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Trial record 2 of 6 for:    "Brain Injury" | "Norepinephrine"

Target Hemodynamics and Brain Injury During General Anesthesia in the Elderly (THE BRIDGE)

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ClinicalTrials.gov Identifier: NCT02428062
Recruitment Status : Suspended (Pending Pilot study results evaluation)
First Posted : April 28, 2015
Last Update Posted : April 13, 2018
Sponsor:
Information provided by (Responsible Party):
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

Brief Summary:

BACKGROUND: Post-operative cognitive dysfunction (POCD) is a potentially irreversible loss of brain functions observed in elderly patients after surgical operations under general anaesthesia. POCD at 3 post-operative months is observed in up to 15% of patients aged 70 years and more, and the only recognized risk factor for this condition is increasing age. Importantly, the incidence of POCD at 3 months has been associated to an increased disability and mortality.

OBJECTIVES: The present study will evaluate in patients aged 75 years and older undergoing general anaesthesia for non-cardiac surgery, whether an hemodynamic strategy, aiming at maintaining intra-operative arterial blood pressure close to patient's preoperative blood pressure, i.e., to avoid hypotensive episodes, reduces the incidence of POCD at three months.

METHODS: Around 1800 consecutive patients scheduled to undergo general anaesthesia for elective non-cardiac surgery will be enrolled. Each patient's cognitive function will be evaluated preoperatively and at 3 months and 1 year postoperatively, together with the occurrence of hearing loss and vestibular function impairment. Furthermore, the incidence of postoperative delirium and cardiovascular, respiratory and infectious complications will be evaluated.

EXPECTED RESULTS: The primary outcome is a 25% relative reduction in the incidence of POCD at 3 postoperative months. Secondary outcomes are the reduction of POCD incidence at 1 postoperative year, a reduction in postoperative hearing loss and vestibular impairment at 3 months, a reduction in the incidence of delirium. Hospital length of stay and 90 day mortality will also be assessed. This present study could have a high socio-economic impact, reduce healthcare costs and patient morbidity and mortality with a simple not expensive intraoperative intervention.


Condition or disease Intervention/treatment Phase
Post-operative Cognitive Dysfunction Procedure: Hemodynamic target Drug: Phenylephrine Drug: Intravenous fluids Procedure: Patient's positioning Procedure: Reduction of depth of anesthesia Drug: Ephedrine Drug: Epinephrine Drug: Norepinephrine Drug: Dopamine Phase 2 Phase 3

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1812 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Effect of Target Intraoperative Blood Pressure on the Incidence of Post-operative Cognitive Dysfunction in Patients Aged 75 and Older Undergoing General Anesthesia for Non-cardiac Surgery: an International Multicenter Randomized Controlled Trial
Study Start Date : October 2014
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2019

Arm Intervention/treatment
No Intervention: Standard-of-Care
The intraoperative hemodynamic management of the patients assigned to this arm will be left to the discretion of the anesthesiologist, without any indication as to the intraoperative hemodynamic strategy to be adopted.
Experimental: Treatment
The anesthesiologist will have as hemodynamic target for patients assigned to this arm the maintenance of mean arterial blood pressure within 10% of the baseline blood pressure value (recorded at the preoperative evaluation). The strategy to reach this hemodynamic target will be left to the clinical judgment of the anaesthesiologist in charge. The possible strategies include a vasoconstrictor agent (either phenylephrine, ephedrine, epinephrine, norepinephrine or dopamine), intravenous fluids, patient's positioning or reduction of depth of anesthesia.
Procedure: Hemodynamic target

The anaesthesiologist is requested to maintain intraoperative mean arterial blood pressure of the patient within 10% of the baseline mean arterial blood pressure (recorded during the preoperative evaluation) of that patient. In order to reach this hemodynamic target the anesthesiologist can choose between one or more of the following four sub-interventions:

  1. vasoconstrictor agents (either phenylephrine, ephedrine, epinephrine, norepinephrine or dopamine)
  2. intravenous fluids
  3. patient's positioning
  4. reduction of depth of anesthesia

Drug: Phenylephrine
Phenylephrine 0.1-0.2 mg intravenous bolus
Other Name: Sub-intervention 1: Vasoconstrictor agent

