Respiratory and Hemodynamic Targets During General Anesthesia (GA-TARGETS)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Patients Undergoing General Anesthesia
• Intervention / Treatment: Procedure: Blood pressure; Procedure: Positive end expiratory pressure; Procedure: Tidal volume; Procedure: Fraction of inspired oxygen

• Study Type: Interventional
• Enrollment (Estimated): 480
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Lars W Andersen; Phone Number: +4551781511; Email: lwandersen@clin.au.dk
• Study Contact Backup: Name: Maria B Pælestik; Email: marbolpe@rm.dk

Study Locations

• Denmark
  • Aalborg, Denmark
    • Not yet recruiting
    • Aalborg University Hospital
    • Contact: Olav Schjørring
  • Aarhus, Denmark
    • Not yet recruiting
    • Aarhus University Hospital
    • Contact: Maria B Pælestik
  • Gødstrup, Denmark
    • Not yet recruiting
    • Gødstrup Regional Hospital
    • Contact: Kristian K Hansen
  • Horsens, Denmark
    • Recruiting
    • Horsens Regional Hospital
    • Contact: Ulrick S Espelund
  • Randers, Denmark
    • Recruiting
    • Randers Regional Hospital
    • Contact: Leif Bach
  • Viborg, Denmark
    • Not yet recruiting
    • Viborg Regional Hospital
    • Contact: Christoffer Sølling

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

12

Arms and Interventions

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

What is the study measuring?

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
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
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
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

Collaborators and Investigators

• Sponsor: Lars Wiuff Andersen

Publications and helpful links

General Publications

• Hoybye M, Lind PC, Holmberg MJ, Bolther M, Jessen MK, Vallentin MF, Hansen FB, Holst JM, Magnussen A, Hansen NS, Johannsen CM, Enevoldsen J, Jensen TH, Roessler LL, Klitholm MP, Eggertsen MA, Caap P, Boye C, Dabrowski KM, Vormfenne L, Henriksen J, Karlsson M, Balleby IR, Rasmussen MS, Paelestik K, Granfeldt A, Andersen LW. Fraction of inspired oxygen during general anesthesia for non-cardiac surgery: Systematic review and meta-analysis. Acta Anaesthesiol Scand. 2022 Sep;66(8):923-933. doi: 10.1111/aas.14102. Epub 2022 Jun 23.
• Bolther M, Henriksen J, Holmberg MJ, Jessen MK, Vallentin MF, Hansen FB, Holst JM, Magnussen A, Hansen NS, Johannsen CM, Enevoldsen J, Jensen TH, Roessler LL, Caroe Lind P, Klitholm MP, Eggertsen MA, Caap P, Boye C, Dabrowski KM, Vormfenne L, Hoybye M, Karlsson M, Balleby IR, Rasmussen MS, Paelestik K, Granfeldt A, Andersen LW. Ventilation Strategies During General Anesthesia for Noncardiac Surgery: A Systematic Review and Meta-Analysis. Anesth Analg. 2022 Nov 1;135(5):971-985. doi: 10.1213/ANE.0000000000006106. Epub 2022 Oct 21.
• Bolther M, Henriksen J, Holmberg MJ, Granfeldt A, Andersen LW. Blood pressure targets during general anaesthesia for noncardiac surgery: A systematic review of clinical trials. Eur J Anaesthesiol. 2022 Nov 1;39(11):903-905. doi: 10.1097/EJA.0000000000001703. Epub 2022 Jul 5. No abstract available.
• Holst JM, Klitholm MP, Henriksen J, Vallentin MF, Jessen MK, Bolther M, Holmberg MJ, Hoybye M, Lind PC, Granfeldt A, Andersen LW. Intraoperative respiratory and hemodynamic strategies for reducing nausea, vomiting, and pain after surgery: Systematic review and meta-analysis. Acta Anaesthesiol Scand. 2022 Oct;66(9):1051-1060. doi: 10.1111/aas.14127. Epub 2022 Aug 22.

Study record dates

Study Major Dates

• Study Start (Actual): October 9, 2023
• Primary Completion (Estimated): March 31, 2024
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: August 10, 2023
• First Submitted That Met QC Criteria: September 14, 2023
• First Posted (Actual): September 21, 2023

Study Record Updates

• Last Update Posted (Actual): November 2, 2023
• Last Update Submitted That Met QC Criteria: November 1, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Other Study ID Numbers: 00005

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Six months after the publication of the last results, all de-identified individual patient data will be made available for data sharing. Procedures, including re-coding of key variables, will be put in place to allow for complete de-identification of the data. Data will be completely anonymized according to Danish law.

All relevant trial-related documents, including the protocol, data dictionary, and the main statistical code, will be shared along with the data. There will be no predetermined end date for the data sharing.

• IPD Sharing Access Criteria: Data will be available for any research purpose to all interested parties who have approval from an independent review committee and who have a methodological sound proposal as determined by the steering committee of the current trial. Only the methodological qualities and not the purpose or objective of the proposal will be considered. Interested parties will be able to request the data by contacting the principal investigator. Authorship of publications emerging from the shared data will follow standard authorship guidelines from the International Committee of Medical Journal Editors and might or might not include authors from the steering committee depending on the nature of their involvement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No