Respiratory and Hemodynamic Targets During General Anesthesia

Study Overview
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Brief Summary
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This trial is an investigator-initiated, multicenter, randomized, factorial, single-blind trial of multiple hemodynamic and respiratory targets during general anesthesia. These targets include blood pressure, positive end expiratory pressure, tidal volume, and fraction of inspired oxygen. Patients will be randomized to different targets using a factorial design, i.e., each patient is simultaneously randomized to four interventions. There will be five enrolling sites in the Central Denmark Region. 480 high-risk patients will be enrolled.

Official Title
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Respiratory and Hemodynamic Targets During General Anesthesia - A Randomized Clinical Trial

Conditions
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Patients Undergoing General Anesthesia

Intervention / Treatment
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* Procedure: Blood pressure
* Procedure: Positive end expiratory pressure
* Procedure: Tidal volume
* Procedure: Fraction of inspired oxygen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years American Society of Anesthesiologists (ASA) classification 3 to 5 Planned endotracheal intubation with positive pressure ventilation Expected operating time ≥ 90 minutes Certain types of surgery Exclusion Criteria: Inability to obtain consent (e.g., patient is unconscious, hyperacute surgery) Known or suspected pregnancy Out-patient/same-day surgery Intubated prior to surgery Clinical judgement by the anesthesiologist that any of the interventions could be potentially harmful to the patient

