Alpha-2-adrenergic receptor agonists for the prevention of delirium and cognitive decline after open heart surgery (ALPHA2PREVENT): protocol for a multicentre randomised controlled trial

Bjørn Erik Neerland; Rolf Busund; Rune Haaverstad; Jorunn L Helbostad; Svein Aslak Landsverk; Ieva Martinaityte; Hilde Margrethe Norum; Johan Ræder; Geir Selbaek; Melanie R Simpson; Elisabeth Skaar; Nils Kristian Skjærvold; Eva Skovlund; Arjen Jc Slooter; Øyvind Sverre Svendsen; Theis Tønnessen; Alexander Wahba; Henrik Zetterberg; Torgeir Bruun Wyller

doi:10.1136/bmjopen-2021-057460

Alpha-2-adrenergic receptor agonists for the prevention of delirium and cognitive decline after open heart surgery (ALPHA2PREVENT): protocol for a multicentre randomised controlled trial

Bjørn Erik Neerland, Rolf Busund, Rune Haaverstad, Jorunn L Helbostad, Svein Aslak Landsverk, Ieva Martinaityte, Hilde Margrethe Norum, Johan Ræder, Geir Selbaek, Melanie R Simpson, Elisabeth Skaar, Nils Kristian Skjærvold, Eva Skovlund, Arjen Jc Slooter, Øyvind Sverre Svendsen, Theis Tønnessen, Alexander Wahba, Henrik Zetterberg, Torgeir Bruun Wyller

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Abstract

INTRODUCTION: Postoperative delirium is common in older cardiac surgery patients and associated with negative short-term and long-term outcomes. The alpha-2-adrenergic receptor agonist dexmedetomidine shows promise as prophylaxis and treatment for delirium in intensive care units (ICU) and postoperative settings. Clonidine has similar pharmacological properties and can be administered both parenterally and orally. We aim to study whether repurposing of clonidine can represent a novel treatment option for delirium, and the possible effects of dexmedetomidine and clonidine on long-term cognitive trajectories, motor activity patterns and biomarkers of neuronal injury, and whether these effects are associated with frailty status.

METHODS AND ANALYSIS: This five-centre, double-blind randomised controlled trial will include 900 cardiac surgery patients aged 70+ years. Participants will be randomised 1:1:1 to dexmedetomidine or clonidine or placebo. The study drug will be given as a continuous intravenous infusion from the start of cardiopulmonary bypass, at a rate of 0.4 µg/kg/hour. The infusion rate will be decreased to 0.2 µg/kg/hour postoperatively and be continued until discharge from the ICU or 24 hours postoperatively, whichever happens first.Primary end point is the 7-day cumulative incidence of postoperative delirium (Diagnostic and Statistical Manual of Mental Disorders, fifth edition). Secondary end points include the composite end point of coma, delirium or death, in addition to delirium severity and motor activity patterns, levels of circulating biomarkers of neuronal injury, cognitive function and frailty status 1 and 6 months after surgery.

ETHICS AND DISSEMINATION: This trial is approved by the Regional Committee for Ethics in Medical Research in Norway (South-East Norway) and by the Norwegian Medicines Agency. Dissemination plans include publication in peer-reviewed medical journals and presentation at scientific meetings.

TRIAL REGISTRATION NUMBER: NCT05029050.

Original language	English
Article number	e057460
Journal	BMJ Open
Volume	12
Issue number	6
DOIs	https://doi.org/10.1136/bmjopen-2021-057460
Publication status	Published - 1 Jun 2022

Bibliographical note

Funding Information:
The trial is funded by KLINBEFORSK, The National Programme for Clinical Therapy Research in the Specialist Health Service in Norway, grant number 2020204. HZ is a Wallenberg Scholar.

Publisher Copyright:
© 2022 BMJ Publishing Group. All rights reserved.

Copyright:
Copyright 2022 Elsevier B.V., All rights reserved.

Keywords

Adrenergic alpha-2 Receptor Agonists/therapeutic use
Aged
Cardiac Surgical Procedures/adverse effects
Clonidine/therapeutic use
Cognitive Dysfunction/etiology
Delirium/diagnosis
Dexmedetomidine/therapeutic use
Double-Blind Method
Frailty/complications
Humans
Multicenter Studies as Topic
Randomized Controlled Trials as Topic

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Neerland, B. E., Busund, R., Haaverstad, R., Helbostad, J. L., Landsverk, S. A., Martinaityte, I., Norum, H. M., Ræder, J., Selbaek, G., Simpson, M. R., Skaar, E., Skjærvold, N. K., Skovlund, E., Slooter, A. J., Svendsen, Ø. S., Tønnessen, T., Wahba, A., Zetterberg, H., & Wyller, T. B. (2022). Alpha-2-adrenergic receptor agonists for the prevention of delirium and cognitive decline after open heart surgery (ALPHA2PREVENT): protocol for a multicentre randomised controlled trial. BMJ Open, 12(6), Article e057460. https://doi.org/10.1136/bmjopen-2021-057460

