Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001335886
Ethics application status
Approved
Date submitted
10/08/2021
Date registered
5/10/2021
Date last updated
17/05/2023
Date data sharing statement initially provided
5/10/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Survivorship of Patients post Long Intensive care stay, Exploration/Experience in a New Zealand cohort.
Scientific title
Survivorship of Patients post Long Intensive care stay, Exploration/Experience in a New Zealand cohort.
Secondary ID [1] 305004 0
Nil known
Universal Trial Number (UTN)
Trial acronym
SPLIT ENZ
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Post Intensive Care Syndrome 323165 0
disability 323166 0
Recovery post critical illness 323167 0
Condition category
Condition code
Other 320753 320753 0 0
Conditions of unknown or disputed aetiology (such as chronic fatigue syndrome/myalgic encephalomyelitis)
Mental Health 320980 320980 0 0
Other mental health disorders
Neurological 320981 320981 0 0
Other neurological disorders
Public Health 320982 320982 0 0
Health service research

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
There is a growing emphasis on the survivorship journey, morbidity, and poor quality of life for patients post Critical Illness (Hodgson et al. 2017). New or worsening of impairments in any of the physical, mental health or cognitive function is collectively known as the Post Intensive Care Syndrome (PICS) a common occurrence post critical illness (Needham et al. 2012). Not only do impairments relating to cognition, mental health, and physical function create new and lasting disability, but quality of life, return to work and social aspects, are also affected. This observational study will be the first of its kind in New Zealand exploring level of disability, quality of life, impairments in Mental health, cognition, and physical function in patients discharged from Wellington Hospital ICU. This study overall will be a mixed methods design (observational and qualitative). The first component is a prospective cohort study using validated tools (questionnaires) to assess and quantify the level of disability in the 12 months following critical illness. Functional disability will be assessed using WHODAS 2.0. Other important variables related to disability are Health-related quality of life, mental health, and cognition; and these will be assessed post-discharge, and after six months and 12 months using the following:
• Health-related Quality of Life: EQ-5D-5L derived health utilities
• Mental health– Impact of events Scale Revised (IES-R), Hospital Anxiety and Depression scale (HADS), Cognitive function - The Montreal Cognitive Assessment – Blind (MOCA-Blind)

All questionnaires will be delivered by the research coordinator over the phone. The questionnaires will likely take around 25 mins which the research team and ETHICS panel felt was manageable for participants and are also a minimum core set of tools to evaluate PICS suggested by Critical Care Experts (Needham et al. 2018; Mikkelsen et al. 2020).