Drug: Intravenous fluids
A crystalloid fluid bolus is given intravenously (5-10 ml/kg)
Other Name: Sub-intervention 2

Procedure: Patient's positioning
The operating table is positioned so that the patient's head lies below the level of the patient's feet (Trendelenburg position) in order to increase venous return
Other Name: Sub-intervention 3

Procedure: Reduction of depth of anesthesia
The halogenated anesthetic vapor's inspiratory fraction is decreased in order to reduce the associated peripheral vasodilation
Other Name: Sub-intervention 4

Drug: Ephedrine
Ephedrine 5-25 mg intravenous bolus
Other Name: Sub-intervention 1: Vasoconstrictor agent

Drug: Epinephrine
Epinephrine 5-10 mcg intravenous bolus
Other Name: Sub-intervention 1: Vasoconstrictor agent

Drug: Norepinephrine
Norepinephrine 0.01 - 0.1 mcg/kg/min intravenous continuous infusion
Other Name: Sub-intervention 1: Vasoconstrictor agent

Drug: Dopamine
Dopamine 5 - 10 mcg/kg/min intravenous continuous infusion
Other Name: Sub-intervention 1: Vasoconstrictor agent

No Intervention: Control
Subjects assigned to this arm will undergo the same geriatric, neuropsychologic and audiologic evaluations administered to patients of the "Standard-of-Care" and "Treatment" arms at the same time points (baseline, 3 months and 1 year). These subjects will not undergo any surgical procedure and will therefore not be evaluated for post-operative complications or delirium occurrence.



Primary Outcome Measures :
  1. Post-operative cognitive dysfunction (POCD) at 3 months [ Time Frame: 3 months after surgical operation ]

    For each of the neuropsychological tests a Z-score will be calculated. The Z score represents the magnitude of the deviation (in number of standard deviations) in the test results from the reference (Control Group).

    The Z-score is calculated as the difference between the baseline and the 3 months test result for a patient, corrected for the expected difference (the mean difference for that test observed in the Control Group), divided by the standard deviation of the mean difference for that test observed in the Control Group.

    From the Z-scores of the single tests a combined Z-score can be calculated. Patients in whom the difference (worsening) in the score at 3 months to the score at baseline in at least 2 tests will be greater than 2 standard deviations from the expected difference (i.e. Z-score ≥ 2 in at least 2 tests), will be diagnosed with POCD. Also patients in which the combined Z-score will be equal or greater than 2 will be diagnosed with POCD.



Secondary Outcome Measures :
  1. Post-operative cognitive dysfunction (POCD) at 1 year [ Time Frame: 1 year after surgical operation ]

    For each of the neuropsychological tests a Z-score will be calculated. The Z score represents the magnitude of the deviation (in number of standard deviations) in the test results from the reference (Control Group).

    The Z-score is calculated as the difference between the baseline and the 1 year test result for a patient, corrected for the expected difference (the mean difference for that test observed in the Control Group), divided by the standard deviation of the mean difference for that test observed in the Control Group.

    From the Z-scores of the single tests a combined Z-score can be calculated. Patients in whom the difference (worsening) in the score at 1 year to the score at baseline in at least 2 tests will be greater than 2 standard deviations from the expected difference (i.e. Z-score ≥ 2 in at least 2 tests), will be diagnosed with POCD. Also patients in which the combined Z-score will be equal or greater than 2 will be diagnosed with POCD.


  2. Post-operative delirium [ Time Frame: Within 7 days after surgical operation ]

    During the first postoperative week all patients will be evaluated on a daily basis for delirium occurrence by the CAM-ICU scale (Confusion Assessment Method for the ICU).

    The CAM-ICU scale defines delirium by the simultaneous occurrence of items 1, 2 and one between items 3 and 4. Items are listed below:

    1. Acute alteration of mental status or fluctuating mental status in the preceding 24 hours
    2. Inattention
    3. Altered level of consciousness (Richmond Agitation and Sedation Scale, RASS ≠ 0)
    4. Disorganized thinking

  3. Hearing loss at 3 months [ Time Frame: 3 months after surgical operation ]
    Clinical evaluation of worsening in hearing function

  4. Hospital length of stay [ Time Frame: Up to 30 days after surgical operation ]
    Number of days of hospitalization after the surgical operation

  5. Mortality [ Time Frame: 90 days ]
  6. Number of patients with at least one post-operative complication [ Time Frame: Within 7 days after surgical operation ]
    During the first postoperative week patients will be assessed on a daily basis for the occurrence of cardio-pulmonary (acute myocardial infarction, congestive heart failure, pulmonary embolism, cardiac arrest, atrial fibrillation, pneumonia), neurologic (ischemic or hemorrhagic stroke), renal or hemorrhagic complications.