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: Factorial Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mean arterial blood pressure above 60 mmHg during general anesthesia and 2 hours after<br> | Procedure: Blood pressure<br>* Blood pressure targets during general anesthesia and 2 hours after<br>|
| Experimental: Mean arterial blood pressure above 70 mmHg during general anesthesia and 2 hours after<br> | Procedure: Blood pressure<br>* Blood pressure targets during general anesthesia and 2 hours after<br>|
| Experimental: Mean arterial blood pressure above 80 mmHg during general anesthesia and 2 hours after<br> | Procedure: Blood pressure<br>* Blood pressure targets during general anesthesia and 2 hours after<br>|
| Experimental: Systolic blood pressure above 90% of baseline during general anesthesia and 2 hours after<br> | Procedure: Blood pressure<br>* Blood pressure targets during general anesthesia and 2 hours after<br>|
| Experimental: Positive end expiratory pressure 5 cm H20 during general anesthesia<br> | Procedure: Positive end expiratory pressure<br>* Positive end expiratory pressure during general anesthesia<br>|
| Experimental: Positive end expiratory pressure 8 cm H20 during general anesthesia<br> | Procedure: Positive end expiratory pressure<br>* Positive end expiratory pressure during general anesthesia<br>|
| Experimental: Positive end expiratory pressure 10 cm H20 during general anesthesia<br> | Procedure: Positive end expiratory pressure<br>* Positive end expiratory pressure during general anesthesia<br>|
| Experimental: Tidal volume 5 ml/kg during general anesthesia<br> | Procedure: Tidal volume<br>* Tidal volume during general anesthesia<br>|
| Experimental: Tidal volume 8 ml/kg during general anesthesia<br> | Procedure: Tidal volume<br>* Tidal volume during general anesthesia<br>|
| Experimental: Tidal volume 10 ml/kg during general anesthesia<br> | Procedure: Tidal volume<br>* Tidal volume during general anesthesia<br>|
| Experimental: Fraction of inspired oxygen 30% during general anesthesia and 2 hours after<br> | Procedure: Fraction of inspired oxygen<br>* Fraction of inspired oxygen during general anesthesia and 2 hours after<br>|
| Experimental: Fraction of inspired oxygen 80% during general anesthesia and 2 hours after<br> | Procedure: Fraction of inspired oxygen<br>* Fraction of inspired oxygen during general anesthesia and 2 hours after<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility: Proportion of eligible patients randomized | Eligible patients will be defined as those meeting all inclusion criteria and none of the exclusion criteria 1 to 4. | Up to 90 days | 
| Feasibility: Proportion of patient with adherence to the assigned interventions | Adherence will be defined as follows: The allocated positive end expiratory pressure (± 1 cm H2O), tidal volume (± 1 ml/kg), and FiO2 (± 5%) is used in a minimum of 90% of the randomized patients for the duration of the surgery. Vasopressors/inotropes are only initiated and continued if the blood pressure declines below the allocated target in at least 60% of the patients and at least 60% of time during general anesthesia, i.e., 60% of the registered blood pressures should be within +/- 10 mmHg of the target when vasopressor/inotropes are administered. | During surgery | 
| Feasibility: Proportion of patients with separation of mean arterial pressure | We aim to achieve at least 5 mmHg separation in mean/median mean arterial pressure for the three blood pressure groups targeting mean arterial pressure. | During surgery | 
| Feasibility: Proportion of patients lost to follow-up | We aim to obtain data from more than 90% of patients still alive at 30- and 90-days follow-up. | Up to 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with pulmonary post-operative complications (composite) | A composite of the following based on European Perioperative Clinical Outcome definitions: Respirator infection, respirator failure, pleural effusion, atelectasis, pneumothorax, bronchospasms, and aspiration pneumonitis. | 30 days | 
| Proportion of patient with pneumonia | Based on the United States of America Centers for Disease Control and Prevention (CDC) definition of pneumonia | 30 days | 
| Proportion of patient with pulmonary embolism | Presence of pulmonary embolus on computerized tomography (CT) or magnetic resonance (MR) imaging, or a high probability of pulmonary embolus based on ventilation perfusion scan. | 30 days | 
| Proportion of patient with acute kidney injury | Composite of post-operative renal complications using Kidney Disease Improving Global Outcomes (KDIGO) criteria | 30 days | 
| Creatinine | Measured in umol/L | 2 hours after the surgery | 
| Creatinine | Measured in umol/L | The day after the surgery | 
| Proportion of patient with major adverse cardiac events | A composite of the following based on European Perioperative Clinical Outcome definitions: Non-fatal cardiac arrest, acute myocardial infarction, congestive heart failure, new cardiac arrhythmia, and angina. | 30 days | 
| Troponin-I | Measured in ng/L | 2 hours after the surgery | 
| Troponin-I | Measured in ng/L | The day after the surgery | 
| Proportion of patients with myocardial injury after non-cardiac surgery | Post-operative troponin-I above the 99% percentile for the respective assay. | 3 days | 
| Alanine transaminase | Measured in U/L | 2 hours after the surgery | 
| Alanine transaminase | Measured in U/L | The day after the surgery | 
| Proportion of patients with emergence delirium | Based on the nursing delirium screening scale to evaluate emergence delirium 90-120 minutes after admission to the post-aesthesia care unit. | 2 hours after the surgery | 
| Proportion of patients with post-operative delirium | We will categorize delirium as delirium if this is either stated in the medical journal or retrospectively categorized as delirium if it meets pre-defined criteria based on the diagnostic and statistical manual of mental disorders, fifth edition from the American psychiatric association | 7 days | 
| Post-operative pain | Highest numeric rating scale (NRS) score (from 0 to 10 with higher scores indicating worse pain) documented | 2 hours after the surgery | 
| Opioid administered | Total opioid administered using morphine equivalent units. | 24 hours | 
| Proportion of patients with post-operative nausea and vomiting | Highest numeric rating scale (NRS) score (from 0 to 10 with higher scores indicating worse nausea and vomiting) documented | 2 hours after the surgery | 
| Antiemetic treatment | Administered antiemetic treatment (ondansetron, dexamethasone, cyclizine, droperidol, metoclopramide) within the first 24 hours after the operation. | 24 hours | 
| Proportion of patients with surgical site infections | Based on the United States of America Centers for Disease Control and Prevention (CDC) definition. | 30 days | 
| Clavien-Dindo grading of complications | In addition to reporting the individual post-operative complications, we will use the validated Clavien-Dindo classification to grade post-operative complications by the interventions needed. | 30 days | 
| Proportion of patients with intensive care unit admission | Both planned and unplanned stays at the intensive care unit. | 30 days | 
| Length of hospital stay | Reported in days. | Up to 90 days | 
| Days alive and out of the hospital | Reported in days. Patients that die during the 30 days, will receive a value of 0. All admissions at acute care hospitals in Denmark will be included in this outcome. | Within 30 days | 
| Proportion of patients with who die |  | 30 days | 
| Proportion of patients with who die |  | 90 days | 
| Health related quality of life | Based on the EQ-5D-5L questionnaire | 30 days | 
| Health related quality of life | Based on the EQ-5D-5L questionnaire | 90 days | 
| Proportion of patients with intraoperative complications | Specific complications occurring during the surgery: Bleeding, need of blood product transfusions, arrhythmia, pneumothorax, cardiac arrest, mortality. | During surgery | 
| Quality of recovery | Based on the quality of recovery-15 (QoR-15) score. The score ranges from 0-150 with higher scores indicating better recovery. | 30 days | 
| Quality of recovery | Based on the quality of recovery-15 (QoR-15) score. The score ranges from 0-150 with higher scores indicating better recovery. | 90 days |