The second component is a qualitative study that will explore the process of recovery for participants. The major impetus will be to identify the ongoing needs (met and unmet) in the year following critical illness, (aim III of the study). This design will use a nested convenience sample conducting semi-structured Interviews, conducted by the primary coordinating investigator at around 6-8 months post discharge home.
This part of the study will use grounded theory, so sample size cannot be pre-determined, however it is anticipated that around 10-20 participants may be used (the first 10-20 participants who are called at the 6 months follow up). The interviews will be wherever the participant chooses to be conducted, but preference will be for the participants home (with other options offered such as a meeting room in the hospital, or via ZOOM or over the phone).
Intervention code [1] 321399 0
Early Detection / Screening
Comparator / control treatment
no control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 328562 0
The proportion of participants who score 'mild', 'moderate' or 'severe' level of disability according to WHODAS 2.0 scores will be assessed as the primary composite outcome dichotomised into mild, moderate, severe level of disability:
The total score between 0 and 48, is then divided by 48 and multiplied by 100 to convert it to a percentage of maximum disability.
• No disability 0–4%
• Mild disability 5–24%
• Moderate disability 25–49%
• Severe disability 50–95%
• Complete disability 96–100%
Timepoint [1] 328562 0
At 1 month, 6 months and 12 months post hospital discharge
Secondary outcome [1] 399433 0
EQ-5D-5L - Health Related Quality of Life (HRQOL)
Measured in five domains: mobility, personal care, usual activities, pain, anxiety, and depression.
Each dimension has five levels (‘no problems’ = 1 to ‘extreme problems’ = 5).
Timepoint [1] 399433 0
At 1 month, 6 months and 12 months post hospital discharge
Secondary outcome [2] 399437 0
Hospital Anxiety and Depression Scale (HADS) - depression subscale
For the 14 questions, a four-point Likert scale (range 0–3) gives a possible score of 0 (none) to 21 (severe) for each of the two subscales (Depression)
• 0-7 indicate normal/no anxiety or depression
• 8 to 10 indicate clinically significant anxiety or depression symptoms (borderline cases)
• >11 indicate severe psychological distress
Timepoint [2] 399437 0
At 1 month, 6 months and 12 months post hospital discharge
Secondary outcome [3] 399439 0
Impact of Events Scale Revised (IES-r) - PTSS/PTSD.
The IES-R yields a total score (ranging from 0 to 88) and subscale scores can also be calculated for the Intrusion, Avoidance, and Hyperarousal subscales. However, only the total score will be used in the analysis. The total mean IES-R score = The sum of the means of the three subscale scores. The maximum mean score on each of the three subscales is ‘4’, therefore the maximum ‘total mean’ IES- R score is 12. A total IES-R score of 33 or over from a theoretical maximum of 88 signifies the likely presence of PTSD.
Timepoint [3] 399439 0
At 1 month, 6 months and 12 months post hospital discharge
Secondary outcome [4] 399443 0
Montreal Cognitive Assessment (MOCA-blind) - telephone delivered cognitive screening tool.
Timepoint [4] 399443 0
At 1 month, 6 months and 12months post hospital discharge
Secondary outcome [5] 399445 0
Return to work - WHODAS 2.0
Timepoint [5] 399445 0
At 1 month, 6 months and 12 months post hospital discharge
Secondary outcome [6] 399446 0
Needs unmet will be assessed during semi-structured one-on-one audio recorded qualitative interviews of up to 1 hour duration in the first 10-20 participants (who consent). this will be asked at the 6-month follow up call.
Timepoint [6] 399446 0
at 6-8 months post hospital discharge
Secondary outcome [7] 401143 0
Hospital Anxiety and Depression Scale (HADS) - Anxiety subscale
For the 14 questions, a four-point Likert scale (range 0–3) gives a possible score of 0 (none) to 21 (severe) for each of the two subscales
• 0-7 indicate normal/no anxiety or depression
• 8 to 10 indicate clinically significant anxiety or depression symptoms (borderline cases)
• >11 indicate severe psychological distress
Timepoint [7] 401143 0
At one month, 6 months and 12 months post discharge

Eligibility
Key inclusion criteria
All patient participants will be adult ICU patients admitted to Wellington ICU who are > 18 years old, been in an ICU for seven or more consecutive days, or patients who were mechanical ventilated for >48 hours. Patients who have been in another New Zealand ICU/Critical Care Unit prior to retrieval to Wellington ICU will be included once both admissions = >7 days.

Mechanical Ventilation is defined as a positive pressure ventilation (PPV) mode via an Endotracheal, Nasotracheal or Tracheostomy tube. Patients who have been extubated from PPV for a period and then reintubated are also included if both periods of PPV exceed 72 hours.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients who are < 18 years old
• Non-English speakers
• Patients not expected to survive their hospital stay (deemed by ICU Senior Medical Officer (SMO) once inclusion criteria met).
• Patients in whom follow up would be challenging/impossible (e.g., prisoners, people who are homeless).
• Patients with pre-existing neuromuscular disorder (e.g., Muscular Dystrophy, Multiple Sclerosis, Myasthenia Gravis, Guillain Barre).
• Neurovascular/neurotrauma/status epilepticus.
• Patients who have hypoxic/ischemic brain injury/encephalopathy.
• Significant pre-existing psychiatric disease or intellectual disability such that the patient was mentally, cognitively, or functionally impaired prior to ICU admission.
• Patients with diagnosed neurodegenerative disease
• Patients with prior moderate to severe cognitive impairment (as recorded in the patient health records/medical notes).
• Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant’s ability to participate in the trial.


Study design
Purpose
Screening
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Continuous variables will be described by mean and standard deviation (SD); median and inter-quartile range, and minimum to maximum. Where appropriate frequency histograms and boxplots will also be used to summarise data distributions. Categorical variables will be described by numerators and denominators and proportions expressed as percentages.