  7. Hearing loss at 1 year [ Time Frame: 1 year after surgical operation ]
    Clinical evaluation of worsening in hearing function

  8. Vestibular dysfunction at 3 months [ Time Frame: 3 months after surgical operation ]
    Clinical evaluation of worsening of vestibular function

  9. Vestibular dysfunction at 1 year [ Time Frame: 1 year after surgical operation ]
    Clinical evaluation of worsening of vestibular function


Other Outcome Measures:
  1. Per protocol analysis of outcomes [ Time Frame: Up to 30 days after surgical operation, at 3 months and 1 year ]
    The incidence of the primary and secondary outcomes will be assessed in the Standard of Care arm vs the patients in the Treatment arm who spent at least 75% of the anesthesia time within the hemodynamic target (within 10% of baseline mean arterial blood pressure)

  2. Intraoperative hypotensive times [ Time Frame: Up to 30 days after surgical operation, at 3 months and 1 year ]
    The incidence of the primary and secondary outcomes will be assessed in relation to the absolute and relative time spent in any category of blood pressure defined as "hypotension" (either mild, moderate or severe) and to the absolute and relative time spent in each category of hypotension (mild, moderate or severe). This analysis will be performed on the entire patients population, irrespective of allocation arm.

  3. Intraoperative cerebral desaturations [ Time Frame: Up to 30 days after surgical operation, at 3 months and 1 year ]
    The incidence of the primary and secondary outcomes will be assessed in relation to the absolute and relative time spent with cerebral desaturation (non-invasive cerebral saturimetry < 50%) and to the magnitude of cerebral desaturation episodes. This analysis will be performed on the entire patients population, irrespective of allocation arm.

  4. Subgroup analyses [ Time Frame: Up to 30 days after surgical operation, at 3 months and 1 year ]

    The incidence of the primary and secondary outcomes will be assessed in the following subgroup of patients:

    age stratification categories (age 75-79; 80-84; ≥ 85) surgery stratification categories (minor vs major surgery) education level (<8 years; 8-13 years; > 13 years education) normotensive vs hypertensive patients non-frail patients vs cognitive frail patients




Information from the National Library of Medicine

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Ages Eligible for Study:   75 Years and older   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • any patient aged 75 years and more scheduled for elective non-cardiac surgery under general anesthesia.

Exclusion criteria:

  • Failure to obtain informed consent to the study;
  • Impossibility to perform scheduled geriatric and neuropsychological tests during the preoperative evaluation;
  • Mini-mental state examination score (corrected for age and education) ≤ 23 at the preoperative evaluation;
  • Patients scheduled to undergo intracranic neurosurgical procedures or vascular surgery;
  • Patients who have been subjected to a surgical procedure under general anesthesia in the preceding 6 months;
  • Patients with metastatic cancer; patients falling in the category of the American Society of Anaesthesiologists (ASA) physical status 4;
  • Patients already included in the study, i.e. second surgical procedure;

Inclusion criteria for the Control Group:

• Subjects of 75 years and more in whom no hospitalization or surgical procedure is scheduled in the following 3 months.

Exclusion criteria for the Control Group:

  • Failure to obtain informed consent to the study;
  • Impossibility to perform scheduled geriatric and neuropsychological tests during the baseline evaluation;
  • Mini-mental state examination score (corrected for age and scholarity) ≤ 23 at the baseline evaluation;
  • Subjects who have undergone a surgical procedure under general anesthesia in the preceding 6 months;
  • Subjects who have undergone an unexpected surgical procedure under general anesthesia in the timeframe between baseline 3 months evaluation.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02428062


