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Trial registered on ANZCTR


Registration number
ACTRN12623001268639p
Ethics application status
Submitted, not yet approved
Date submitted
9/05/2023
Date registered
6/12/2023
Date last updated
6/12/2023
Date data sharing statement initially provided
6/12/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Safety and Efficacy of the Application of Photobiomodulation (PBM) on Intensive Care Unit (ICU) Patients with Acute Delirium
Scientific title
Safety and Efficacy of the Application of Photobiomodulation (PBM) on Intensive Care Unit (ICU) Patients with Acute Delirium
Secondary ID [1] 309613 0
Nil known to date
Universal Trial Number (UTN)
U1111-1292-2165
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute delirium 329931 0
Condition category
Condition code
Neurological 326837 326837 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
There is no gold standard treatment for delirium. Its presentation in people admitted to the Intensive Care Unit (ICU) is complex and it complicates treatment of other conditions requiring ICU admission. ICU patients with acute delirium can be a danger to themselves and others. Presence of delirium confers an adverse prognosis for ICU patients, and management of delirium when it occurs is largely supportive. There is an urgent need for the exploration of new treatment modalities to manage acute delirium in critically ill patients. One such alternative is photobiomodulation (PBM) therapy which is the use of specific wavelengths of light to induce activation of the mitochondrial electron transport chain of nerve cells and to impact cerebral blood flow.
Primary aim: To determine if the pre-defined PBM treatment protocol delivered using a proprietary device (Neuronic 1070) influences the clinical (QEEG) presentation of acute delirium in patients admitted to ICU.
Secondary aim: To determine if there are any adverse effects from the PBM treatment protocol.

Procedures, activities, and/or processes to be used (including enabling or support activities):
To address the primary aim we will assess changes in Quantitative EEG (QEEG) before and after implementation of the treatment protocol.
To address the secondary aim we will:
- assess changes in physiological parameters including Heart Rate Variability (HRV; weekly), Blood Pressure and Heart Rate (HR) before and after each application of the treatment;
- collect nursing observations of restlessness in the period immediately before and after each application;
- collate pathology results routinely collected daily in ICU (including electrolytes, urea and creatinine, liver function tests, full blood count, and blood sugar levels); and
- assess safety and tolerability of the treatment protocol.

Who will deliver the intervention and if relevant, their expertise?
The intervention will be delivered under medical (intensivist) supervision by intensive care nursing and/or physiotherapy staff. Staff likely to be applying the intervention will be trained in the safe application of the device, and its removal.

The mode of delivery and whether it will be provided individually or in a group:
The intervention will be applied in person by intensive care staff directly to individual eligible and consented participants.

Number of times the intervention will be delivered and over what period of time (number of sessions, the schedule, and duration, intensity, or dose):
The intervention is delivered using the Neuronic 1070 brain photobiomodulation helmet. The treatment protocol will titrate PBM up to 20 minutes twice daily in a stepwise daily exposure progression (3-6-9-12-16-20 min) thus reducing likelihood of overstimulation reactions. A set of 5 x pre-determined light stimulation protocols with different pulse rates, and intensity variables will be used daily on week days for 1 month or for the duration of ICU admission, whichever is shorter. A pulse frequency of light at 10Hz will stimulate EEG Alpha wave production through the process of neural entrainment and so supporting increased parasympathetic tone. Dosing will be twice daily Monday to Friday, with the first dose commencing after the commencement of the morning nursing staff shift (approximately 8am) and the second dose 6 hours later.
Each participant will receive an initial light sensitivity test, otherwise called Protocol 1. A light sensitivity test is necessary to understand whether a participant is sensitive to photonic energy. Patients' first use of PBM (i.e., Protocol 1) starts at 3 minutes duration with 75% intensity and pulsing frequency at 10Hz. A pulse frequency of light at 10Hz will stimulate EEG Alpha production through the process of neural entrainment and so supports increased parasympathetic tone. Should no perturbation be noted, the participant will advance to a treatment protocol.
The first consented patient will be treated with and continue with Protocol 2. The second consented participant will be treated with and continue with Protocol 3. The third participant who enters the study will receive Protocol 4, and the fourth participant will receive Protocol 5. Each subsequent participant will follow in the same manner (wherein the fifth participant will receive Protocol 2, sixth participant will receive Protocol 3 and so on until all participants have been recruited).
Treatment will be applied to the whole of the cranium to irradiate all brain networks. Each treatment protocol consists of the same treatment and rest times (3 minutes of treatment applied twice in the same session) with 10 minutes rest in between. The first 3-minute treatment is applied at 8Hz, and the second 3-minute treatment is applied at 10Hz. The intensity of applied photonic energy is lowest during Protocol 2 (at 25% and 50%) and is gradually increased in each subsequent protocol (up to 100% for each 3-minute treatment in Protocol 5). By titrating the applied dose by adjusting the percentage intensity, we hope to detect which dose may have the greatest brain responsiveness for reducing the behavioural signs of delirium.
Adherence to the intervention protocols will be monitored by audit of nursing bedside care records.

