combining different drugs to reduce side effects and increase safety. Dexmedetomidine, ketamine, magnesium sulfate, and NSAIDs form the backbone of this approach.

Ketamine is a well-established anesthetic with analgesic and sedative effects, maintaining cardiovascular stability and respiratory function with bronchodilatory effects. Meta-analyses confirm that rational use of NSAIDs, paracetamol, and ketamine enables effective analgesia with minimal side effects, making opioid-free pharmacotherapy particularly valuable in pediatric anesthesia. Recent studies suggest that ketamine and dexmedetomidine reduce opioid requirements.

Dexmedetomidine is an α2-agonist with pronounced sedative and analgesic effects. It provides hemodynamic stability and a favorable safety profile (no respiratory depression, reduced PONV) and shows preventive effects on EA/ED.

Studies in children undergoing cleft palate surgery have confirmed hemodynamic stability and reduced incidence of EA. PROSPECT guidelines recommend its use as an adjunct to regional blocks or intravenously, while opioids remain reserved for rescue therapy. Although not always superior, it is recommended as a valuable agent in the prevention of EA/ED, especially within a multimodal approach.

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Objectives Primary Outcomes

1. Level of postoperative pain intensity will be assessed by the Children and Infants Postoperative Pain Scale (CHIPPS). Scores range from 0 to 10, with higher scores indicating more severe pain. Assessments will be performed at 5 minutes, 15 minutes, 1 hour, 2 hours, 12 hours, and 24 hours after extubation. A score ≥4 indicates clinically significant pain.

2. Existence of emergence agitation will be assessed by the PAEDS scale and Cravero scale at 5 minutes, 15 minutes, 1 hour, and 2 hours after extubation. Values ≥12 for PAEDS and ≥4 for Cravero indicate clinically significant agitation.

   Secondary Outcomes

3. Perioperative stress response assessed by serum cortisol levels measured before administration of intravenous anesthetics and before emergence from anesthesia.

4. Perioperative stress response assessed by serum alpha-amylase levels measured before administration of intravenous anesthetics and before emergence from anesthesia.

5. Perioperative stress response assessed by serum neuropeptide Y levels measured before administration of of intravenous anesthetics and before emergence from anesthesia.

6. Incidence of postoperative adverse events including nausea, vomiting, pruritus, constipation, respiratory depression, and altered consciousness within 24 hours postoperatively.

   ________________________________________

Participants The study will include 90 children aged 3 months to 7 years with cleft lip and/or palate. Participants will be recruited at the Outpatient Clinic for Malformations and Deformities of the Jaws and Face, University Hospital Dubrava, and divided into two groups of 45 children.

Group O (opioid group): fentanyl Group NO (opioid-free group): ketamine and dexmedetomidine Both groups will also receive propofol, vecuronium, sevoflurane, and nitrous oxide.

Inclusion criteria: ASA I-II, body weight >5 kg (10 lbs), age ≥3 months (for cheiloplasty) or ≥9 months (for palatoplasty), hemoglobin >100 g/L.

Exclusion criteria: ASA III-IV, body weight <5 kg (10 lbs), inappropriate age, hemoglobin <100 g/L, acute illness, respiratory infection or vaccination within 2 weeks, need for perioperative intensive care.

________________________________________ Materials and Methods

Postoperative pain and agitation will be assessed using observational scales and objective biomarkers.

1. Indirect assessment via observational scales

1.1. Pain scale

CHIPPS (Children and Infants Postoperative Pain Scale)

CHIPPS scale is validated scale used for assessment of postoperative pain in infants and children. It is based on behavioral observation and includes five categories scored from 0 to 2:

Crying:

0 - none

1 - moaning/whimpering 2 - persistent, strong crying

Facial expression:

0 - relaxed/smiling

1. - grimace
2. - pronounced grimace

Trunk position:

0 - relaxed

1. - variable/restless
2. - rigid/arched

Leg position:

0 - relaxed

1. - restless
2. - flexed/tense

Motor restlessness:

0 - calm

1. - moderate restlessness
2. - marked restlessness Total score ranges from 0 to 10; values ≥4 indicate clinically significant pain.

