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Trial registered on ANZCTR


Registration number
ACTRN12617001459314
Ethics application status
Approved
Date submitted
12/10/2017
Date registered
16/10/2017
Date last updated
17/07/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A feasibility study comparing an approach of individualized blood pressure targets to standard care among critically ill patients with shock
Scientific title
A multicenter before-and-after feasibility study comparing an approach of individualized blood pressure targets to standard care among critically ill patients with shock
Secondary ID [1] 293113 0
None
Universal Trial Number (UTN)
U1111-1203-6505
Trial acronym
REACT Before-After Study
Linked study record
ACTRN12613001368729

Health condition
Health condition(s) or problem(s) studied:
Critically ill patients with shock 305066 0
Relative hypotension 305067 0
Condition category
Condition code
Cardiovascular 304385 304385 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention that will be tested is that of individualizing the blood pressure (BP) target for vasopressor therapy during management of shock in ICU over a period of 4 months. In the individualized BP target arm, patient’s own pre-morbid basal mean perfusion BP (MPP) will be considered as an initial target for the vasopressor support. The pre-morbid basal MPP will be derived as the difference between pre-morbid basal mean arterial BP (MAP) estimated from most recent pre-illness BP readings following a standardized method (Panwar et al,. Blood Press. 2017:1-9) and the pre-morbid central venous BP (CVP) estimated from the most recent pre-illness echocardiogram or assumed based on epidemiological data as in previous studies. Clinicians’ discretion to tailor these BP targets as guided by current clinical state will be allowed. Study posters and information material about the intervention will be presented to all clinicians who are working in participating ICUs.

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. 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 is suffering adverse effects (such as myocardial ischemia with concomitant rise in troponin, mesenteric ischemia, new onset arrhythmias and distal limb ischemia) from high vasopressor dose, then the BP targets may be adjusted as deemed fit by the treating clinician and the reasons would be duly recorded.

Intervention adherence will be assessed by principal investigators at each participating site. Regular education will be imparted explaining the rationale for the study to encourage strict protocol adherence.
Intervention code [1] 299358 0
Prevention
Intervention code [2] 299375 0
Treatment: Other
Comparator / control treatment
The comparator arm would comprise of patients with conventional BP targets for vasopressor therapy during management of shock in ICU. These patients would be admitted over 4 months prior to the commencement of the intervention period and would be sourced from those recruited in our linked previous observational study (ACTRN12613001368729) at two participating sites. The usual mean arterial BP targets for vasopressor therapy are in the range of 65-70 mmHg in conventional practice.
Control group
Historical

Outcomes
Primary outcome [1] 303630 0
Degree of relative hypotension, measured as the mean percentage deficit between basal-MPP and achieved-MPP
Timepoint [1] 303630 0
Until a patient is weaned off vasopressor for at least 24 hours or until a maximum of five days, whichever is earlier.
Secondary outcome [1] 339696 0
Enrolment rate
Timepoint [1] 339696 0
per week
Secondary outcome [2] 339697 0
Percentage patients with complete follow up with >90% data collection
Timepoint [2] 339697 0
90 days from enrolment
Secondary outcome [3] 339698 0
Incidence of significant acute kidney injury (AKI) progression, defined as an increase by at least two AKI stages (as per KDIGO staging)
Timepoint [3] 339698 0
14 days from enrolment
Secondary outcome [4] 339699 0
Incidence of acute kidney injury (AKI) progression, defined as an increase of at least one AKI stage (as per KDIGO staging)
Timepoint [4] 339699 0
14 days from enrolment
Secondary outcome [5] 339700 0
Median [interquartile range] shift in AKI staging,
Timepoint [5] 339700 0
14 days from enrolment
Secondary outcome [6] 339701 0
Time in days until two AKI stage increase
Timepoint [6] 339701 0
14 days from enrolment
Secondary outcome [7] 339702 0
Area-under-curve for change in serum creatinine among patients (while not on renal replacement therapy)
Timepoint [7] 339702 0
14 days from enrolment
Secondary outcome [8] 339703 0
Renal replacement therapy free days
Timepoint [8] 339703 0
Day 28 from enrolment
Secondary outcome [9] 339704 0
Percentage of time-points with >20% MPP-deficit
Timepoint [9] 339704 0
5 days from enrolment
Secondary outcome [10] 339705 0
Incidence of new-onset atrial or ventricular arrhythmia that required any anti-arrhythmic treatment
Timepoint [10] 339705 0
5 days from enrolment
Secondary outcome [11] 339706 0
Hospital mortality
Timepoint [11] 339706 0
Hospital discharge
Secondary outcome [12] 339707 0
Mortality
Timepoint [12] 339707 0
90 days from enrolment
Secondary outcome [13] 344011 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 [13] 344011 0
14 days

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
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
4 months of 'individualized BP targeting' (the intervention) will be preceded by 4 months of 'conventional practice' (the control)
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Outcome analysis
A two-sided p-value of 0.05 will be considered statistically significant. Continuous normally distributed variables will be compared using student t-tests and reported as mean (standard deviation, or 95% CI), whilst non-normally distributed data will be compared using Wilcoxon Rank Sum tests and reported as median (interquartile range). Group comparisons of proportions will be made using Chi-square tests or Fishers exact tests where numbers are small and will be reported as numbers (%). In order to examine association between secondary end-points and the mean %MPP-deficit, logistic or linear regression analyses adjusting for pre-specified covariates will be performed. Given that the sample size is small, only those covariates with p <0.15 on univariate analysis will be adjusted for in the multivariate analysis. Clinically less relevant covariates that show significant collinearity with other predictor variables will also be excluded. Time-to-event data will be displayed as Kaplan-Meier curves and analysed using a log-rank test. Estimates of hazard ratios for survival, with corresponding 95% CI and P values, will be obtained from the Cox proportional hazards models incorporating treatment group and independent covariates used in the multivariate logistic models as detailed below.