The location where the intervention occurs:
The Mater Adult Intensive Care Service, South Brisbane (either the Mater Hospital Brisbane (Salmon Building) Intensive Care Unit, or the Mater Private Hospital Brisbane Intensive Care Unit).
Intervention code [1] 326037 0
Treatment: Devices
Comparator / control treatment
No control group.
Within subject measures of change in the different protocols will be made by comparing baseline (pre-intervention) measure of QEEG and the post-intervention QEEG recording.
As this is an exploratory study, we will review the within-subject results at the end of the study, to decide whether and how to advance to the next stage of research.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 334692 0
Change in quantitative electroencephalography (QEEG) to determine cortical electrical activity of brainwaves (beta, alpha, theta and delta).
Timepoint [1] 334692 0
Once at: Baseline prior to commencement of intervention.
Once more: At end of intervention phase to assess for any changes.
Secondary outcome [1] 421709 0
Confusion Assessment Method for ICU (CAM-ICU) to determine effect of transcranial PBM on clinical status of diagnosed acute delirium in intensive care unit.
Timepoint [1] 421709 0
Baseline for diagnostic purposes.
Daily until intervention terminated (to determine if change in clinical status of delirium).
Secondary outcome [2] 421712 0
Heart rate variability (HRV) via 5-minute ECG recording to understand potential effects or side effects of transcranial PBM on autonomic nervous system activity.
Timepoint [2] 421712 0
Baseline
End of each week for 4 weeks (or sooner, if PBM intervention terminated).
Secondary outcome [3] 421713 0
Blood pressure (BP) measured by sphygmomanometer to understand potential effects or side effects of transcranial PBM on autonomic nervous system activity.
Timepoint [3] 421713 0
Baseline prior to commencement of PBM intervention.
Daily thereafter (before and after application) until intervention terminated.
Secondary outcome [4] 421714 0
To assess tolerability of transcranial PBM application, nursing observations of restlessness in period immediately before, during and after each PBM application. Nursing observations are recorded at the ICU bedside during each shift. The nursing notes will be retrospectively audited.
Timepoint [4] 421714 0
Baseline prior to commencement of PBM intervention.
Daily thereafter (before and after application) until PBM intervention terminated.
Secondary outcome [5] 421715 0
To assess safety of transcranial PBM pathology results routinely collected in ICU - electrolytes as obtained from routine ICU blood tests.
Timepoint [5] 421715 0
Baseline prior to commencement of PBM intervention.
Daily thereafter (before and after application) until PBM intervention terminated.
Secondary outcome [6] 421716 0
To assess safety of transcranial PBM pathology results routinely collected in ICU - urea and creatinine levels as obtained from routine ICU blood tests.
Timepoint [6] 421716 0
Baseline prior to commencement of PBM intervention.
Daily thereafter (before and after application) until PBM intervention terminated.
Secondary outcome [7] 421717 0
To assess safety of transcranial PBM pathology results routinely collected in ICU - liver function tests including alanine transaminase (ALT) and aspartate transaminase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), serum bilirubin, prothrombin time (PT), the international normalized ratio (INR), total protein and albumin, estimated globulins.
Timepoint [7] 421717 0
Baseline prior to commencement of PBM intervention.
Daily thereafter (before and after application) until PBM intervention terminated.
Secondary outcome [8] 421718 0
To assess safety of transcranial PBM pathology results routinely collected in ICU - full blood count.
Timepoint [8] 421718 0
Baseline prior to commencement of PBM intervention.
Daily thereafter (before and after application) until PBM intervention terminated.
Secondary outcome [9] 421719 0
To assess safety of transcranial PBM pathology results routinely collected in ICU - blood sugar levels.
Timepoint [9] 421719 0
Baseline prior to commencement of PBM intervention.
Daily thereafter (before and after application) until PBM intervention terminated.
Secondary outcome [10] 429306 0
Heart rate (HR; using oxygen saturation monitor or ECG as per availability for each patient in an ICU bed) to understand potential effects or side effects of transcranial PBM on autonomic nervous system activity.
Timepoint [10] 429306 0
Baseline prior to commencement of PBM intervention.
Daily thereafter (before and after application) until intervention terminated.

