Prevention of Organ Dysfunction and Mortality by Monitoring the Administration of Opioids and Hypnotics in Patients at High Postoperative Risk

Study Overview
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Brief Summary
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Intraoperative hypotension is a common situation. It increases postoperative morbidity and mortality, especially in patients at high postoperative risk undergoing high-risk surgery. Intraoperative hypotension is partly related to anesthesia, and mainly to the combined, dose-dependent, synergistic effect of hypnotics and opioids. Monitoring sedation and monitoring analgesia reduce intraoperative consumption of each anesthetic agent. To date, the beneficial effect of combined sedation and analgesia monitoring on the reduction of intraoperative hypotension has only been found in one study, involving major abdominal surgery. Up to now, no study has been designed to demonstrate the benefit of monitoring the two components of anesthesia on postoperative organ dysfunction and mortality. The study propose to evaluate the relevance of a combined optimization of hypnotic and opioid agents on the most frequently encountered dysfunctions related to intraoperative hypotension.

Official Title
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Prevention of Organ Dysfunction and Mortality by Monitoring the Administration of Opioids and Hypnotics in Patients at High Postoperative Risk: the Opti-Two Study. A Multi-center Controlled Randomized Study.

Conditions
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Sedation and Analgesia Monitoring

Intervention / Treatment
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* Procedure: anesthesia guided by sedation and analgesia monitoring
* Procedure: anesthesia performed according only to the clinical judgment of the anesthetist as usual practice


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients affiliated to the French Social Security; informed and signed consent to participating in the study; planned postoperative hospitalization > 48 hours; patients over 75 years of age with at least one of the following postoperative risk factors: ischemic coronary disease; history of compensated or prior heart failure; stroke; significant arrhythmias: fibrillation or auricular flutter with ventricular response > 100/minute, multiform QRS complex) or cardiac conduction abnormalities (trifascicular block, auriculoventricular block of the second or third degree); peripheral vascular disease; chronic obstructive pulmonary disease; chronic respiratory failure; renal insufficiency, defined by a creatinine > 175 µmol.l-1 (2 mg.dl-1); insulin therapy for diabetes; active cancer; chronic alcohol abuse; dementia. elective or emergency high-risk surgery under general anesthesia with a combination of hypnotic and opioid, and intubation or placement of a supraglottic airway control device: Non inclusion criteria: Patients who meet one or more of the preoperative following criteria will not be included: acute heart failure or acute myocardial infarction; acute respiratory failure or pneumonia; septic shock; acute stroke; cardiac surgery; open chest surgery; opioid free anesthesia; intraoperative ketamine at a dose > 0.2 mg.kg-1; lidocaine or dexmedetomidine by continuous infusion; refusal to participate in the study;

Ages Eligible for Study
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Minimum Age: 75 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention Group<br> | Procedure: anesthesia guided by sedation and analgesia monitoring<br>* Anesthesia guided by sedation and analgesia monitoring The level of sedation will be monitored by Monitoring System BIS™ : Bispectral index (BIS) between 45 and 60 AND Suppression Ratio (SR) at 0; or SedLine® Sedation Monitor : Patient State Index (PSi) between 25 and 50; or Entropy Sensor™: State entropy (SE) between 45 and 60 AND Burst Suppression Ratio (BSR) at 0; and the level of nociception by : Nociception monitor PMD-200® : Nociception Level (NoL) between 10 and 25.<br>|
| Placebo Comparator: Control Group<br> | Procedure: anesthesia performed according only to the clinical judgment of the anesthetist as usual practice<br>* Administration of anesthesia will be performed according to the clinical judgment of the anesthetist as usual practice without sedation and analgesia monitoring<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| death |  | Day 30 | 
| Postoperative acute kidney injury (PO-AKI) | The PO-AKI will be defined as an increase to 1.5 times the reference level, or as more than 0.3 mg.dl-1 (i.e. 26.5 µmol.l-1) between the last preoperative value and the maximal value observed after surgery, or urine volume < 0.5 ml.kg-1.h-1 for 6 hours, according to the recommendations of the Acute Kidney Injury Network | Day 30 | 
| cardiovascular complication | postoperative myocardial infarction, acute heart failure, acute/non pre-existing atrial fibrillation or flutter, cardiac arrest with successful resuscitation, coronary revascularisation | Day 30 | 
| neurological complication | Stroke or transient ischemic attack | Day 30 | 
| Post-operative delirium (POD) | Post-operative delirium (POD) will be evaluated using the 3-minute Diagnostic Confusion Assessment Method (3D-CAM), appropriated and validated for the assessment of delirium in the postoperative period, or the Confusion Assessment Method for Intensive Care Unit (CAM-ICU) for the intubated patients. | Day 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| doses of hypnotics administered |  | during surgery | 
| doses opioids administered; |  | during surgery | 
| number and duration of hypotensive periods | an hypotensive event will be defined as a Mean Arterial Pressure (MAP) ≤ 65 mmHg. | during surgery | 
| time spent within the desired range of sedation: | Monitoring System BIS™ : Bispectral index (BIS) between 45 and 60 AND Suppression Ratio (SR) at 0 or SedLine® Sedation Monitor : Patient State Index (PSI) between 25 and 50 AND Suppression Ratio (SR) at 0 or Entropy Sensor™: State entropy (SE) between 45 and 60 AND Burst Suppression Ratio (BSR) at 0 The anesthetist will have access to the value of sedation monitoring in the intervention group; these data will be recorded but not available to the anesthetist in the control group: they will be analyzed at the end of the study to answer this point. | during surgery | 
| time spent within the desired range of analgesia: | Nociception monitor PMD-200® : Nociception Level (NOL) between 10 and 25. The anesthetist will have access to the value of sedation and analgesia monitoring in the intervention group; these data will be recorded but not available to the anesthetist in the control group: they will be analyzed at the end of the study to answer this point. | during surgery | 
| doses of vasopressive amines (ephedrine or norepinephrine) administered; |  | during surgery | 
| pain ≥ 5 as assessed with the Visual Analogic Scale (VAS) | VAS 0 to 10 [0 corresponds to no pain - 10 corresponds to maximum pain] | At 48 Hours after surgery | 
| dose of opioid administered; |  | At 48 Hours after surgery | 
| incidence of awareness and recall during anesthesia (explicit memory). |  | At 48 Hours after surgery | 
| acute respiratory failure or Acute Respiratory Distress Syndrome (ARDS) |  | Day 30 | 
| duration of stay in Intensive Care Unit (ICU); |  | Day 30 | 
| rate of unexpected ICU admission, or readmission |  | Day 30 | 
| duration of hospital stay; |  | Day 30 | 
| early hospital readmission rate |  | Day 30 |