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Trial registered on ANZCTR


Registration number
ACTRN12615001164583
Ethics application status
Approved
Date submitted
28/09/2015
Date registered
2/11/2015
Date last updated
27/11/2018
Date data sharing statement initially provided
27/11/2018
Date results information initially provided
27/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Stress hyperglycaemia and mortality in critical illness
Scientific title
Single-centre, observational trial of stress hyperglycaemia and in-hospital mortality in adult patients admitted to intensive care
Secondary ID [1] 287545 0
Nil
Universal Trial Number (UTN)
Nil
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
hyperglycaemia 296316 0
critical illness 296317 0
Condition category
Condition code
Metabolic and Endocrine 296594 296594 0 0
Diabetes
Public Health 296714 296714 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
Stress hyperglycaemia ratio as defined by the admission blood glucose level divided by the estimated average glycaemia. Estimated average glycaemia will be computed from the HbA1c using the formula as suggested by Nathan, D.M. et al. Diabetes Care 31, 1473–8 (2008). The patients will have routine intensive care. Bloods needed for testing (e.g. for HbA1c) are those already drawn during routine intensive care and added retrospectively if not already ordered in standard care. The patients will be followed up until hospital discharge.
Intervention code [1] 292943 0
Not applicable
Comparator / control treatment
admission glucose concentration by blood sample performed as part of standard care for admission into intensive care.
Control group
Active

Outcomes
Primary outcome [1] 296206 0
all-cause mortality
Timepoint [1] 296206 0
in-hospital admission
Secondary outcome [1] 317813 0
Composite: major adverse cardiac events, acute renal injury (by KDIGO criteria), all-cause mortality, nosocomial infection, neurological complication (stroke or transient ischaemic attack) as assessed by review of hospital records, imaging results and laboratory results.
Timepoint [1] 317813 0
in-hospital admission
Secondary outcome [2] 317821 0
major adverse cardiac events as assessed by review of hospital records and laboratory results.
Timepoint [2] 317821 0
in-hospital admission
Secondary outcome [3] 317822 0
acute renal injury (by KDIGO criteria) as assessed by review of hospital records and laboratory results.
Timepoint [3] 317822 0
in-hospital admission
Secondary outcome [4] 317823 0
nosocomial infection as assessed by review of hospital records and laboratory results.
Timepoint [4] 317823 0
in-hospital admission
Secondary outcome [5] 317824 0
neurological complication (stroke or transient ischaemic attack) as assessed by review of hospital records, laboratory results and imaging results.
Timepoint [5] 317824 0
in-hospital admission
Secondary outcome [6] 317825 0
length of stay as assessed by review of hospital records.
Timepoint [6] 317825 0
in-hospital admission

Eligibility
Key inclusion criteria
admission to intensive care unit within study period
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
elective admissions to ICU (e.g. post-operative), glycaemia-related admission to ICU, pregnancy, major blood loss

Study design
Purpose
Screening
Duration
Cross-sectional
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
A statistician has undertaken a simulation analysis using a previous study on the stress hyperglycaemia ratio (SHR) to determine the sample size required for this study. Assuming an event rate of 15%, a sample size of 1200 subjects has 80% power to detect an independent association between SHR and mortality with an estimated odds ratio of 1.25 per 0.1 increase in SHR at the two-tailed 0.05 significance level. To ensure we have sufficient power, we will recruit 1400 subjects. We will perform univariate as well as multi-variate analyses to compare the SHR with other predictors of outcome in intensive care, including absolute glycaemia, APACHE III scores.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 4385 0
Flinders Medical Centre - Bedford Park

Funding & Sponsors
Funding source category [1] 292112 0
Government body
Name [1] 292112 0
National Health and Medical Research Council
Address [1] 292112 0
Level 1
16 Marcus Clarke Street
Canberra ACT 2601
Country [1] 292112 0
Australia
Funding source category [2] 292113 0
Other
Name [2] 292113 0
Royal Australasian College of Physicians
Address [2] 292113 0
145 Macquarie St, Sydney NSW 2000
Country [2] 292113 0
Australia
Funding source category [3] 292114 0
Commercial sector/Industry
Name [3] 292114 0
Novo Nordisk Regional Diabetes Scheme
Address [3] 292114 0
Novo Nordisk Pharmaceuticals Pty. Ltd.
PO Box 7586
Baulkham Hills Business Centre NSW 2153
Country [3] 292114 0
Australia
Funding source category [4] 292115 0
Charities/Societies/Foundations
Name [4] 292115 0
FMC Foundation
Address [4] 292115 0
Flinders Medical Centre Foundation
Flinders Drive
Bedford Park 5042
South Australia
Country [4] 292115 0
Australia
Primary sponsor type
Individual
Name
Assoc Prof Morton Burt
Address
Southern Adelaide Diabetes and Endocrinology Services
Repatriation General Hospital
216 Daws Rd, Daw Park SA 5041
Country
Australia
Secondary sponsor category [1] 290801 0
None
Name [1] 290801 0
Address [1] 290801 0
Country [1] 290801 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293598 0
Southern Adelaide Clinical Human Research Ethics Committee
Ethics committee address [1] 293598 0
The Flats G5 – Rooms 3 and 4
Flinders Drive
Flinders Medical Centre, Bedford Park SA 5042
Ethics committee country [1] 293598 0
Australia
Date submitted for ethics approval [1] 293598 0
15/06/2015
Approval date [1] 293598 0
07/08/2015
Ethics approval number [1] 293598 0
AU/15/F77F18

