Pupillary Dilation Reflex Assessment for Intraoperative Analgesic Titration.

Study Overview
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Brief Summary
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In this double blinded randomized controlled study, the pupillary dilation reflex is used for as a nociceptive indicator for opioid administration during elective surgery under general anesthesia.

Detailed Description
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An infrared camera of the video pupillometer measures the pupillary dilation reflex (PDR) in response of a nociceptive stimulus. This autonomic reflex, parasympathetic mediated in sedated patients, can be generated by various pain stimuli (built in standardized protocol, surgical incision, …) The PDR is a robust reflex, even in patients under general anesthesia, and provides a potential evaluation of the autonomous circuit within the nociceptive evaluation based on pupil dilation upon A-delta and C fibers in both electrical or mechanic stimulation. This double blind randomized controlled trial involving American Society of Anesthesiologists (ASA) classification I-III patients undergoing elective surgery under general anesthesia are recruited. Enrolled patients are randomized in four groups: (1) remifentanil administration depending on PDR results, (2) remifentanil administration depending on decision attending anesthesiologist, (3) sufentanil administration depending on PDR results, (4) sufentanil administration depending on decision attending anesthesiologist.

Official Title
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Pupillary Dilation Reflex Assessment for Intraoperative Analgesic Titration [PUP-AIT]. A Double Blinded Randomized Trial.

Conditions
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Pain, Acute, Anesthesia

Intervention / Treatment
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* Diagnostic Test: Pupillary dilation reflex
* Other: Standard of care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: > 18 jaar Elective abdominal or gynaecological operation ASA (American Society of Anesthesiologists classification): I - II - III Exclusion Criteria: History of invasive ophthalmological surgery Known bilateral eye disease Known optical of oculomotor nerve deficit Active psychiatrical disease Proven active pheochromocytoma Opioid usage > 7 days preoperative Ongoing oncological treatment with chemotherapeutic agents Usage of A-1 adrenergic of beta-blocking agents Preoperative usage of benzodiazepines Topical atropine or phenylephrine (eye droplets) Planned perioperative usage of dopamine antagonists

Ages Eligible for Study
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Minimum Age: 18 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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double blinded randomized controlled trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention 1<br>Pupillary dilation reflex based perioperative intravenous remifentanil administration. Starting dose 5 ng/ml by continous infusion, dosage adjustments are made after pupillary dilation reflex assessment every 10 minutes. When PPI score is 1, the dosage is decreased with 0.2 ng/ml. When PPI score is greater than 1, the dosage is increased with 0.2 ng/ml. | Diagnostic Test: Pupillary dilation reflex<br>* Perioperative pupillary dilation reflex assessment is executed every 10 minutes from start sedation until extubation in patients allocated to study arm Intervention 1 and Intervention 3<br>|
| Active Comparator: Intervention 2<br>Anesthesiologist based perioperative intravenous remifentanil administration (daily practice, standard of care). Starting dose 5 ng/ml, dosage adjustments are made when deemed necessary by attending anesthesiologist. | Other: Standard of care<br>* Perioperative opioid administration based on the attending anesthesiologist decision (mainly including assessment of heart rate, blood pressure, and limb movement)<br>|
| Experimental: Intervention 3<br>Pupillary dilation reflex based perioperative intravenous sufentanil administration. Starting dose 0.1 mcg/kg bolus, dosage adjustments are made after pupillary dilation reflex assessment every 10 minutes. When PPI score is 1, no supplementary administration is executed. When PPI score is greater than 1, a supplementary bolus of 0.1 mcg/kg is given. | Diagnostic Test: Pupillary dilation reflex<br>* Perioperative pupillary dilation reflex assessment is executed every 10 minutes from start sedation until extubation in patients allocated to study arm Intervention 1 and Intervention 3<br>|
| Active Comparator: Intervention 4<br>Anesthesiologist based perioperative intravenous sufentanil administration (daily practice, standard of care). Starting dose 0.1 mcg/kg bolus, dosage adjustments are made when deemed necessary by attending anesthesiologist. | Other: Standard of care<br>* Perioperative opioid administration based on the attending anesthesiologist decision (mainly including assessment of heart rate, blood pressure, and limb movement)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postoperative pain | Numeric rating scale (NRS) pain assessment | From patient extubation until postoperative day 5 | 
| Postoperative analgesia | Analgetic consumption | From patient extubation until postoperative day 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stimulation intensity to elicit PDR | Necessary stimulation intensity generated by the pupillometer to elicit a PDR | From the day of surgery at the start of general anesthesia, assessed every 10 minutes until the end of surgery or extubation, whichever came first, assessed up to 4 hours | 
| Baseline pupil diameter | Pupil size before stimulation | From the day of surgery at the start of general anesthesia, assessed every 10 minutes until the end of surgery or extubation, whichever came first, assessed up to 4 hours | 
| Pupillary dilation reflex amplitude | The amplitude of the pupil enlargement after nociceptive stimulation | From the day of surgery at the start of general anesthesia, assessed every 10 minutes until the end of surgery or extubation, whichever came first, assessed up to 4 hours | 
| Pupillary pain index (PPI) | Generated PPI score by the pupillometer in accordance to given stimulation and pupillary dilation reflex amplitude | From the day of surgery at the start of general anesthesia, assessed every 10 minutes until the end of surgery or extubation, whichever came first, assessed up to 4 hours | 
| Opioid usage during surgery | Total dose remifentanil or sufentanil administrated during surgery, in microgram | From the day of surgery at the start of general anesthesia, assessed every 10 minutes until the end of surgery or extubation, whichever came first, assessed up to 4 hours | 
| Extubation time | The time between stop of propofol administration and patient extubation, in minutes | From the day of surgery at the termination of propofol infusion until patient extubation, assessed up to 2 hours | 
| Postoperative nausea and vomiting | Frequency of nausea or vomiting after surgery, in numbers of events | From patient extubation until postoperative day 5 | 
| Length of stay at the postanesthesia care unit | Hours of admission at the postanesthesia care unit after surgery until discharge to the nursing ward, in minutes | From admission at the postanesthesia care unit until discharge to the nursing ward, assessed up to 24 hours | 
| Length of hospital stay | Length of hospital stay, in days | From the day of the planned surgery until hospital discharge, assessed up to 5 days | 
| Postoperative health status | Assessed by 5-level EQ-5D version (EQ-5D-5L), quality of life and health status questionnaire | From extubation until 1 month after surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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heart rate, pupillary reflex, nociception, intraoperative monitoring