Eligibility
Key inclusion criteria
Patients in the ICU
Aged 18 years or older and
Who have been diagnosed with acute delirium using the CAM-ICU tool.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
(i) Pregnancy
(ii) Intracranial metal implants, e.g., Deep Brain Stimulator
(iii) Uncontrolled psychiatric condition within the last 3 months
(iv) Suspected acute drug or alcohol withdrawal
(v) Structural lesion on neuroimaging which excludes a diagnosis of delirium

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Five pre-determined light stimulation protocols with different pulse rates and intensity variables will be investigated.
All protocols are pre-set to initiate light stimulation on the four brain quadrants equally and simultaneously and will integrate non-stimulation steps to avoid over-stimulation of the brain.
Each participant will receive an initial light sensitivity test.
Protocol 1 is a light sensitivity test necessary to understand whether a participant is sensitive to photonic energy. Patients' first use of PBM starts at 3 minutes duration with 75% intensity and pulsing frequency at 10Hz. A pulse frequency of light at 10Hz will stimulate EEG Alpha production through the process of neural entrainment and so supports increased parasympathetic tone.
Should no perturbation be noted, the participant will advance to a treatment protocol. The first consented patient will be treated with and continue with Protocol 2. The second consented participant will be treated with and continue with Protocol 3. The third participant who enters the study will receive Protocol 4, and the fourth participant will receive Protocol 5. Each subsequent participant will follow in the same manner (wherein the fifth participant will receive Protocol 2, sixth participant will receive Protocol 3 and so on until all participants have been recruited).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
As this is a preliminary observational case series, no power calculations have been performed.
This is an exploratory study.
QEEG results will be analysed by building pre-/post-intervention spectrograms (a.k.a. colour spectral array or colour density spectral array) to see if there are brainwave frequency changes. Spectrograms display a plot of time (x axis), frequency (y axis), and power (as colour). The latter is further categorised in to absolute and relative power. Amplitude asymmetry, coherence and phase lag for each frequency can also be mapped. The QEEG analysis is done using normative database comparisons of scalp voltage measurements at the standard 19 locations outlined in the international 10-20 measurement system. Impedance <10 kO and test retest and split half reliability = >0.90.
Descriptive statistics and parametric and non-parametric tests will be applied as relevant to the variables collected.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
17/12/2023
Actual
Date of last participant enrolment
Anticipated
30/06/2024
Actual
Date of last data collection
Anticipated
29/08/2024
Actual
Sample size
Target
12
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 24698 0
Mater Hospital Brisbane - South Brisbane
Recruitment hospital [2] 24699 0
Mater Private Hospital Brisbane - South Brisbane
Recruitment postcode(s) [1] 40309 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 313793 0
Other Collaborative groups
Name [1] 313793 0
Mater Hospital Brisbane
Country [1] 313793 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Mater Research
Address
Aubigny PlaceRaymond TerraceSouth Brisbane Queensland 4101
Country
Australia
Secondary sponsor category [1] 315625 0
Commercial sector/Industry
Name [1] 315625 0
Neuronic
Address [1] 315625 0
Quietmind Foundation, 6060 Lyceum Ave, Philadelphia, PA 19128
Country [1] 315625 0
United States of America
Other collaborator category [1] 282672 0
Commercial sector/Industry
Name [1] 282672 0
Neuronic
Address [1] 282672 0
Quietmind Foundation, 6060 Lyceum Ave, Philadelphia, PA 19128
Country [1] 282672 0
United States of America