Additional analysis
Effect estimates will be derived from multivariate logistic regression models with AKI progression and 90-day mortality as the dependent variable. We will incorporate adjustment for the independent covariates of age, gender, APACHE-III score, time lapsed from vasopressor initiation to study enrolment, exposure to nephrotoxic agents as well as for any significant baseline differences. Pre-specified subgroup analysis will be performed for patients with baseline (T0) creatinine <150 versus >150 µmol/l.

Sensitivity analysis
Additionally, sensitivity analyses will be performed to assess any association between a composite of death or significant AKI progression and quintiles of % MPP-deficit and quintiles of the % time-points that were spent with >20% MPP-deficit.

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)
ACT,NSW
Recruitment hospital [1] 9181 0
John Hunter Hospital - New Lambton
Recruitment hospital [2] 9182 0
The Canberra Hospital - Garran
Recruitment postcode(s) [1] 17817 0
2305 - New Lambton
Recruitment postcode(s) [2] 17818 0
2605 - Garran

Funding & Sponsors
Funding source category [1] 297742 0
Charities/Societies/Foundations
Name [1] 297742 0
Intensive Care Foundation
Address [1] 297742 0
Level 2, 10 Ievers Terrace, Carlton, VIC 3053
Country [1] 297742 0
Australia
Funding source category [2] 297743 0
Charities/Societies/Foundations
Name [2] 297743 0
John Hunter Charitable Trust
Address [2] 297743 0
Lookout road, New Lambton, NSW 2305
Country [2] 297743 0
Australia
Primary sponsor type
Hospital
Name
Intensive Care Unit, John Hunter Hospital
Address
Lookout road, New Lambton, NSW 2305
Country
Australia
Secondary sponsor category [1] 296776 0
None
Name [1] 296776 0
Address [1] 296776 0
Country [1] 296776 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298806 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 298806 0
Hunter New England Human Research Ethics Committee,
Locked Bag No. 1
New Lambton, NSW 2305
Ethics committee country [1] 298806 0
Australia
Date submitted for ethics approval [1] 298806 0
Approval date [1] 298806 0
10/10/2017
Ethics approval number [1] 298806 0
17/08/16/4.01
Ethics committee name [2] 299828 0
Hunter New England Human Research Ethics Committee
Ethics committee address [2] 299828 0
Locked Bag 1
New Lambton NSW 2305
Ethics committee country [2] 299828 0
Australia
Date submitted for ethics approval [2] 299828 0
Approval date [2] 299828 0
11/11/2013
Ethics approval number [2] 299828 0
13/07/17/3.03

Summary
Brief summary
Aims: The aim of the proposed study 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 demonstrate that compared to the standard care of patients with shock in ICU, a strategy of targeting patients’ basal-BP would minimize the degree of untreated relative hypotension (BP-deficit) during vasopressor therapy by at least 75%.

Secondary objectives: To determine whether in this study design, the interventional phase, as compared to conventional care, can (a) enrol at least one patient per week (b) complete follow up for all patients with >90% of data collection (c) reduce the incidence of significant AKI (at least two AKI-stage increase) during the first 14 study days, (d) reduce the peak increase in serum creatinine during the first 7 days among patients not on renal replacement therapy (RRT), (e) reduce percentage of time-points spent with >20% BP-deficit by at least 75%, and (f) be implemented without any appreciable increase in new-onset arrhythmias or serious adverse events.

Methods: This is a prospective before-and-after pilot study at multidisciplinary academic ICUs. The study will be conducted over eight consecutive months- first four months of conventional care, followed by the last four months of individualized BP targets. All consecutive eligible patients screened during the two periods will be enrolled in the study. 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 78282 0
Dr Rakshit Panwar
Address 78282 0
ICU, John Hunter Hospital
Locked Bag 1,
Hunter Regional Mail Centre, NSW, 2310
Country 78282 0
Australia
Phone 78282 0
+61410218808
Fax 78282 0
Email 78282 0
rakshit.panwar@hnehealth.nsw.gov.au
Contact person for public queries
Name 78283 0
Dr Rakshit Panwar
Address 78283 0
ICU, John Hunter Hospital
Locked Bag 1,
Hunter Regional Mail Centre, NSW, 2310
Country 78283 0
Australia
Phone 78283 0
+61410218808
Fax 78283 0
Email 78283 0
rakshit.panwar@hnehealth.nsw.gov.au
Contact person for scientific queries
Name 78284 0
Dr Rakshit Panwar
Address 78284 0
ICU, John Hunter Hospital
Locked Bag 1,
Hunter Regional Mail Centre, NSW, 2310
Country 78284 0
Australia
Phone 78284 0
+61410218808
Fax 78284 0
Email 78284 0
rakshit.panwar@hnehealth.nsw.gov.au

No information has been provided regarding IPD availability
Summary results
No Results