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Trial registered on ANZCTR


Registration number
ACTRN12618000571279
Ethics application status
Approved
Date submitted
6/04/2018
Date registered
13/04/2018
Date last updated
27/03/2019
Date data sharing statement initially provided
27/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A pilot randomized study comparing an approach of individualized blood pressure targets to standard care among critically ill patients with shock
Scientific title
A pilot randomized controlled trial comparing an approach of individualized blood pressure targets to standard care among critically ill patients with shock
Secondary ID [1] 294516 0
None
Universal Trial Number (UTN)
U1111-1209-8560
Trial acronym
REACT Shock Pilot-RCT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Critically ill patients with shock 307287 0
Condition category
Condition code
Cardiovascular 306404 306404 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The project will test an intervention that initially targets a patient's own pre-illness basal mean perfusion pressure (MPP) during vasopressor support in ICU. The pre-illness basal MPP will be derived as the difference between the pre-illness basal mean arterial pressure (MAP) estimated from most recent pre-illness BP readings following a standardized method (Panwar et al,. Blood Press. 2017:1-9) and the pre-illness central venous pressure (CVP) estimated from the most recent pre-illness echocardiogram or assumed based on epidemiological data as in previous studies. The treating clinician can tailor these BP targets as deemed suitable for changing clinical state.

Determining pre-morbid basal MPP as soon as a patient is commenced on vasopressors may be logistically difficult during after-hours. Therefore, until a patient's pre-morbid MPP can be traced, a default MAP target of 75 mmHg will be recommended for patients. We chose this value considering that the actual MAP achieved during the first 24 hours of management of shock was 73 to 81 mmHg in several major RCTs, and the interquartile range for the pre-morbid basal MAP in our observational cohort study was 74 to 88 mmHg. For those patients who also have a history of hypertension according to their recent medical notes, a default MAP target of 80-85 mmHg will be recommended. We chose this value considering that this was the MAP range achieved in a recent major RCT in the higher MAP arm, which was found to be beneficial for patients with chronic hypertension. These default targets will be adjusted to the individualized BP targets as soon as a research associate is able to trace previous BP measurements and determine the patient's pre-morbid basal MPP. The individualized MAP target would then be the sum-total of current CVP and basal-MPP. The ceiling for MAP target is 95 mmHg. During the period of study treatment, a range of ±2 mmHg around the set target is acceptable. If the total additional vasopressor dose required to achieve these individualized MAP targets exceeds 0.75 microgram/kg/minute, or if in the opinion of the treating clinician the patient may be suffering possible adverse effects from high vasopressor dose, then the BP targets may be adjusted as deemed fit by the treating clinician. Protocol adherence for participants will be monitored during the screening rounds.

Study intervention will cease when the patient either stops receiving ventilatory support in ICU or is considered well enough by the treating clinician for invasive hemodynamic monitoring (arterial line or central line) to cease. If a patient is transported out of ICU for procedural intervention, then standard (non-study) treatment should be provided.
Intervention code [1] 300819 0
Prevention
Comparator / control treatment
The comparator or the control group will be comprised of patients assigned to standard care, where vasopressor support will be titrated to maintain a default MAP of 60-70 mmHg, in accordance with recommendations by Canadian Critical Care Society and the Scandinavian Society of Anaesthesiology and Intensive Care Medicine (Can J Anesth 2017; 64), unless the treating clinician considers a different MAP target as more appropriate.
Control group
Active