1.2. Emergence agitation scales The Pediatric Anesthesia Emergence Delirium Scale (PAEDS) is the only scale formally validated for the assessment of emergence agitation in the pediatric population. However, it has several important limitations: results are often falsely positive, it is not quite convenient for children younger than 2 years, and its multiple assessment items make it less practical for rapid clinical use.

In contrast, the Cravero scale, although not formally validated, is more commonly used in everyday practice due to its simplicity, speed, and better clinical applicability. It is generally considered more practical and, in many cases, more accurate in distinguishing agitation from other postoperative conditions.

For these reasons, both scales will be used in this study in order to combine their respective strengths and provide a more comprehensive and reliable assessment of emergence agitation.

1.2.1. PAED (Pediatric Anesthesia Emergence Delirium)

PAEDS scale is a validated observational tool used for assessment of emergence delirium in pediatric patients following general anesthesia. It is based on behavioral observation and includes five items scored from 0 to 4:

Eye contact with caregiver:

0 - makes eye contact

1. - reduced eye contact
2. - inconsistent eye contact
3. - rarely makes eye contact
4. - no eye contact

Purposeful actions:

0 - appropriate actions

1. - slightly inappropriate actions
2. - moderately inappropriate actions
3. - markedly inappropriate actions
4. - no purposeful actions

Awareness of surroundings:

0 - fully aware

1. - slightly impaired awareness
2. - moderately impaired awareness
3. - markedly impaired awareness
4. - no awareness

Restlessness:

0 - calm

1. - mild restlessness
2. - moderate restlessness
3. - marked restlessness
4. - severe agitation

Inconsolability:

0 - easily consoled

1. - slightly difficult to console
2. - moderately difficult to console
3. - very difficult to console
4. - inconsolable Total score ranges from 0 to 20; higher scores indicate more severe emergence delirium. Values ≥10-12 are commonly considered clinically significant.

1.2.2. Cravero Emergence Agitation Scale

The Cravero scale is used to assess postoperative agitation in children during emergence from anesthesia and classifies it into one of five categories according to the level of agitation:

1. - child asleep, calm
2. - child awake, calm
3. - mildly agitated but consolable
4. - moderately agitated, difficult to console
5. - severely agitated, uncontrolled behavior Values ≥4 are considered indicative of clinically significant agitation. The scale is easy to use, does not require additional equipment, and allows rapid assessment of the child's condition in the postoperative period.

2. Direct assessment via determination of biochemical markers From 2 mL of blood, levels of cortisol, alpha-amylase, and neuropeptide Y will be determined at predefined time points before and after administration of anesthetics. These compounds are released as part of the physiological stress response to postoperative pain and will be used to objectively assess the effectiveness of the anesthetic protocols.

CLIA method will be used for quantitative determination of cortisol and amylase.

ELISA (BT LAB) will be used for quantitative determination of neuropeptide Y. After centrifugation, serum samples will be collected and stored at -80°C until analysis.

3. Postoperative complications Incidence of nausea, vomiting, pruritus, constipation, respiratory depression, and altered consciousness will be recorded in the first 24 postoperative hours.

________________________________________ Statistical Analysis Sample size was determined using power analysis: assuming an effect size of 0.6, a significance level (α) of 0.05, and a statistical power (1-β) of 0.80, the minimum required sample size was calculated to be 45 participants per group (total of 90 participants), which will ensure sufficient statistical power and reliability for detecting differences between groups.

