Evaluation of the Nociception Guided by NoL Index and PK of Fentanyl in Pediatric Patients Under General Anesthesia

Study Overview
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Brief Summary
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Fentanyl is one of the most common used opioids for analgesia during general anesthesia, however there are few studies that describe the relationship between its pharmacokinetics and pharmacodynamics, especially in the pediatric population. The monitoring of the analgesia component during general anesthesia has been traditionally by changes in patient's vital signs, with new devices that measure nociceptive indexes like the Nociception level (NoL) index currently being validated for adults. There is still lacking evidence with nociceptive indexes in the pediatric population. Insufficient dose of opioids may cause sympathetic response, respiratory complications, development of persistent post-surgical pain and even prolonged hospitalization. In the other hand, and overdose of opioids may cause over sedation, postoperatory nausea and vomiting, respiratory depression, hyperalgesia and tolerance. Given the lack of evidence on the Pharmacokinetic and pharmacodynamic (PK/PD) of fentanyl in this group of patients, has led to raise the development of this observational prospective study; which is to describe a PK/PD model of fentanyl in pediatric population, through evaluation of the NoL index, in patients submitted to elective general non-cardiac surgery.

Detailed Description
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Patients will be invited to participate before surgery, the inclusion criteria will be revised and the informed consent will be signed by one of the parents or legal tutor. In the operating room will be recorded demographic data and relevant background such as: Age, Weight, Size, BMI. Afterwards, in the operating room, the patient will be monitored regularly: EKG, pulse oximetry, non invasive blood pressure. Induction of anesthesia with sevoflurane 6% in 100% oxygen, once loss of consciousness, 2 peripheral IV lines will be installed, one for medication and the other in the contralateral arm for blood samples. After that, a laryngeal mask device (LMA) appropriate for the weight for the management of the airway. In addition, the EEG will be monitored through a frontal electroencephalographic monitoring (BIS) system and a NoL index sensor, both of which will be recorded throughout the surgery. Once all monitors are installed, a caudal block with 0,5-1 ml of bupivacaine 0,25% will be performed, in the left decubitus lateral position. Ventilator and vaporizer adjustments for an EtCO2 of 35-40 mmHg and a BIS index of 50-60 with Sevoflurane. After 12 minutes, because of the latency of caudal block; surgeons may start. If an effective caudal block is proven, the study will continue; if there is movement of the child, laryngospasm or an increase of more than 10% in the base values of heart rate or blood pressure, the patient will be excluded from the study. Standardized nociceptive stimulus will be administered through a tetanic stimulus (70 Hz, 80 mA) for 5 seconds in the forearm. An initial tetanic stimulus will be performed, 2 minutes afterwards a unique dose of fentanyl of 2 micrograms per kg will be administered. New tetanic stimulus will be applied at 5, 15, 30 and 45 minutes after the fentanyl dose and blood samples for fentanyl plasmatic levels will be taken at the same time in the operating room and at 75 or 120 minutes in the post anesthesia care unit (PACU). NoL index values will be recorded after each tetanic stimulus. After surgery, sevoflurane will be discontinued, LMA removed and the patients transferred to the PACU. Pain scores will be evaluated in the PACU using Visual analogue scale. Analgesic management with NSAIDs and Acetaminophen. PK/PD profile of fentanyl will be evaluated with NONMEM (non-linear mixed effects modelling) software for the analysis.

Official Title
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Evaluation of the Nociception Guided by NoL Index and Pharmacokinetics of Fentanyl in Pediatric Patients Under General Anesthesia for Non-cardiac Elective Surgery

Conditions
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Pain, Anesthesia, Pediatric ALL

Intervention / Treatment
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* Drug: Fentanyl
* Other: Tetanic stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children 3-10 years old ASA I - II Lower abdominal or urological surgery, requiring general anesthesia and caudal block Exclusion Criteria: Obese patients ASA III - IV - V Allergy to fentanyl Emergency surgery Patients with sleep apnea Surgeries anticipated to have an increased volume exchange or transfusion

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 10 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Tetanic stimulation<br>Single arm study | Drug: Fentanyl<br>* Standard dose of 2 ug/kg after tetanic stimulation.<br>Other: Tetanic stimulation<br>* Standard tetanic stimulation will be used as the stimulus to evaluate response of the intraoperative pain index (NoL) at a standard fentanyl dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NoL index. | Variations in the NoL index (0-100). NoL has a range from 0-100, with 0 indicates no pain and 100 indicates worst pain. Data will also be analyzed using nonlinear mixed effect modeling (NONMEM) | Since induction of anesthesia until emergence of anesthesia (one hour in average) | 
| Change of the plasmatic levels of fentanyl | Describe the change of the levels of fentanyl plasmatic levels (ng/mL) measured by high pressure liquid chromatography (HPLC). | 5, 15, 30, 45, 75 until 120 minutes after one dose of fentanyl. | 
| Peak Plasma Concentration (Cmax) | Calculate maximum plasma concentration (Cmax) fentanyl plasma levels measured with high pressure fluid (HPLC) after a single bolus of fentanyl in enrolled pediatric patients. | 5, 15, 30, 45, 75 until 120 minutes after one dose of fentanyl. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemodynamics | Arterial pressure (mmHg) | At time of surgery, up to 120 minutes. | 
| Heart rate (bpm) | Heart rate (bpm) | At time of surgery, up to 120 minutes | 
| Pulse oximetry | % oximetry saturation | At time of surgery, up to 120 minutes. | 
| Bispectral index | Depth of anesthesia will be recorded with BIS monitor | At time of surgery, up to 120 minutes | 
| Pain in Visual analogue scale (0-10) | Postoperative pain will be evaluated with Visual analogue scale (0-10), being a score of 10 worst outcome, in the PACU for 120 minutes immediately after surgery. | Every 15 minutes in the PACU, up to 120 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NoL, Nociception level, Fentanyl, Pediatric anesthesia, Pharmacokinetics