Dexmedetomidine to Lessen Intensive Care Unit (ICU) Agitation (DahLIA)

A Randomised, Double-blind, Multi-centre Placebo Controlled Trial of Dexmedetomidine for Patients With Agitation and Delirium in the Intensive Care Unit

The primary aim of the DahLIA trial is to determine, in patients with ICU-associated delirium and agitation who are otherwise pathophysiologically stable (as defined), the number of ventilator-free hours in the incident ICU admission in the 7 days following commencement of trial medication, in patients randomised to receive dexmedetomidine or placebo while receiving all other aspects of standard care.

The null hypothesis assumes no difference in the median number of ventilator-free hours in this ICU admission in the following 7 days, between patients receiving dexmedetomidine and placebo for ICU-associated agitation and delirium.

Study Overview

• Status: Completed
• Conditions: Delirium
• Intervention / Treatment: Drug: Dexmedetomidine; Drug: Saline placebo

• Study Type: Interventional
• Enrollment (Actual): 96
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • St Leonards, New South Wales, Australia, 2065
      • Royal North Shore Hospital
  • Queensland
    • Toowoomba, Queensland, Australia, 4350
      • Toowoomba Hospital
  • Victoria
    • Epping, Victoria, Australia, 3076
      • Northern Hospital
    • Footscray, Victoria, Australia, 3011
      • The Western Hospital
    • Melbourne, Victoria, Australia, 3084
      • Austin Hospital
    • Prahran, Victoria, Australia, 3181
      • The Alfred Hospital
  • Western Australia
    • Perth, Western Australia, Australia, 6001
      • Royal Perth Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patients will be eligible for the study if, in the opinion of the treating clinician, they continue to require mechanical ventilation only because their degree of agitation requires such a high dose of sedative medication (midazolam or propofol, the only commonly used specific sedatives in our unit) that extubation is not possible, AND in the opinion of their treating intensivist their agitation is so severe as to make lessening their sedation unsafe.

These criteria will be objectively quantified as follows:

• they have required either mechanical restraint and/or anti-delirium or sedative medication in the 4 hours prior to seeking consent AND
• their Confusion Assessment Method for the ICU (CAM-ICU) test is positive for delirium in the 4 hours prior to seeking consent AND
• their Motor Activity Assessment Scale (MAAS) score is 5 or more in the 4 hours prior to seeking consent, confirming psychomotor agitation AND
• their SOFA score is less than or equal to 5 in the 4 hours prior to seeking consent, predicting a mortality or around 5%.

Exclusion Criteria:

• Age less than 18 years old
• Pregnancy or breastfeeding
• Advanced dementia (in the premorbid state requiring professional nursing care)
• Open or closed head injury
• Death is deemed imminent and inevitable
• The patient has previously been enrolled in the DahLIA study

• Patients who could not be extubated, or who would be intubated within the following 48 hours, even if delirium or agitation were corrected. This will include:

  • Patients receiving high dose opioid for analgesia (not sedation) ( > 40 mg/morphine/day)
  • Patients shortly to return to the operating theatre
  • Patients undergoing repeated invasive procedures, in whom it is desirable to maintain deep sedation
  • Patients likely to require ongoing airway protection or control, or ventilatory support (for example, spinal patients with an inadequate vital capacity)
• Known allergy to haloperidol or alpha 2 agonists