Statistical analysis will be performed using MedCalc software. Prior to applying inferential statistical methods, the normality of data distribution will be assessed using the Kolmogorov-Smirnov test. For comparison between two independent groups, Student's t-test will be used for normally distributed data, while the Mann-Whitney U test will be applied for data that do not meet the assumption of normality. For comparison of repeated measurements and longitudinal data, repeated measures ANOVA will be used in the case of normally distributed data, and the Kruskal-Wallis test will be applied for non-normally distributed data.

Correlation between variables will be analyzed using Pearson's correlation coefficient for parametric data and Spearman's rank correlation coefficient for non-parametric data.

Multivariate regression analysis will be performed to identify independent predictors, and the diagnostic value of individual variables will be evaluated using Receiver Operating Characteristic (ROC) analysis, including calculation of the Area Under the Curve (AUC). Statistical significance will be set at p < 0.05. All results will be presented with corresponding p-values, confidence intervals, and measures of effect where applicable.

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Study Plan

One surgeon and one anesthesiologist will be involved in the study. A child will be included in the study if the inclusion criteria are met and the parents sign an informed consent. All children will undergo the surgical procedure at the same time, in the morning period, thereby avoiding the potential influence of different circadian rhythms of cortisol on laboratory results.

After premedication with an intramuscular injection of midazolam (1 mg/kg) and atropine (0.012 mg/kg), in the operating room, following sedation with sevoflurane, an intravenous cannula will be placed, thereby avoiding traumatization of the child due to the painful nature of the procedure. At that time, the first blood sample will be taken for determination of cortisol, alpha-amylase, and neuropeptide Y.

Patients will be randomly assigned to one of two groups using a computer-generated list of random numbers with allocation in a 1:1 ratio, and the sequence of assignment will be predetermined and sealed in numbered envelopes, which will be opened immediately before the induction of anesthesia. In this way, objectivity will be ensured and the possibility of bias reduced. Due to the principles of ethical conduct in an extremely sensitive population of neonates, and in order to maintain control over all events in the study at all times and ensure maximum safety of the child, the doctoral candidate will not be blinded to the type of protocol the patient receives.

The first group will receive fentanyl (5 mcg/kg), propofol (4 mg/kg), and vecuronium (0.1 mg/kg), while the second group will receive ketamine (1 mg/kg), propofol and vecuronium in the same doses, and dexmedetomidine in continuous infusion (1→0.4 mcg/kg/h). Anesthesia will be conducted with endotracheal intubation and standard monitoring of vital functions (blood pressure, pulse, ECG, peripheral oxygen saturation - SpO₂, end-tidal CO₂ - etCO₂). For maintenance of anesthesia, a mixture of O₂/N₂O and sevoflurane will be used. Children will receive antibiotic and anti-edematous prophylaxis.

At the beginning of the procedure, the surgeon will infiltrate the operative site in all children with a commercially pre-mixed combination of the local anesthetic lidocaine and adrenaline, dosed according to body weight (5 mg/kg).

Toward the end of the operation, analgesia will be administered with intravenous paracetamol, with the addition of nonsteroidal anti-inflammatory drugs. Before emergence, the second blood sample will be taken. Pain assessment will be performed 5 minutes, 15 minutes, 1 hour, 2 hours, 12 hours, and 24 hours after extubation, and agitation assessment at 5 minutes, 15 minutes, 1 hour, and 2 hours after extubation.

In the ward, the intensity of pain and agitation will continue to be monitored over the next 24 hours. Analgesia will be administered regularly, according to professional guidelines, as a combination of nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol, and adjusted as needed. If required, additional analgesia will be administered with intravenous fentanyl at a dose of 0.025-0.5 mcg/kg with appropriate monitoring of the child.

________________________________________ Expected Scientific Contribution

The opioid-free protocol aims to provide effective anesthesia with improved analgesia, reduced agitation, faster recovery, and fewer opioid-related side effects.

The translational value of this study lies in the implementation of objective biomarkers into clinical practice and in improving clinical care, as well as providing a foundation for future regional guidelines.

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.

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

This is a single-investigator study, and there are no plans to share individual participant data (IPD).