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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

4/08/2022

Date data sharing statement initially provided

27/03/2019

Type of registration

Prospectively registered

Titles & IDs

Public title

A pilot multicenter randomized study comparing an approach of individualized blood pressure targets to standard care among critically ill patients with shock

Scientific title

A pilot multicenter randomized controlled trial comparing an approach of individualized blood pressure targets to standard care among critically ill patients with shock

Secondary ID [1]

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

Condition category

Condition code

Cardiovascular

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 mean arterial pressure (MAP) during vasopressor support in ICU. The pre-illness MAP will be estimated from most recent pre-illness BP readings following a standardized method (Panwar et al,. Blood Press. 2017:1-9) and will be targeted for the duration of vasopressor therapy for up to a maximum of five days. The treating clinician can tailor these BP targets as deemed suitable for current clinical state.

The range for MAP target is 55-95 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. Protocol deviation will be defined as failure to adjust dose of vasopressor agents while the MAP remained at least 6 mmHg above or below the set target for 4 consecutive hours, without a documented change of MAP target by the treating clinician.

Study intervention will cease if a patient is considered well enough by the treating clinician for discharge out of ICU. If a patient is transported out of ICU for procedural intervention, then standard (non-study) treatment should be provided.

Intervention code [1]

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 65 mmHg, in accordance with standard recommendations, unless the treating clinician considers a different MAP target as more appropriate. The default target MAP, if revised, will be recorded.

Control group

Active

Outcomes

Primary outcome [1]

The degree of relative hypotension, assessed as the mean percentage MAP-deficit, which will be derived as an area-under-curve (AUC) - as an integrated expression of mean percentage MAP-deficit achieved over the active treatment period. MAP-deficit will be the percentage deficit between the pre-illness MAP and the achieved-MAP that will be derived from the MAP recorded in the patient's observation chart during ICU stay.

Timepoint [1]

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]

Peak increase in serum creatinine levels

Timepoint [2]

Performed at least daily during the first 5 days of randomization

Secondary outcome [1]

Area-under-the-curve for change in serum cystatin C

Timepoint [1]

Performed daily during the first 3 days of randomization

Secondary outcome [2]

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]

Within 14 days of enrolment

Secondary outcome [3]

Percentage of time-points with >20% MAP-deficit

Timepoint [3]

Based on 4 hourly timepoints during the first 5 days of randomization

Secondary outcome [4]

Renal replacement therapy free days until day 28 (assessed using medical record)

Timepoint [4]

Day 28 from enrolment

Secondary outcome [5]

Time to death through day 14 (assessed using medical records)

Timepoint [5]

First 14 days of randomization

Secondary outcome [6]

Mortality, as assessed from medical case records

Timepoint [6]

90 days from enrolment

Secondary outcome [7]

Death

Timepoint [7]

14 days of enrolment

Secondary outcome [8]

Time to death through day 90 (assessed from medical record))

Timepoint [8]

90 days of enrolment

Eligibility

Key inclusion criteria

• ICU patients aged greater than or equal to 40 years
• 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 Urine output less than or equal to 0.5 ml/kg/h or <40 ml/h for 2 or more consecutive hours
o Respiratory rate >22 per minute
o Altered mentation (Glasgow Coma Score <14)

Minimum age

40 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

• Patients who are moribund, or have documented not-for-resuscitation orders
• At least 24 hours have lapsed from the time of initiation of vasopressor or inotropic support
• 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

Statistical analyses will be carried out using a standard statistical software. All patients who are randomized will be included in an intention-to-treat analysis. Continuous normally distributed variables will be compared using student-t test and reported as mean (± standard deviation or 95% confidence interval), whilst non-normally distributed data will be compared using Wilcoxon Rank Sum tests and reported as median (interquartile range). Between group comparison of categorical variables will be made using Chi-square tests and reported as numbers (%). 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. 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 outcome events as the dependent variable. We will incorporate adjustment for the independent covariates of age, gender, APACHE score, exposure to nephrotoxic agents as well as for any significant baseline differences. Time-to-event data for day-14 and day-90 mortality will be displayed as Kaplan- Meier curves and analysed using a log-rank test. A two-sided p-value of 0.05 will be considered statistically significant. A separate sensitivity analysis for patients enrolled after the latest protocol amendment will be reported. Patients enrolled post protocol variation of this pilot RCT may also be included in the main analysis of the phase 3 RCT,

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

16/07/2018

Actual

20/12/2018

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]

John Hunter Hospital - New Lambton

Recruitment hospital [2]

The Maitland Hospital - Maitland

Recruitment hospital [3]

Port Macquarie Base Hospital - Port Macquarie

Recruitment hospital [4]

