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Trial registered on ANZCTR


Registration number
ACTRN12618000370202
Ethics application status
Approved
Date submitted
2/03/2018
Date registered
12/03/2018
Date last updated
15/03/2019
Date data sharing statement initially provided
15/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
REINSTATE trial: Resolution of Elements Influencing Nutritional STatus After criTical illnEss
Scientific title
Resolution of delayed gastric emptying, reduced glucose absorption and hypercatabolism in survivors of critical illness
Secondary ID [1] 294208 0
Nil known
Universal Trial Number (UTN)
U1111-1210-1554
Trial acronym
REINSTATE trial: Resolution of Elements Influencing Nutritional STatus After criTical illnEss
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Critical illness 306852 0
Condition category
Condition code
Diet and Nutrition 305949 305949 0 0
Other diet and nutrition disorders
Oral and Gastrointestinal 305954 305954 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Prospective observational study in critically ill adults conducted at three time-points:
Study day 1: During mechanical ventilation early in the intensive care admission (within seven days of ICU admission); and
Study day 2: Within seven days of discharge to the post-ICU ward
Study day 3: 3-months after ICU admission
All study procedures are the same on all three study days

On study day 1, patients will be mechanically ventilated in the Intensive Care Unit with a nasogastric (NG) tube in situ. Correct NG tube placement will be confirmed radiologically and by measurement of pH aspirates. The NG tube will be aspirated and contents of the stomach discarded prior to the commencement of the study. No prokinetics will be administered during the fasting and study period.

After a four hour fast and 20 minute rest period all participants will have their energy expenditure measured via indirect calorimetry using a metabolic cart (Quark CPET, Cosmed) over a 30 minute period. For ventilated patients, this will be via a ventilator attachment to the metabolic cart, and for self-ventilating patients and healthy subjects this will be via a canopy hood.

Following measurement of energy expenditure, participants will be administered (enterally or orally) a ‘test meal’ over a five minute period comprising 100 ml Ensure Original (Abbott, 237 ml, 920 kJ, 9 g protein, 33 g carbohydrate, 6 g fat), 100 mg of 13C-octanoic acid (Cambridge Isotope Laboratories, Andover, MA) dissolved in 1 ml water for the measurement of gastric emptying, and 3 g of 3-O-Methyl-D-gluco-pyranose (3-OMG) (Sigma-Aldrich, Castle Hill, New South Wales) dissolved in 5 ml water for the measurement of glucose absorption. Self-ventilating patients on the hospital ward following ICU discharge may or may not have an NG tube in situ. Therefore the test meal will be administered by their current feeding route (enteral or oral). Healthy subjects will consume the test meal orally.

Blood samples will be obtained either via an arterial or, where arterial access is not available clinically, via a cannula placed in an antecubital vein. Samples will be taken at t= -5 mins, then every 15 minutes for the first hour, and half hourly for the remaining 3 hours. A total of 143 ml of blood will be collect on each study day (1 x 5 ml serum and 2 x 4 ml plasma samples at each of the 11 time points) for the measurement of glucose absorption, blood glucose and gut hormones.

Breath samples will be collected to assess gastric emptying and taken at baseline prior to the ‘test meal’, then 5 minutely for the first hour after the ‘test meal’ and subsequently every 15 minutes for the remaining 3 hours. For mechanical ventilated patients, expiratory breath samples will be collected from the expiratory limb of the ventilation tubing using an airway adapter (Smiths Medical, Waukesha, WI) and venoject holder containing a needle (Venoject Luer Adapter; Terumo, Tokyo, Japan). Breath samples will be collected from the self-ventilating patients and healthy participants during expiration through a straw. Both techniques allowed reliable filling of Exetainer (Labco, Buckinghamshire, UK) breath collection tubes.
Intervention code [1] 300498 0
Early Detection / Screening
Comparator / control treatment
Healthy participants - Data will be compared with that from age, sex, and BMI-matched healthy participants.
Control group
Active

Outcomes
Primary outcome [1] 304995 0
Gastric emptying using (13)C-octanoate isotope breath test
Timepoint [1] 304995 0
4 hours post-test meal (1) during mechanical ventilation in ICU; (2) on the hospital ward within 7 days of discharge from ICU; (3) 3 months after ICU admission

Breath samples will be collected at baseline and 5 minutely for the first hour and subsequently every 15 minutes for the remaining 3 hours to measure 13Co2 concentrations. Area under the concentration curve for the four hours of measurements will be used to calculate the gastric emptying coefficient (GEC), a global index of the gastric emptying rate, with a higher number indicating faster emptying.
Secondary outcome [1] 343824 0
Glucose absorption assessed using serum concentrations of the non-absorbable glucose analogue 3-O-Methyl-D-gluco-pyranose (3-OMG)
Timepoint [1] 343824 0
4 hours post-test meal (1) during mechanical ventilation in ICU; (2) on the hospital ward within 7 days of discharge from ICU; (3) 3 months after ICU admission