Locations
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Italy
Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico; Via F. Sforza 35
Milano, Italy, 20135
Sponsors and Collaborators
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Investigators
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Principal Investigator: Luciano Gattinoni, MD, FRCP Dipartimento di anestesiologia terapia intensiva e scienze dermatologiche
Study Chair: Thomas Langer, MD Dipartimento di Anestesia, Rianimazione ed Emergenza Urgenza, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milano, Italy
Study Chair: Alessandro Santini, MD Dipartimento di anestesiologia terapia intensiva e scienze dermatologiche
Study Chair: Michael Quintel, MD, PhD University of Göttingen, Zentrum Anaesthesiologie-, Rettungs- und Intensivmedizin
Study Chair: Antonio Pesenti, MD Dipartimento di Emergenza Urgenza, Azienda Ospedaliera San Gerardo, Monza,Italy

Publications:
Novelli G., Papagno C., Capitani E., Laiacona N., Vallar G., Cappa S.F., Tre test clinici di ricerca e produzione lessicale. Taratura su soggetti normali, Archivio di Psicologia, Neurologia e Psichiatria 1986 oct-dec; vol. 47 (4): 477-506
Audiometria pratica : casi clinici / A. Cesarani ; [a cura di] A. Cesarani. - Torino : Omega Edizioni, 2012. - ISBN 8872415454.
Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD; Joint ESC/ACCF/AHA/WHF Task Force for Universal Definition of Myocardial Infarction; Authors/Task Force Members Chairpersons, Thygesen K, Alpert JS, White HD; Biomarker Subcommittee, Jaffe AS, Katus HA, Apple FS, Lindahl B, Morrow DA; ECG Subcommittee, Chaitman BR, Clemmensen PM, Johanson P, Hod H; Imaging Subcommittee, Underwood R, Bax JJ, Bonow JJ, Pinto F, Gibbons RJ; Classification Subcommittee, Fox KA, Atar D, Newby LK, Galvani M, Hamm CW; Intervention Subcommittee, Uretsky BF, Steg PG, Wijns W, Bassand JP, Menasche P, Ravkilde J; Trials & Registries Subcommittee, Ohman EM, Antman EM, Wallentin LC, Armstrong PW, Simoons ML; Trials & Registries Subcommittee, Januzzi JL, Nieminen MS, Gheorghiade M, Filippatos G; Trials & Registries Subcommittee, Luepker RV, Fortmann SP, Rosamond WD, Levy D, Wood D; Trials & Registries Subcommittee, Smith SC, Hu D, Lopez-Sendon JL, Robertson RM, Weaver D, Tendera M, Bove AA, Parkhomenko AN, Vasilieva EJ, Mendis S; ESC Committee for Practice Guidelines (CPG), Bax JJ, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Kirchhof P, Knuuti J, Kolh P, McDonagh T, Moulin C, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Torbicki A, Vahanian A, Windecker S; Document Reviewers, Morais J, Aguiar C, Almahmeed W, Arnar DO, Barili F, Bloch KD, Bolger AF, Botker HE, Bozkurt B, Bugiardini R, Cannon C, de Lemos J, Eberli FR, Escobar E, Hlatky M, James S, Kern KB, Moliterno DJ, Mueller C, Neskovic AN, Pieske BM, Schulman SP, Storey RF, Taubert KA, Vranckx P, Wagner DR. Third universal definition of myocardial infarction. J Am Coll Cardiol. 2012 Oct 16;60(16):1581-98. doi: 10.1016/j.jacc.2012.08.001. Epub 2012 Sep 5.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
ClinicalTrials.gov Identifier: NCT02428062     History of Changes
Other Study ID Numbers: TB-POCD
First Posted: April 28, 2015    Key Record Dates
Last Update Posted: April 13, 2018
Last Verified: April 2018
Keywords provided by Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico:
Post-operative complications
Mild cognitive impairment
Delirium
Additional relevant MeSH terms:
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Norepinephrine
Cognitive Dysfunction
Cognition Disorders
Neurocognitive Disorders
Mental Disorders
Phenylephrine
Dopamine
Epinephrine
Racepinephrine
Oxymetazoline
Ephedrine
Pseudoephedrine
Anesthetics
Epinephryl borate
Vasoconstrictor Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Adrenergic beta-Agonists
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Anti-Asthmatic Agents
Respiratory System Agents
Mydriatics
Sympathomimetics