Postoperative and Opioid Free Anesthesia (POFA)

Effect of Opioid-free Anesthesia on Postoperative Opioid-related Adverse Events After Major or Intermediate Non-cardiac Surgery: a Multicenter Prospective Randomized Controlled Study

Since the 1960's, intraoperative administration of opioids is considered a keystone of anesthesia as well as hypnotics and muscle relaxants. Synthetic opioids were introduced to achieve hemodynamic stability during anesthesia. They allow an inhibition of the sympathetic system without cardiovascular collapse and histamine release. Since then, anesthesia has changed from inhalation to multimodal anesthesia with lower doses of hypnotic. In 2017, the intraoperative objectives of hypnosis, hemodynamic stability, immobility and anticipation of postoperative analgesia can be achieved without opioids. Moreover, opioid administration consequences are neither scarce nor benign for the patient. Perioperative opioids are associated with nausea and vomiting, sedation, ileus, confusion/delirium, respiratory depression, increased postoperative pain and morphine consumption, immunodepression, hyperalgesia and chronic postoperative pain. Among these complications, hypoxemia, ileus and confusion/delirium are the most frequent.

Efficacious multimodal analgesia and anesthesia are the basis of successful fast-track surgery. These multidrug regimens aim at decreasing postoperative pain, intra- and postoperative opioid requirements, and subsequently, opioid-related adverse effects and to fasten recovery. Opioid-free postoperative analgesia has been recommended for more than 10 years. Opioid-free anesthesia (OFA) is based on the idea that hemodynamic stability can be achieved without opioids during anesthesia. OFA is multimodal anesthesia associating hypnotics, N-methyl-D-aspartate (NMDA) antagonists, local anesthetics, anti-inflammatory drugs and alpha-2 agonists (Dexmedetomidine).

Proofs of the effect of OFA on reducing opioid-related adverse effects after major or intermediate non-cardiac surgery are still scarce. We hypothesized that the reduced opioid consumption during and after surgery allowed by OFA compared with standard of care will be associated with a reduction of postoperative opioid-related adverse events.

Study Overview

• Status: Terminated
• Conditions: Opioid-Related Disorders; Anesthesia
• Intervention / Treatment: Drug: Dexmedetomidine; Drug: Remifentanil

• Study Type: Interventional
• Enrollment (Actual): 316
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Clermont-Ferrand, France
    • Clermont-Ferrand University Hospital
  • Clichy, France
    • Beaujon Hospital
  • Lille, France
    • Lille University Hospital
  • Metz, France
    • Metz-Thionville Hospital
  • Montpellier, France
    • Montpellier University Hospital
  • Nantes, France
    • Nantes University Hospital
  • Nîmes, France
    • Nimes University Hospital
  • Périgueux, France
    • Perigueux Hospital
  • Rennes, France
    • Rennes University Hospital
  • Saint-Brieuc, France
    • Saint-Brieuc Hospital
  • Toulouse, France
    • Toulouse University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Undergoing a scheduled major or intermediate non-cardiac surgery,
• Benefiting from the health insurance system,
• Having signed an informed consent.

Exclusion Criteria:

• Pregnant or breast feeding women,
• Allergy to dexmedetomidine or one of its excipients,
• Allergy to one of the drugs used for anesthesia or one of their excipients,
• Urgent surgery,
• Intracranial surgery,
• Transplant surgery or transplanted patients,
• Surgery with planned regional anesthesia,
• Outpatient surgery,
• Atrioventricular block, intraventricular or sinoatrial block,
• Treatment by chronic betablockers and HR < 50 bpm,
• Heart failure with LVEF < 40%,
• Adam-Stokes syndrome,
• Epilepsy or seizures,
• Uncontrolled hypotension,
• Acute cerebral pathology,
• Obstructive sleep apnea syndrome,
• Severe hepatic insufficiency (Prothrombin Ratio < 15%),
• Patients in whom the CAM-ICU cannot be performed (deaf patients for example)
• Adults legally protected (under judicial protection, guardianship, or supervision), persons deprived of their liberty.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dexmedetomidine	Drug: Dexmedetomidine; Opioid-free anesthesia
Active Comparator: Control	Drug: Remifentanil; Opioid anesthesia

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurence of a severe postoperative opioid-related adverse event defined as : postoperative hypoxemia or postoperative ileus (POI) or postoperative cognitive dysfunction (POCD).	Postoperative hypoxemia is defined as an oxygen saturation (SpO2) < 95% with a need for oxygen supplementation within the first 48h after extubation; the duration of oxygen treatment will also be recorded. Postoperative ileus is defined as an absence of flatus or stools within the first 48h after extubation. Postoperative cognitive dysfunction will be evaluated using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) by a care provider (either anesthesiologist or nurse).	Within the first 48 hours after extubation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of episodes of postoperative pain (numeric rating scale ≥ 3), at rest		Within 48 hours after extubation
Opioid consumption		During the 48 hours following extubation
Time between the end of remifentanil or dexmedetomidine administration and an Aldrete score > 9 (when applicable)		Within 48 hours after extubation
Time between the end of remifentanil or dexmedetomidine administration and extubation		Hour 0 = extubation
Rate of unscheduled admission in intensive care unit		Within 48 hours after extubation
Number of postoperative nausea and vomiting (PONV) episodes		During the 48 hours following extubation
Hospital length of stay (max 28 days) defined as the number of days after extubation before first hospital discharge		Day 28
Number of bradycardia, hypotension and hypertension events during surgery and number of rescue medications during surgery	Bradycardia is defined as the number of episodes with atropine administration. Hypotension is defined as mean arterial blood pressure < 65 mmHg. Hypertension is defined as mean arterial blood pressure > 90 mmHg.	During surgery (maximum duration of 7 hours)

Collaborators and Investigators

• Sponsor: Rennes University Hospital
• Investigators: Principal Investigator: Hélène BELOEIL, Rennes University Hospital

Publications and helpful links

General Publications

• Beloeil H, Laviolle B, Menard C, Paugam-Burtz C, Garot M, Asehnoune K, Minville V, Cuvillon P, Oger S, Nadaud J, Lecoeur S, Chanques G, Futier E; SFAR research network. POFA trial study protocol: a multicentre, double-blind, randomised, controlled clinical trial comparing opioid-free versus opioid anaesthesia on postoperative opioid-related adverse events after major or intermediate non-cardiac surgery. BMJ Open. 2018 Jun 30;8(6):e020873. doi: 10.1136/bmjopen-2017-020873.

Study record dates

Study Major Dates

• Study Start (Actual): November 29, 2017
• Primary Completion (Actual): January 29, 2019
• Study Completion (Actual): June 19, 2019

Study Registration Dates

• First Submitted: October 13, 2017
• First Submitted That Met QC Criteria: October 19, 2017
• First Posted (Actual): October 20, 2017

Study Record Updates

• Last Update Posted (Actual): October 18, 2019
• Last Update Submitted That Met QC Criteria: October 16, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Narcotic-Related Disorders; Opioid-Related Disorders; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Analgesics, Opioid; Narcotics; Hypnotics and Sedatives; Remifentanil; Dexmedetomidine
• Other Study ID Numbers: 35RC16_9842_POFA

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No