Blood samples will be collected at timed intervals for four hours (0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240 min) following test meal administration, and analysed for plasma 3-OMG The rate of glucose absorption is indicated by the area under the 3-OMG concentration curve for the 4 hours of measurements.
Secondary outcome [2] 343825 0
Fasting energy expenditure measured using indirect calorimetry via a metabolic cart (Quark CPET, Cosmed) for a 30 minute period prior to all study days
Timepoint [2] 343825 0
Prior to commencement of study 4 hours post-test meal (1) during mechanical ventilation in ICU; (2) on the hospital ward within 7 days of discharge from ICU; (3) 3 months after ICU admission
Secondary outcome [3] 343826 0
Endogenous insulin secretion by serum assay
Timepoint [3] 343826 0
4 hours post-test meal (1) during mechanical ventilation in ICU; (2) on the hospital ward within 7 days of discharge from ICU; (3) 3 months after ICU admission

Blood samples will be collected at timed intervals for four hours (0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240 min) following test meal administration, and analysed for serum insulin. Insulin secretion is indicated by the area under the insulin concentration curve for the 4 hours of measurements.
Secondary outcome [4] 344100 0
Endogenous glucagon secretion by plasma assay
Timepoint [4] 344100 0
4 hours post-test meal (1) during mechanical ventilation in ICU; (2) on the hospital ward within 7 days of discharge from ICU; (3) 3 months after ICU admission


Blood samples will be collected at timed intervals for four hours (0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240 min) following test meal administration, and analysed for plasma glucagon. Glucagon secretion is indicated by the area under the glucagon concentration curve for the 4 hours of measurements.
Secondary outcome [5] 344101 0
Endogenous glucagon-like peptide-1 (GLP-1) secretion by plasma assay
Timepoint [5] 344101 0
4 hours post-test meal (1) during mechanical ventilation in ICU; (2) on the hospital ward within 7 days of discharge from ICU; (3) 3 months after ICU admission

Blood samples will be collected at timed intervals for four hours (0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240 min) following test meal administration, and analysed for plasma GLP-1. GLP-1 secretion is indicated by the area under the GLP-1 concentration curve for the 4 hours of measurements.
Secondary outcome [6] 344102 0
Endogenous cholecystokinin (CCK) secretion by plasma assay
Timepoint [6] 344102 0
4 hours post-test meal (1) during mechanical ventilation in ICU; (2) on the hospital ward within 7 days of discharge from ICU; (3) 3 months after ICU admission

Blood samples will be collected at timed intervals for four hours (0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240 min) following test meal administration, and analysed for plasma CCK. CCK secretion is indicated by the area under the CCK concentration curve for the 4 hours of measurements.
Secondary outcome [7] 344103 0
Endogenous peptide YY (PYY) secretion by plasma assay
Timepoint [7] 344103 0
4 hours post-test meal (1) during mechanical ventilation in ICU; (2) on the hospital ward within 7 days of discharge from ICU; (3) 3 months after ICU admission

Blood samples will be collected at timed intervals for four hours (0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240 min) following test meal administration, and analysed for plasma PYY. PYY secretion is indicated by the area under the PYY concentration curve for the 4 hours of measurements.
Secondary outcome [8] 344104 0
Endogenous glucose-dependent insulinotropic polypeptide (GIP) secretion by plasma assay
Timepoint [8] 344104 0
4 hours post-test meal (1) during mechanical ventilation in ICU; (2) on the hospital ward within 7 days of discharge from ICU; (3) 3 months after ICU admission

Blood samples will be collected at timed intervals for four hours (0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240 min) following test meal administration, and analysed for plasma GIP. GIP secretion is indicated by the area under the GIP concentration curve for the 4 hours of measurements.
Secondary outcome [9] 344105 0
Endogenous c-peptide secretion by serum assay
Timepoint [9] 344105 0
4 hours post-test meal (1) during mechanical ventilation in ICU; (2) on the hospital ward within 7 days of discharge from ICU; (3) 3 months after ICU admission

Blood samples will be collected at timed intervals for four hours (0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240 min) following test meal administration, and analysed for serum c-peptide. c-peptide secretion is indicated by the area under the c-peptide concentration curve for the 4 hours of measurements.
Secondary outcome [10] 344184 0
Blood glucose
Timepoint [10] 344184 0
For 4 hours post-test meal (1) during mechanical ventilation in ICU; (2) on the hospital ward within 7 days of discharge from ICU; (3) 3 months after ICU admission

Blood samples will be collected at timed intervals for four hours (0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240 min) following test meal administration and analysed for blood glucose using a portable glucometer.

Eligibility
Key inclusion criteria
Critically ill patients:
Patients admitted to the Royal Adelaide Hospital Intensive Care Unit (ICU) from March 2018 will be assessed for eligibility. Thirty eligible patients will be recruited (accounting for drop-outs to reach the target of 20 patients).