Outcomes
Primary outcome [1] 305419 0
The degree of relative hypotension, assessed as the mean percentage MPP-deficit, which will be derived as an area-under-curve (AUC) - as an integrated expression of mean percentage MPP-deficit achieved over the active treatment period. MPP-deficit will be the percentage deficit between the pre-illness MPP and the achieved-MPP that will be derived from the MAP and CVP as recorded in the patient's observation chart during ICU stay.
Timepoint [1] 305419 0
Measurements will be assessed four hourly, until a patient is weaned off vasopressor support for at least 24 hours or until a maximum of five days, whichever is earlier.
Primary outcome [2] 305420 0
Peak increase in serum creatinine levels
Timepoint [2] 305420 0
Performed at least daily during the first 5 days of randomization
Secondary outcome [1] 345120 0
Area-under-the-curve for change in serum cystatin C
Timepoint [1] 345120 0
Performed daily during the first 3 days of randomization
Secondary outcome [2] 345121 0
Major Adverse Kidney Events (defined as a composite of death, new renal replacement therapy, or final serum creatinine level >= 200% of the latest premorbid creatinine level)
Timepoint [2] 345121 0
Within 14 days of enrolment
Secondary outcome [3] 345122 0
Percentage of time-points with >20% MPP-deficit
Timepoint [3] 345122 0
Based on 4 hourly timepoints during the first 5 days of randomization
Secondary outcome [4] 345123 0
Enrolment rate at our site, assessed using study records
Timepoint [4] 345123 0
Per week until the study is closed for recruitment
Secondary outcome [5] 345124 0
Incidence of increase in Acute Kidney Injury stage (as per KDIGO classification based only on creatinine level)
Timepoint [5] 345124 0
First 14 days of randomization
Secondary outcome [6] 345128 0
Mortality, as assessed from medical case records
Timepoint [6] 345128 0
90 days from enrolment

Eligibility
Key inclusion criteria
• ICU patients aged greater than or equal to 40 years
• The patient is within 48 hours of ICU/HDU admission
• The patient is either receiving or is deemed to imminently need positive pressure ventilation (includes invasive or non-invasive ventilation or high-flow oxygen)
• The patient is deemed to be in shock, defined as clinician-initiated vasopressor therapy AND supported by any of the following within the last 24 hours:
o Lactate level greater than or equal to 2 mmol/l or base deficit greater than or equal to 3 mmol/l,
o Central venous oxygen saturation (ScvO2) less than or equal to 60%
o Creatinine increase by greater than or equal to 44 µmol/l or urine output less than or equal to 0.5 ml/kg/h or <40 ml/h for 2 hours
Minimum age
40 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Patients who are moribund, or have not-for-resuscitation orders, or are deemed to have life expectancy of less than 6 months.
• Patients who are either receiving or are deemed to imminently need renal replacement therapy.
• Patients who already have an increase in serum creatinine of >350 µmol/l from baseline.
• End stage renal disease
• Patients where trauma is the main reason for the current ICU admission.
• Pregnancy, if known
• Active bleeding (clinical suspicion or >2 packed red blood cells within 24 hours)
• Insufficient (less than two) pre-morbid BP readings are available.
• Patients on extracorporeal support (ECMO, IABP, VAD).
• Potential contraindications to either higher or lower BP targets (including but not limited to)
o Cerebral perfusion pressure guided therapy e.g. intracranial hemorrhage or subarachnoid hemorrhage or traumatic brain injury
o Abdominal perfusion pressure guided therapy
o Aortic injury (e.g. dissection or post-operative)
o Post cardiac surgery
o Any other condition requiring higher or lower BP target specifically

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Yes, enrolled patients will be randomly allocated to either standard blood pressure target arm or individualized blood pressure target arm using sealed opaque envelopes.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Using a web-based computer program, a third party will generate a randomization list. The randomization method would be via permuted block randomization with random block sizes.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
An independent statistician will carry out the statistical analyses. All patients who are randomized will be included in an intention-to-treat analysis. Group comparisons of means and proportions will be made using student-t test and Fisher exact test respectively. Comparison of longitudinal data will be performed using mixed linear modelling, to handle repeated measures of AUC and repeated measures of creatinine or cystatin C, fitting main effects for treatment and time and an interaction between the two to determine if treatments differed over time. The advantage of mixed models in this setting is that they can handle missing data, and that they will test association between AUC over day 1 with creatinine on day 1, AUC over day 1+2 with creatinine on day 2, AUC over day 1+2+3 with creatinine on day 3, etc. A two-sided p-value of 0.05 will be considered statistically significant. Given this is a pilot study, no adjustment will be made for the co-primary outcomes. Effect estimates will be derived from multivariate logistic regression models with AKI progression or 90-day mortality as the dependent variable.