Summary
Brief summary
Hyperglycaemia in hospitalised patients is independently associated with increased morbidity and mortality in a wide range of patient groups, including the critically ill. The association between hyperglycaemia and poor inpatient outcomes is strong in patients without diabetes. However, despite a greater elevation in plasma glucose concentration and poorer prognosis, hyperglycaemia is a weaker predictor of morbidity and mortality in patients with diabetes.

A high plasma glucose concentration in a hospitalised patient can occur because of chronic poor diabetes control and be “normal” for that patient, represent a transient physiologic response to an inter­current illness (stress hyperglycaemia), or be a combination of the above. Stress hyperglycaemia arises because of the inflammatory and neuro­hormonal derangements that occur during a major illness. Therefore, stress hyperglycaemia develops in proportion to the severity of an inter­current illness, and an association between hyperglycaemia and adverse patient outcomes will be, at least in part, a reflection of this. However, stress hyperglycaemia may also directly contribute to adverse outcomes by inducing endothelial dysfunction and oxidative stress.

The Endocrine Research Unit, Southern Adelaide Diabetes and Endocrine Services recently developed a metric for stress hyperglycaemia. Estimated average glucose concentration was calculated from glycosylated haemoglobin in 2290 patients acutely admitted to Flinders Medical Centre, Adelaide. Relative hyperglycaemia was defined by the stress hyperglycaemia ratio (SHR), calculated by dividing admission glucose by estimated average glucose. Thus, a patient with a SHR of 1.5 has an admission glucose concentration 50% higher than their average glucose over the prior 3 months.
Using data gathered from a research primarily focused on validating the use of HbA1c for diagnosis of diabetes mellitus, a multivariable analysis including glucose, SHR and other potential predictors of poor outcome (e.g age, sex, renal function), the odds ratio for in­-hospital death or ICU admission per 0.1 SHR increment was 1.20 (p<0.001). In contrast, the odds ratio per one mmol/L glucose increment was 1.03 (p=0.31). In contrast to glucose, the association between diabetes and SHR was not affected by diabetic status. These data suggest that SHR is a better predictor of adverse outcomes than glucose and that SHR is associated with poor outcomes in patients with and without diabetes.
In this study, we will evaluate whether SHR is more strongly associated with in-­hospital mortality in critically ill patients than absolute glucose. If true, this may create a new paradigm whereby patients in ICU are selected for glucose­lowering therapy based on relative, rather than absolute, hyperglycaemia.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 60610 0
A/Prof Morton Burt
Address 60610 0
Southern Adelaide Diabetes and Endocrine Services
Repatriation General Hospital
216 Daws Road,
Daw Park, SA 5041
Country 60610 0
Australia
Phone 60610 0
+61882751094
Fax 60610 0
Email 60610 0
morton.burt@health.sa.gov.au
Contact person for public queries
Name 60611 0
Dr Tien Lee
Address 60611 0
Southern Adelaide Diabetes and Endocrine Services
Repatriation General Hospital
216 Daws Road,
Daw Park, SA 5041
Country 60611 0
Australia
Phone 60611 0
+61455982828
Fax 60611 0
Email 60611 0
lee0522@flinders.edu.au
Contact person for scientific queries
Name 60612 0
Dr Tien Lee
Address 60612 0
Southern Adelaide Diabetes and Endocrine Services
Repatriation General Hospital
216 Daws Road,
Daw Park, SA 5041
Country 60612 0
Australia
Phone 60612 0
+61455982828
Fax 60612 0
Email 60612 0
lee0522@flinders.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Undecided
No/undecided IPD sharing reason/comment
Info collected are deidentified but due to the large amount of data collected on each patient in a single centre, it may be reidentifiable to specific patients. Ethics committee and approval will need to be sought and granted for specific requests prior to release of data.
What supporting documents are/will be available?
Study protocol
Ethical approval
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
Yes
Results – basic reporting
Results – plain English summary