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 312960 0
Mater Misericordiae Ltd Human Research Ethics Committee
Ethics committee address [1] 312960 0
Aubigny Place, Raymond Terrace,South Brisbane, Queensland 4101
Ethics committee country [1] 312960 0
Australia
Date submitted for ethics approval [1] 312960 0
08/05/2023
Approval date [1] 312960 0
Ethics approval number [1] 312960 0

Summary
Brief summary
Patients who are admitted to the Intensive Care Unit (ICU) are at high risk of developing delirium, a form of acute brain failure which can manifest with agitation and confusion, and/or withdrawal from interaction. When delirium occurs, the overall prognosis for the hospital stay is adversely affected, and there is a risk of future cognitive decline and dementia. There is no gold standard treatment for delirium. Its presentation in people admitted to the Intensive Care Unit (ICU) is complex and it complicates treatment of other conditions requiring ICU admission. ICU patients with acute delirium can be a danger to themselves and others. Presence of delirium confers an adverse prognosis for ICU patients, and management of delirium when it occurs is largely supportive. There is an urgent need for the exploration of new treatment modalities to manage acute delirium in critically ill patients. This exploratory study assesses the application of a helmet (twice daily from Monday to Friday, for up to 4 weeks) that delivers pulses of near-infrared light to the brain in patients admitted to the Mater Adult Intensive Care Service who are diagnosed with acute delirium. Four slightly different protocols (with variations of application parameters) will be used. Patients enrolled in the study will have assessment of brainwaves using Quantitative Electroencephalography (QEEG) before and after treatment. Other behavioural and physiological observations that are routinely collected and recorded in the medical record in ICU patients will also be assessed.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 126490 0
Dr Liisa Laakso
Address 126490 0
Mater ResearchAubigny PlaceRaymond TerraceSouth Brisbane QLD 4101
Country 126490 0
Australia
Phone 126490 0
+61 7 419686134
Fax 126490 0
Email 126490 0
Liisa.Laakso@mater.uq.edu.au
Contact person for public queries
Name 126491 0
Dr Liisa Laakso
Address 126491 0
Mater ResearchAubigny PlaceRaymond TerraceSouth Brisbane QLD 4101
Country 126491 0
Australia
Phone 126491 0
+61 7 419686134
Fax 126491 0
Email 126491 0
Liisa.Laakso@mater.uq.edu.au
Contact person for scientific queries
Name 126492 0
Dr Liisa Laakso
Address 126492 0
Mater ResearchAubigny PlaceRaymond TerraceSouth Brisbane QLD 4101
Country 126492 0
Australia
Phone 126492 0
+61 7 419686134
Fax 126492 0
Email 126492 0
Liisa.Laakso@mater.uq.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The study is exploratory and recruits participants via consent by a substitute decision maker not the necessarily the participant themselves.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.