Inclusion criteria:
- Aged greater than or equal to 18 years of age
- Receiving invasive mechanical ventilation
- Planned to receive enteral nutrition
- Patients expected to remain ventilated for greater than 48 hours and stay in ICU for greater than 72 hours
- Feed intolerant (defined as at least one gastric residual volume of greater than or equal to 250 mL in the 24 hrs preceding enrolment, or if gastrokinetic drugs were already prescribed to the patient on the basis of gastric residual volume of greater than or equal to 250 mL)

Healthy participants:
Data will be compared with that from 10 age, sex, and BMI-matched healthy participants. Healthy participants will be recruited by advertisement within the Royal Adelaide Hospital.

Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Critically ill patients:
Exclusion criteria:
- Patients expected to be unable to follow commands and give informed consent after extubation (i.e. head injured, subarachnoid haemorrhage and history of dementia)
- Gastrointestinal surgery on this admission
- Previous upper gastrointestinal surgery (oesophageal, stomach or duodenal)
- Unable to obtain informed consent
- Lives greater than 50km from Adelaide (therefore unable to return for 3 month study day)
- Patient’s next of kin believe the patient will not be willing to have study measurements completed on hospital ward after ICU discharge and also return to the hospital for follow up at 3 months.
- Likely not survive ICU
- Haemoglobin <80g/L

Healthy participants:
Exclusion criteria:
- Inability to give informed consent
- Pregnant or breastfeeding
- Previous gestational diabetes
- Acute or chronic pancreatitis
- Medications known to affect glucose metabolism (e.g. steroids) or gastrointestinal motility (e.g. prokinetics, antidepressants, sedatives, opiates, anticonvulsant agents)
- Previous gastrointestinal surgery (apart from appendectomy)
- Current or previous gastrointestinal disease or major dysfunction
- Regular consumption >20 g alcohol or >10 cigarettes per day

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Case control
Timing
Prospective
Statistical methods / analysis
The primary outcome will be the change in Gastric Emptying Coefficient (GEC) measurement from the stable isotope breath tests from time-point one (ICU) to time-point two (post-ICU acute ward). Published data on intra-patient variability demonstrated a within-subject standard deviation in GEC of 1.0 in ICU patients. Assuming a GEC of 3.2 at time-point one, 20 patients would provide 80% power at the 5% significance level to detect a change of 0.66 units, which corresponds to a 21% difference from time-point one to time-point two. The change in GEC will be assessed using a paired t-test.

Recruitment
Recruitment status
Recruiting
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] 10242 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 21907 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 298845 0
Hospital
Name [1] 298845 0
ROYAL ADELAIDE HOSPITAL CLINICAL PROJECT GRANT
Address [1] 298845 0
Port Road Adelaide SA 5000
Country [1] 298845 0
Australia
Primary sponsor type
Individual
Name
Dr Lee-anne Chapple
Address
Intensive Care Unit Research, Royal Adelaide Hospital, Port Road Adelaide SA 5000
Country
Australia
Secondary sponsor category [1] 298043 0
None
Name [1] 298043 0
Address [1] 298043 0
Country [1] 298043 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299789 0
Central Adelaide Local Health Network Human Research Ethics Committee (CALHN HREC)
Ethics committee address [1] 299789 0
Level 3 Roma Mitchell House, 136 North Terrace, Adelaide, 5000, South Australia, Australia
Ethics committee country [1] 299789 0
Australia
Date submitted for ethics approval [1] 299789 0
23/01/2018
Approval date [1] 299789 0
10/05/2018
Ethics approval number [1] 299789 0

Summary
Brief summary
Nutrition delivery to critically ill patients is largely inadequate, resulting in muscle wasting and reduced physical function in the long-term. While factors such as delayed gastric emptying and reduced glucose absorption are relatively well described early in critical illness, there is a paucity of data on the resolution of these derangements. Further, nutrition intake post-extubation and on the post intensive care unit (ICU) ward are also inadequate. Whether factors that are known to influence nutritional intake in ICU are still prevalent post-ICU requires exploration.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 81570 0
Dr Lee-anne Chapple
Address 81570 0
Intensive Care Unit Research, Royal Adelaide Hospital, Port Road, ADELAIDE SA 5000
Country 81570 0
Australia
Phone 81570 0
+61870741763
Fax 81570 0
+6187074 6182
Email 81570 0
lee-anne.chapple@adelaide.edu.au
Contact person for public queries
Name 81571 0
Mr Matthew Summers
Address 81571 0
Intensive Care Unit Research, Royal Adelaide Hospital, Port Road, ADELAIDE SA 5000
Country 81571 0
Australia
Phone 81571 0
+61870741765
Fax 81571 0
+6187074 6182
Email 81571 0
matthew.summers@sa.gov.au
Contact person for scientific queries
Name 81572 0
Mr Matthew Summers
Address 81572 0
Intensive Care Unit Research, Royal Adelaide Hospital, Port Road, ADELAIDE SA 5000
Country 81572 0
Australia
Phone 81572 0
+61870741765
Fax 81572 0
+6187074 6182
Email 81572 0
matthew.summers@sa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Confidentiality
What supporting documents are/will be available?
No other documents available
Summary results
No Results