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)
NSW
Recruitment hospital [1] 10577 0
John Hunter Hospital - New Lambton
Recruitment postcode(s) [1] 22296 0
2305 - New Lambton

Funding & Sponsors
Funding source category [1] 299140 0
Hospital
Name [1] 299140 0
NSW health innovation grant, John Hunter Hospital
Address [1] 299140 0
John Hunter Hospital,
Lookout road,
New Lambton,
NSW 2305
Country [1] 299140 0
Australia
Funding source category [2] 299141 0
Charities/Societies/Foundations
Name [2] 299141 0
John Hunter Charitable Trust
Address [2] 299141 0
Lookout road, New Lambton, NSW 2305
Country [2] 299141 0
Australia
Primary sponsor type
Hospital
Name
Intensive Care Unit, John Hunter Hospital
Address
ICU, John Hunter Hospital,
Lookout road, New Lambton, NSW 2305
Country
Australia
Secondary sponsor category [1] 298400 0
None
Name [1] 298400 0
Address [1] 298400 0
Country [1] 298400 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300071 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 300071 0
Hunter New England Human Research Ethics Committee,
Locked Bag No. 1
New Lambton, NSW 2305
Ethics committee country [1] 300071 0
Australia
Date submitted for ethics approval [1] 300071 0
28/02/2018
Approval date [1] 300071 0
17/04/2018
Ethics approval number [1] 300071 0
18/03/21/3.04 (2018/ETH00019)

Summary
Brief summary
Aims: The aim of the proposed pilot RCT is to determine feasibility and efficacy of a strategy where BP targets during management of shock in ICU are individualized for each patient based on his/her basal-BP.

Primary objective: To determine if, compared to standard care, among patients with shock in ICU, a strategy of targeting patients' basal-MPP would substantially reduce the degree of BP-deficit during vasopressor therapy and result in lower rise in peak creatinine within the first 5 days of randomization.

Secondary objectives: To determine rate of enrolment of eligible patients per week with complete follow up, to compare the percentage time spent with at least 20% MPP-deficit, and to compare area-under-curve for the change in serum cystatin C during the first 3 days of randomization in both arms.

Methods: This is a prospective pilot randomized controlled trial at a tertiary referral academic ICU. The study will randomly assign 30 patients to either standard care or to an individualized BP target strategy. Besides demographics, severity score and clinical outcomes, the study will collect four hourly data on the difference between basal-BP and achieved-BP during the first five days of vasopressor therapy.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 82470 0
Dr Rakshit Panwar
Address 82470 0
ICU, John Hunter Hospital
Locked Bag 1,
Hunter Regional Mail Centre, NSW, 2310
Country 82470 0
Australia
Phone 82470 0
+61410218808
Fax 82470 0
Email 82470 0
rakshit.panwar@hnehealth.nsw.gov.au
Contact person for public queries
Name 82471 0
Dr Rakshit Panwar
Address 82471 0
ICU, John Hunter Hospital
Locked Bag 1,
Hunter Regional Mail Centre, NSW, 2310
Country 82471 0
Australia
Phone 82471 0
+61410218808
Fax 82471 0
Email 82471 0
rakshit.panwar@hnehealth.nsw.gov.au
Contact person for scientific queries
Name 82472 0
Dr Rakshit Panwar
Address 82472 0
ICU, John Hunter Hospital
Locked Bag 1,
Hunter Regional Mail Centre, NSW, 2310
Country 82472 0
Australia
Phone 82472 0
+61410218808
Fax 82472 0
Email 82472 0
rakshit.panwar@hnehealth.nsw.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
This is only a small pilot study. Once the definitive RCT is conducted, we'd be happy to provide all data two years after the publication of the definitive RCT.
What supporting documents are/will be available?
No other documents available
Summary results
No Results