St George Hospital - Kogarah

Recruitment postcode(s) [1]

2305 - New Lambton

Recruitment postcode(s) [2]

2320 - Maitland

Recruitment postcode(s) [3]

2444 - Port Macquarie

Recruitment postcode(s) [4]

2217 - Kogarah

Recruitment outside Australia

Country [1]

Ireland

State/province [1]

Galway

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

John Hunter Charitable Trust

Address [1]

Lookout road, New Lambton, NSW 2305

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Hunter New England Human Research Ethics Committee

Ethics committee address [1]

Hunter New England Human Research Ethics Committee,
Locked Bag No. 1
New Lambton, NSW 2305

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

28/02/2018

Approval date [1]

17/04/2018

Ethics approval number [1]

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 MAP targets during management of shock in ICU are individualized for each patient based on his/her pre-illness MAP. 

Primary objective:  To determine if, compared to standard care, among patients with shock in ICU, a strategy of targeting patients’ pre-illness MAP 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 compare the percentage time spent with at least 20% BP-deficit, and to compare area-under-curve for the change in serum cystatin C during the first 3 days of randomization in both arms. Other outcomes would be day 14 mortality, incidence of MAKE 14, time to death through day 14, renal replacement therapy (RRT) free days until day 28, and time to death through day 90.


Methods: This is a prospective pilot multicenter RCT at academic ICUs. The study will randomly assign 50 patients to either standard care or to an individualized MAP target strategy. Besides demographics, severity score and clinical outcomes, the study will collect four hourly data on MAP-deficit i.e., the difference between pre-illness MAP and achieved-MAP, during the first five days of vasopressor therapy.

Trial website

Trial related presentations / publications

Public notes

The time of initiation of vasopressor therapy will be identified as T0 for each patient enrolled during the study period. Four hourly data on MAP, and norepinephrine-equivalent vasopressor dose, will be monitored until a patient is weaned off vasopressor for at least 24 hours up to a maximum of five days from T0, whichever is earlier. Percentage BP-deficit will be reported for all patients as a measure of ‘relative hypotensive load’. Other data points will include baseline demographic data, Acute Physiology and Chronic Health Evaluation (APACHE) III risk score (for the 24 hours prior to randomisation), comorbidities, pre-illness blood pressure readings, diagnosis at ICU admission, type of shock, requirement for mechanical ventilation, volume of intravenous fluid administered within the prior 24 hours, exposure to nephrotoxic agents within 72 hours prior to T0, pre-morbid creatinine level, and the most recent serum lactate and serum creatinine levels (including the timing of sampling) obtained at or just prior to T0, and time of randomisation). MAKE-14 will be defined as a composite measure of death, new initiation of renal replacement therapy (RRT), or doubling of serum creatinine from the pre-morbid level at day 14. The premorbid serum creatinine level will be sourced as the latest available value from medical records within the last year before hospital admission or, if this value was unavailable, as the latest available value during the hospital stay at least 7 days before ICU admission. When neither of these are available, the premorbid serum creatinine will be estimated following the Kidney Disease: Improving Global Outcome (KDIGO)  guidelines as described previously.(30) 
Adverse events such as new-onset atrial tachyarrhythmia or cardiac arrest requiring chest compressions or defibrillation during the study period will be monitored for all patients. Indications to initiate RRT such as presence of metabolic acidosis (pH <7.2), blood urea nitrogen level of more than 30 mmol/l, hyperkalemia (K >6 mmol/l), creatinine level of >499 micromoles/l, anuria for more than 6 hours, fluid overload or other reasons such as toxin removal or clinician’s preference to start early RRT will be monitored in both arms. Data on covariates such as history of hypertension, other co-morbidities, need for invasive mechanical ventilation, exposure to potentially nephrotoxic agents and etiology of shock state (cardiogenic or septic) will be reported for both study groups.

Contacts

Principal investigator

Name

Dr Rakshit Panwar

Address

ICU, John Hunter Hospital
Locked Bag 1,
Hunter Regional Mail Centre, NSW, 2310

Country

Australia

Phone

+61410218808

Fax

[email protected]

Contact person for public queries

Name

Rakshit Panwar

Address

ICU, John Hunter Hospital
Locked Bag 1,
Hunter Regional Mail Centre, NSW, 2310

Country

Australia

Phone

+61410218808

Fax

[email protected]

Contact person for scientific queries

Name

Rakshit Panwar

Address

ICU, John Hunter Hospital
Locked Bag 1,
Hunter Regional Mail Centre, NSW, 2310

Country

Australia

Phone

+61410218808

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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 Supporting Document Provided

Results publications and other study-related documents

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No additional documents have been identified.

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