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dexmedetomidine; Dexmedetomidine will be administered intravenously as a maintenance infusion of 0.2 to 1.5 mcg/kg/hour, commencing at 0.5 mcg/kg/hour and titrated according to effect, for as long as deemed necessary by the treating physician. Specifically, the study medication may be (as recommended by the manufacturer) continued after extubation, and if discontinued may be restarted at any time up until ICU discharge. The clinician will have the option of using a loading dose of 1.0 mcg/kg IV over 20 minutes, as recommended by the manufacturer. Bedside nursing staff will adjust drug infusion rates as necessary, in consultation with the treating physician, aiming to achieve a Riker Sedation-Agitation Scale 20 score of 4.	Drug: Dexmedetomidine; Dexmedetomidine will be administered intravenously as a maintenance infusion of 0.2 to 1.5 mcg/kg/hour, commencing at 0.5 mcg/kg/hour and titrated according to effect, for as long as deemed necessary by the treating physician. Specifically, the study medication may be (as recommended by the manufacturer) continued after extubation, and if discontinued may be restarted at any time up until ICU discharge. The clinician will have the option of using a loading dose of 1.0 mcg/kg IV over 20 minutes, as recommended by the manufacturer. Bedside nursing staff will adjust drug infusion rates as necessary, in consultation with the treating physician, aiming to achieve a Riker Sedation-Agitation Scale 20 score of 4.; Other Names: Precedex
Placebo Comparator: Saline placebo; An identical syringe to that in the intervention arm, but which does not contain dexmedetomidine, will be provided. The initial rate of infusion and subsequent adjustments will be the same as in the dexmedetomidine group.	Drug: Saline placebo; An identical syringe containing only saline with no dexmedetomidine added will be supplied. Initial rate of infusion and subsequent adjustments will be the same as in the active comparator group.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ventilator-free hours	The primary outcome measure for the study will be the number of ventilator-free hours in the incident ICU admission in the 7 days following commencement of trial medication, in patients randomised to receive dexmedetomidine or normal saline placebo while receiving all other aspects of standard care.	7 days following randomisation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to ICU discharge		On hospital discharge, or 6 months (whichever is sooner)
Overall ICU length of stay		On hospital discharge, or 6 months (whichever is sooner)
Time to first extubation		On hospital discharge, or 6 months (whichever is sooner)
Time taken to achieve a satisfactory sedation score	Time taken to achieve RASS score -2 to +1 and RIKER score 3 or 4	7 days following randomisation
%ICU time spent with a satisfactory sedation score	%ICU time spent with RASS -2 to +1 and RIKER 3 or 4	7 days following randomisation
%ICU time spent with a satisfactory delirium score	% time spent with a negative CAM-ICU assessment	7 days following randomisation
Time taken to achieve a satisfactory agitation score	Time taken to achieve a MAAS score 2-4	7 days following randomisation
%ICU time spent with a satisfactory agitation score	%ICU time spent with a MAAS score 2-4	7 days following randomisation
Need for supplementary sedative medication	total infusion time, mean hourly dose and total dose of propofol, morphine and midazolam.	7 days following randomisation
Need for mechanical restraint	Time to first not requiring restraint and % ICU time spent without mechanical restraint in the 7 days following commencement of trial medication	7 days following randomisation
Need for supplementary antipsychotic medication	Number of doses and total mg delivered of haloperidol, olanzapine, quetiapine, or other anti-psychotic medication as prescribed by the treating physician	7 days following randomisation
Need for tracheostomy	Tracheostomy deemed to be necessary by the treating physician, and actually performed.	On hospital discharge, or 6 months (whichever is sooner)
Acute hospital length of stay	Total duration of admission to the acute hospital, prior to discharge to home or a skilled or unskilled nursing facility.	On hospital discharge, or 6 months (whichever is sooner)
Discharge destination	Discharge to home, a skilled nursing facility, residential care, a physical rehabilitation facility, or death.	On hospital discharge, or 6 months (whichever is sooner)
Daily SOFA score	Daily SOFA score with recording of the component parts	7 days following randomisation
ICU mortality	ICU mortality	On hospital discharge, or 6 months (whichever is sooner)
Hospital mortality	Death in the acute care hospital	On hospital discharge, or 6 months (whichever is sooner)
Duration and rate of vasopressor support	total infusion time, and mean hourly dose of noradrenaline and any other inotrope or vasopressor	7 days following randomisation
Need for insertion of a new central venous catheter to facilitate vasopressor / inotropic support		7 days following randomisation
Requirement for reintubation	Reintubation of the trachea to facilitate airway protection or mechanical ventilation, as indicated in the opinion of the treating physician	On hospital discharge, or 6 months (whichever is sooner)

Collaborators and Investigators

• Sponsor: Austin Health
• Collaborators: Hospira, now a wholly owned subsidiary of Pfizer
• Investigators: Study Chair: Michael C Reade, MBBS DPhil, Austin Hospital & University of Melbourne; Principal Investigator: Rinaldo Bellomo, MD, Austin Hospital and University of Melbourne; Principal Investigator: John Mulder, MBChB, Western Hospital, Melbourne; Principal Investigator: Ben Cheung, MBBS, Toowoomba Hospital; Principal Investigator: Anthony Delaney, MBBS, Royal North Shore Hospital; Principal Investigator: Andrew Davis, MBBS, The Alfred; Principal Investigator: Steve Webb, MBBS, Royal Perth Hospital; Principal Investigator: Michael Bailey, MSc PhD, Monash University; Principal Investigator: Glenn Eastwood, BNurs RN, Austin Hospital, Melbourne Australia

Publications and helpful links

General Publications

• Reade MC, Eastwood GM, Bellomo R, Bailey M, Bersten A, Cheung B, Davies A, Delaney A, Ghosh A, van Haren F, Harley N, Knight D, McGuiness S, Mulder J, O'Donoghue S, Simpson N, Young P; DahLIA Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group. Effect of Dexmedetomidine Added to Standard Care on Ventilator-Free Time in Patients With Agitated Delirium: A Randomized Clinical Trial. JAMA. 2016 Apr 12;315(14):1460-8. doi: 10.1001/jama.2016.2707. Erratum In: JAMA. 2016 Aug 16;316(7):775.

Study record dates

Study Major Dates

• Study Start: February 1, 2011
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: June 18, 2010
• First Submitted That Met QC Criteria: June 28, 2010
• First Posted (Estimate): June 29, 2010

Study Record Updates

• Last Update Posted (Estimate): January 21, 2015
• Last Update Submitted That Met QC Criteria: January 18, 2015
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Keywords: Intensive Care Unit; Dexmedetomidine; Delirium
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Delirium; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Hypnotics and Sedatives; Dexmedetomidine
• Other Study ID Numbers: H2010/03891