Proportions will be estimated together with confidence intervals by standard binomial methods. It is anticipated that asymptotic methods for the confidence intervals will be satisfactory, but should there be many small frequency counts exact binomial methods will also be used (Aim I).

Associations between disability measured by the WHODAS and potential univariate predictors will be by logistic regression with disability categorized and moderate/severe versus lesser degrees of disability. As a sensitivity analysis WHODAS will be treated on a continuous scale and ordinary regression used. For the latter normality assumptions will be assessed by residual analyses to determine if a data transformation will be needed or if another form of regression such as ordinal regression might be more suitable. With the anticipated 25-30 participants with moderate/severe disability this gives limited scope for multivariate analysis but as discussed below a more limited number of potential predictors will be used in a multivariate model to determine if associations remain after adjusting for confounding.

We selected a priori the following covariates as potential predictors of disability after intensive care admission:

Age, Gender, Ethnicity, APACHE II score, SOFA score, duration of sepsis (days), frailty score, Functional Comorbidity Index, length of ICU stay reported in days, presence of ICU-AW (reported as a dichotomous outcome), duration of mechanical ventilation (in hours), duration of delirium (reported as days the patient was CAM-ICU positive), total doses of sedation, benzodiazepines, and neuromuscular blockade drugs (NMBA’s), prior history of depression, anxiety or PTSD (obtained from medical records, ICU database admission and MAP) and whether the ICU admission was for Cardiothoracic surgery and/or cardiopulmonary bypass. Drug doses (sedation, benzodiazepines, MNBA’s) will be transformed into mean doses per day and analysed over number of days received.

Each of those potential predictors will be examined by univariate predictors with accompanying illustrative plots. In general, the analysis strategy will treat disability as a dichotomous variable and use logistic regression to estimate odds ratios for association and as discussed to explore linear regression and ordinal regression treating the WHODAS as a continuous response variable and possibly as an ordinal response variable. Although the primary interest is in disability after 12 months the associations at earlier points; one month and six months, will also be estimated. At least one author has categorized disability based on the WHODAS-12 as: none, mild, and moderate to severe disability (Karnatovskaia et al. (2017); however, it is likely to be more useful to explore if the instrument can be used on its native scale or use ordinal regression based on the full range of scores rather than other cut-off values.

Although not directly related to the study aims, mortality will also be assessed using Kaplan-Meier curves and associated estimates of median, or where relevant other percentiles, survival.

The PICS questionnaire (Jeong & Kang, 2019) is a novel tool which has not been described in a New Zealand clinical sample of ICU survivors. This instrument can be described using an overall raw score from the questionnaire which has a range of zero to 54, with higher scores indicating more severe PICS. The association between this instrument and other important outcomes will be estimated as a form of criterion validity. The associated variables will be: HADS, IES-(r), MOCA-blind, and WHODAS. This will be by linear regression in the first instance with associated plots and if normality assumptions are not met for these analysis by attempting data transformation or ordinal regression. Another association of interest is between the DASS-21 and HADS.


Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/02/2022
Actual
19/01/2022
Date of last participant enrolment
Anticipated
1/07/2023
Actual
Date of last data collection
Anticipated
1/07/2024
Actual
Sample size
Target
125
Accrual to date
26
Final
Recruitment outside Australia
Country [1] 24036 0
New Zealand
State/province [1] 24036 0
Wellington, Waikato and Christchurch

Funding & Sponsors
Funding source category [1] 309384 0
Charities/Societies/Foundations
Name [1] 309384 0
Wellington Medical Research Foundation: Research for life 2021/333
Country [1] 309384 0
New Zealand
Funding source category [2] 309723 0
Charities/Societies/Foundations
Name [2] 309723 0
Perpetual Guardian: Nursing Education funding
Country [2] 309723 0
New Zealand
Funding source category [3] 309724 0
Hospital
Name [3] 309724 0
ICU, Wellington Hospital
Country [3] 309724 0
New Zealand
Primary sponsor type
University
Name
University Of Otago, Wellington
Address
University of Otago
Department of Psychological Medicine
23A Mein Street, Newtown
Wellington
6021
Country
New Zealand
Secondary sponsor category [1] 310361 0
Hospital
Name [1] 310361 0
ICU, Wellington Hospital
Address [1] 310361 0
Intensive Care Unit, Level 3, Wellington regional hospital,
49 Riddiford street,
Newtown.
Wellington
6021
Country [1] 310361 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309199 0
Northern A Health and Disability Ethics Committee
Ethics committee address [1] 309199 0
Health and Disability Ethics Committees
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 309199 0
New Zealand
Date submitted for ethics approval [1] 309199 0
02/08/2021
Approval date [1] 309199 0
16/08/2021
Ethics approval number [1] 309199 0
21/NTA/107 – Approved Application

