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

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.

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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.

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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

• Perioperative stress response assessed by serum cortisol levels [Срок оценки: Before intravenous anesthesia induction and before emergence from anesthesia]
• Perioperative stress response assessed by serum alpha-amylase levels [Срок оценки: Before intravenous anesthesia induction and before emergence from anesthesia]
• Perioperative stress response assessed by serum neuropeptide Y levels [Срок оценки: Before intravenous anesthesia induction and before emergence from anesthesia]
• Incidence of postoperative adverse events [Срок оценки: From anesthesia emergence until 24 hours postoperatively]