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abstract = "INTRODUCTION: Postoperative delirium is common in older cardiac surgery patients and associated with negative short-term and long-term outcomes. The alpha-2-adrenergic receptor agonist dexmedetomidine shows promise as prophylaxis and treatment for delirium in intensive care units (ICU) and postoperative settings. Clonidine has similar pharmacological properties and can be administered both parenterally and orally. We aim to study whether repurposing of clonidine can represent a novel treatment option for delirium, and the possible effects of dexmedetomidine and clonidine on long-term cognitive trajectories, motor activity patterns and biomarkers of neuronal injury, and whether these effects are associated with frailty status.METHODS AND ANALYSIS: This five-centre, double-blind randomised controlled trial will include 900 cardiac surgery patients aged 70+ years. Participants will be randomised 1:1:1 to dexmedetomidine or clonidine or placebo. The study drug will be given as a continuous intravenous infusion from the start of cardiopulmonary bypass, at a rate of 0.4 µg/kg/hour. The infusion rate will be decreased to 0.2 µg/kg/hour postoperatively and be continued until discharge from the ICU or 24 hours postoperatively, whichever happens first.Primary end point is the 7-day cumulative incidence of postoperative delirium (Diagnostic and Statistical Manual of Mental Disorders, fifth edition). Secondary end points include the composite end point of coma, delirium or death, in addition to delirium severity and motor activity patterns, levels of circulating biomarkers of neuronal injury, cognitive function and frailty status 1 and 6 months after surgery.ETHICS AND DISSEMINATION: This trial is approved by the Regional Committee for Ethics in Medical Research in Norway (South-East Norway) and by the Norwegian Medicines Agency. Dissemination plans include publication in peer-reviewed medical journals and presentation at scientific meetings.TRIAL REGISTRATION NUMBER: NCT05029050.",

keywords = "Adrenergic alpha-2 Receptor Agonists/therapeutic use, Aged, Cardiac Surgical Procedures/adverse effects, Clonidine/therapeutic use, Cognitive Dysfunction/etiology, Delirium/diagnosis, Dexmedetomidine/therapeutic use, Double-Blind Method, Frailty/complications, Humans, Multicenter Studies as Topic, Randomized Controlled Trials as Topic",

author = "Neerland, {Bj{\o}rn Erik} and Rolf Busund and Rune Haaverstad and Helbostad, {Jorunn L} and Landsverk, {Svein Aslak} and Ieva Martinaityte and Norum, {Hilde Margrethe} and Johan R{\ae}der and Geir Selbaek and Simpson, {Melanie R} and Elisabeth Skaar and Skj{\ae}rvold, {Nils Kristian} and Eva Skovlund and Slooter, {Arjen Jc} and Svendsen, {{\O}yvind Sverre} and Theis T{\o}nnessen and Alexander Wahba and Henrik Zetterberg and Wyller, {Torgeir Bruun}",

note = "Funding Information: The trial is funded by KLINBEFORSK, The National Programme for Clinical Therapy Research in the Specialist Health Service in Norway, grant number 2020204. HZ is a Wallenberg Scholar. Publisher Copyright: {\textcopyright} 2022 BMJ Publishing Group. All rights reserved. Copyright: Copyright 2022 Elsevier B.V., All rights reserved.",

year = "2022",

month = jun,

day = "1",

doi = "10.1136/bmjopen-2021-057460",

language = "English",

volume = "12",

journal = "BMJ Open",

issn = "2044-6055",

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Neerland, BE, Busund, R, Haaverstad, R, Helbostad, JL, Landsverk, SA, Martinaityte, I, Norum, HM, Ræder, J, Selbaek, G, Simpson, MR, Skaar, E, Skjærvold, NK, Skovlund, E, Slooter, AJ, Svendsen, ØS, Tønnessen, T, Wahba, A, Zetterberg, H & Wyller, TB 2022, 'Alpha-2-adrenergic receptor agonists for the prevention of delirium and cognitive decline after open heart surgery (ALPHA2PREVENT): protocol for a multicentre randomised controlled trial', BMJ Open, vol. 12, no. 6, e057460. https://doi.org/10.1136/bmjopen-2021-057460

TY - JOUR

T1 - Alpha-2-adrenergic receptor agonists for the prevention of delirium and cognitive decline after open heart surgery (ALPHA2PREVENT)

T2 - protocol for a multicentre randomised controlled trial

AU - Neerland, Bjørn Erik

AU - Busund, Rolf

AU - Haaverstad, Rune

AU - Helbostad, Jorunn L

AU - Landsverk, Svein Aslak

AU - Martinaityte, Ieva

AU - Norum, Hilde Margrethe

AU - Ræder, Johan

AU - Selbaek, Geir

AU - Simpson, Melanie R

AU - Skaar, Elisabeth

AU - Skjærvold, Nils Kristian

AU - Skovlund, Eva

AU - Slooter, Arjen Jc

AU - Svendsen, Øyvind Sverre

AU - Tønnessen, Theis

AU - Wahba, Alexander

AU - Zetterberg, Henrik

AU - Wyller, Torgeir Bruun

N1 - Funding Information: The trial is funded by KLINBEFORSK, The National Programme for Clinical Therapy Research in the Specialist Health Service in Norway, grant number 2020204. HZ is a Wallenberg Scholar. Publisher Copyright: © 2022 BMJ Publishing Group. All rights reserved. Copyright: Copyright 2022 Elsevier B.V., All rights reserved.