Summary
Brief summary
This study will be a mixed methods design. The first component is a prospective cohort study using validated tools (questionnaires) to assess and quantify the level of disability in the 12 months following critical illness. Functional disability will be assessed using WHODAS 2.0. Other important variables related to disability are Health-related quality of life, mental health, and cognition; and these will be assessed post-discharge, and after six months and 12 months. This will address Aims I and II of the study.

The second component is a qualitative study that will explore the process of recovery for participants. The major impetus will be to identify the ongoing needs (met and unmet) in the year following critical illness, (aim III of the study). This design will use a nested convenience sample conducting semi-structured Interviews at around 6-8 months post discharge home.
The aims of this study are:
I. To estimate the proportion of intensive care survivors with moderate or severe disability at different time-points after discharge.
II. To describe the data distributions of a variety of relevant clinical variables in intensive care survivors and estimate associations between baseline characteristics of intensive care survivors and disability and its change with time.
III. To describe unmet health needs in ICU survivors.

The primary outcome for the prospective cohort study is the prevalence of moderate or severe disability, as defined by the World Health Organization Disability Assessment Schedule 2.0 (WHODAS-12) 6 months after discharge.

The Hypothesis is “in adult ICU patients who have had a prolonged stay in the ICU, > 20% will experience moderate to severe disability in the year following critical illness”
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 113322 0
Mrs Lynsey Sutton-Smith
Address 113322 0
ICU
Level 3
Wellington Regional Hospital, CCDHB
Riddiford Street
Newtown
Wellington
6021
Country 113322 0
New Zealand
Phone 113322 0
+64 211211385
Fax 113322 0
Email 113322 0
[email protected]
Contact person for public queries
Name 113323 0
Mrs Lynsey Sutton-Smith
Address 113323 0
ICU
Level 3
Wellington Regional Hospital, CCDHB
Riddiford Street
Newtown
Wellington
6021
Country 113323 0
New Zealand
Phone 113323 0
+64 211211385
Fax 113323 0
Email 113323 0
[email protected]
Contact person for scientific queries
Name 113324 0
Mrs Lynsey Sutton-Smith
Address 113324 0
ICU
Level 3
Wellington Regional Hospital, CCDHB
Riddiford Street
Newtown
Wellington
6021
Country 113324 0
New Zealand
Phone 113324 0
+64 211211385
Fax 113324 0
Email 113324 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Only de-identified data will be used in this study in accordance with ethics approval.
This will include raw scores of assessments, mortality data, demographic details etc, clinical scores and diagnoses.
When will data be available (start and end dates)?
At the completion of publication - approx 5 years time no end date
Available to whom?
Anyone who wishes to access the data who can provide evidence of clear ethical rationale and methodologically sound proposal and at the discretion of the primary investigator and primary sponsor.
Available for what types of analyses?
Dependent on the aims of the requestor and only for the intended aim/proposal if clear rationale provided (i.e clear scientific purposes).
How or where can data be obtained?
From the primary investigator [email protected]


What supporting documents are/will be available?

Current supporting documents:
Doc. No.TypeCitationLinkEmailOther DetailsAttachment
12807Study protocol  [email protected] 382566-(Uploaded-24-01-2022-11-52-57)-Study-related document.pdf


Updated to:
Doc. No.TypeCitationLinkEmailOther DetailsAttachment
12807Study protocol  [email protected] 382566-(Uploaded-24-01-2022-11-52-57)-Study-related document.pdf
23757Statistical analysis plan    382566-(Uploaded-10-05-2024-10-53-17)-Study-related document.pdf

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.