PY - 2022/6/1

Y1 - 2022/6/1

N2 - INTRODUCTION: Postoperative delirium is common in older cardiac surgery patients and associated with negative short-term and long-term outcomes. The alpha-2-adrenergic receptor agonist dexmedetomidine shows promise as prophylaxis and treatment for delirium in intensive care units (ICU) and postoperative settings. Clonidine has similar pharmacological properties and can be administered both parenterally and orally. We aim to study whether repurposing of clonidine can represent a novel treatment option for delirium, and the possible effects of dexmedetomidine and clonidine on long-term cognitive trajectories, motor activity patterns and biomarkers of neuronal injury, and whether these effects are associated with frailty status.METHODS AND ANALYSIS: This five-centre, double-blind randomised controlled trial will include 900 cardiac surgery patients aged 70+ years. Participants will be randomised 1:1:1 to dexmedetomidine or clonidine or placebo. The study drug will be given as a continuous intravenous infusion from the start of cardiopulmonary bypass, at a rate of 0.4 µg/kg/hour. The infusion rate will be decreased to 0.2 µg/kg/hour postoperatively and be continued until discharge from the ICU or 24 hours postoperatively, whichever happens first.Primary end point is the 7-day cumulative incidence of postoperative delirium (Diagnostic and Statistical Manual of Mental Disorders, fifth edition). Secondary end points include the composite end point of coma, delirium or death, in addition to delirium severity and motor activity patterns, levels of circulating biomarkers of neuronal injury, cognitive function and frailty status 1 and 6 months after surgery.ETHICS AND DISSEMINATION: This trial is approved by the Regional Committee for Ethics in Medical Research in Norway (South-East Norway) and by the Norwegian Medicines Agency. Dissemination plans include publication in peer-reviewed medical journals and presentation at scientific meetings.TRIAL REGISTRATION NUMBER: NCT05029050.

AB - INTRODUCTION: Postoperative delirium is common in older cardiac surgery patients and associated with negative short-term and long-term outcomes. The alpha-2-adrenergic receptor agonist dexmedetomidine shows promise as prophylaxis and treatment for delirium in intensive care units (ICU) and postoperative settings. Clonidine has similar pharmacological properties and can be administered both parenterally and orally. We aim to study whether repurposing of clonidine can represent a novel treatment option for delirium, and the possible effects of dexmedetomidine and clonidine on long-term cognitive trajectories, motor activity patterns and biomarkers of neuronal injury, and whether these effects are associated with frailty status.METHODS AND ANALYSIS: This five-centre, double-blind randomised controlled trial will include 900 cardiac surgery patients aged 70+ years. Participants will be randomised 1:1:1 to dexmedetomidine or clonidine or placebo. The study drug will be given as a continuous intravenous infusion from the start of cardiopulmonary bypass, at a rate of 0.4 µg/kg/hour. The infusion rate will be decreased to 0.2 µg/kg/hour postoperatively and be continued until discharge from the ICU or 24 hours postoperatively, whichever happens first.Primary end point is the 7-day cumulative incidence of postoperative delirium (Diagnostic and Statistical Manual of Mental Disorders, fifth edition). Secondary end points include the composite end point of coma, delirium or death, in addition to delirium severity and motor activity patterns, levels of circulating biomarkers of neuronal injury, cognitive function and frailty status 1 and 6 months after surgery.ETHICS AND DISSEMINATION: This trial is approved by the Regional Committee for Ethics in Medical Research in Norway (South-East Norway) and by the Norwegian Medicines Agency. Dissemination plans include publication in peer-reviewed medical journals and presentation at scientific meetings.TRIAL REGISTRATION NUMBER: NCT05029050.

KW - Adrenergic alpha-2 Receptor Agonists/therapeutic use

KW - Aged

KW - Cardiac Surgical Procedures/adverse effects

KW - Clonidine/therapeutic use

KW - Cognitive Dysfunction/etiology

KW - Delirium/diagnosis

KW - Dexmedetomidine/therapeutic use

KW - Double-Blind Method

KW - Frailty/complications

KW - Humans

KW - Multicenter Studies as Topic

KW - Randomized Controlled Trials as Topic

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DO - 10.1136/bmjopen-2021-057460

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C2 - 35725264

SN - 2044-6055

VL - 12

JO - BMJ Open

JF - BMJ Open

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M1 - e057460

ER -

Alpha-2-adrenergic receptor agonists for the prevention of delirium and cognitive decline after open heart surgery (ALPHA2PREVENT): protocol for a multicentre randomised controlled trial

Abstract

Bibliographical note

Keywords

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