Trial Review

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12613001368729
Ethics application status
Approved
Date submitted
8/12/2013
Date registered
13/12/2013
Date last updated
17/07/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
An observational study of relative hypotension and risk of acute kidney injury among critically ill patients with shock
Scientific title
A multicentre prospective cohort study of critically ill patients with shock investigating the degree of untreated relative hypotension during vasopressor therapy in current ICU practice, and assessing the relationship between relative hypotension and incidence of new-onset acute kidney injury.
Secondary ID [1] 283719 0
Nil
Universal Trial Number (UTN)
U1111-1151-1601
Trial acronym
REACT Shock I study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Critically ill patients with shock 290684 0
Acute kidney injury 290710 0
Relative hypotension 290711 0
Condition category
Condition code
Cardiovascular 291049 291049 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
The primary exposure variable of ‘relative hypotensive load’ will be measured as the mean perfusion pressure (MPP) deficit during 120 vasopressor-hours in ICU. MPP-deficit will be derived as the percentage difference between the patient's pre-morbid basal-MPP and the achieved-MPP in ICU in relation to basal-MPP. Achieved-MPP will be recorded each hour in ICU until a patient is weaned off vasopressor for at least 24 hours or up to a maximum of 120 hours, whichever is earlier.

The secondary exposure variable is the percentage of vasopressor-hours spent at >20% MPP-deficit. We chose the threshold of 20% as it is considered as a clinically significant drop in blood pressure according to previous studies.
Intervention code [1] 288412 0
Not applicable
Comparator / control treatment
Current standard of care treatment: This is an observational study of current practice, aiming to assess an association between the exposure variables and the study outcomes. The spectrum of MPP-deficit observed in current practice will allow a comparison between patients with higher MPP-deficit to patients with lower MPP-deficit.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 291040 0
Incidence of significant new-onset acute kidney injury (AKI), which will be measured as at least two AKI-stage increase during the first 14 days from T0.
Timepoint [1] 291040 0
T0 is the time-point when a shocked patient is started on vasopressor therapy. AKI will be defined and staged for severity from 0 (no AKI) to 3 (severe AKI) according to the 2012 KDIGO guidelines on all 14 ICU-days. Change in AKI-stage during the first 14 days after T0 will be assessed in relation to AKI stage at T0.
Primary outcome [2] 306778 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] 306778 0
14 days after TO
Secondary outcome [1] 305876 0
Degree of AKI progression within the first 14 days from T0.
Timepoint [1] 305876 0
T0 is the time-point when a shocked patient is started on vasopressor therapy. AKI will be defined and staged for severity from 0 (no AKI) to 3 (severe AKI) according to the 2012 KDIGO guidelines on all 14 ICU-days. Change in AKI-stage during the first 14 days after T0 will be assessed in relation to AKI stage at T0.
Secondary outcome [2] 305877 0
Time in days until two AKI-stage increase from T0
Timepoint [2] 305877 0
AKI will be defined and staged for severity from 0 (no AKI) to 3 (severe AKI) according to the 2012 KDIGO guidelines on all 14 ICU-days after T0.
Secondary outcome [3] 305878 0
Time in days until one AKI-stage increase from T0
Timepoint [3] 305878 0
AKI will be defined and staged for severity from 0 (no AKI) to 3 (severe AKI) according to the 2012 KDIGO guidelines on all 14 ICU-days after T0.
Secondary outcome [4] 305879 0
Area-under-curve of the change in serum creatinine during the first 14 ICU-days among patients who did not receive renal replacement therapy
Timepoint [4] 305879 0
Area-under-curve will be assessed as an integrated expression of change in serum creatinine levels achieved over the first 14 days from T0.
Secondary outcome [5] 305880 0
Days free of renal replacement therapy
Timepoint [5] 305880 0
Until day 28. Patients will be considered as dependent on renal replacement therapy if they received it within last 4 days.
Secondary outcome [6] 305881 0
Incidence of new-onset chronic kidney disease (CKD)
Timepoint [6] 305881 0
New-onset CKD will be defined as decrease in eGFR to below 60 ml/ min/ 1.73 square meter at or beyond 3 months (up to 6 months) from T0
Secondary outcome [7] 305882 0
ICU Mortality
Timepoint [7] 305882 0
At the time of ICU discharge
Secondary outcome [8] 305883 0
Mortality
Timepoint [8] 305883 0
90 day from T0
Secondary outcome [9] 343797 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 [9] 343797 0
90 days

Eligibility
Key inclusion criteria
a. ICU patients aged at least 40 yrs
b. Trauma is not the main reason for the current ICU admission
c. The patient is within 48 hours of ICU admission
d. Patient has a central venous catheter (CVC) in situ or the
placement of a CVC is imminent (within the next hour) as part of routine ICU management.
e. The patient is receiving positive pressure ventilation (PPV) or the treating clinician anticipates the need for PPV (includes invasive or non-invasive ventilation or the use of high-flow oxygen)
f. Shock, defined as clinician-initiated vasopressor therapy for at least 4 hours or more AND supported by any of the following within last 24 hours:
1) Lactate > or =2 mmol/l, or base deficit > or =3 mmol/l,
2) Central venous oxygen saturation (ScvO2) < or =60%
3) Creatinine increase by >44 micromol/l
4) Urine output <0.5 ml/kg/h or <40 ml/h for 2 hours
Minimum age
40 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
a. Patients who are moribund, or deemed to have life expectancy of less than 6 months.
b. Patients with renal failure requiring RRT, or in imminent need of RRT within the next 12 hours in the opinion of treating clinician or increase in serum creatinine of >350 micromol/l
c. End stage renal disease
d. Patients on extracorporeal support (ECMO, IABP, VAD).
e. Patient has already been included in the study.
f. Pregnancy, if known
g. Active bleeding (clinical suspicion or requiring 3 or more packed red blood cells within 24 hours)
h. Potential contraindications to either higher or lower BP targets (including but not limited to)
1) Cerebral perfusion pressure guided therapy e.g. intracranial hemorrhage or subarachnoid hemorrhage or traumatic brain injury
2) Abdominal perfusion pressure guided therapy
3) Aortic injury (e.g. dissection or post-operative)
4) Post cardiac surgery
5) Any other condition requiring higher or lower BP target specifically

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
In order to examine association between outcome measures and the study exposure variables, logistic or linear regression analyses adjusting for pre-specified covariates will be performed. The primary outcome will be analysed using logistic regression model. A two-sided p-value of 0.05 will be considered statistically significant. Multivariate stepwise logistic or linear regression analysis (goodness-of-fit model), adjusting for relevant covariates, will be performed to compare the association between outcome measures and mean % MPP-deficit, % time-points spent with >20% MPP-deficit, mean % MAP-deficit and % time-points spent at MAP <65 mmHg, to identify the best predictor of outcomes. The association, if any, between the study outcomes with the study exposure variables will be assessed for the entire confidence interval.

Following covariates may be included in the initial model: Age; Presence of co-morbidities such as hypertension, coronary artery disease, heart failure, peripheral vascular disease, COPD, diabetes mellitus and CKD; Anti-hypertensive treatment (yes/no); APACHE III score; Admission type (medical/ surgical); Need for mechanical ventilation (yes/no); Type of shock state (septic/ cardiogenic/ other); Noradrenaline-equivalent vasopressor-dose at T0; Amount of intravenous fluids administered during the 24 hours prior to T0; Study site; Exposure to intravenous contrast or other nephrotoxic agents during the 3 days prior to T0 (yes/no); Number of episodes of exposure to intravenous contrast or other nephrotoxic agents within the first 14 days after T0; and number of days with exposure to blood transfusion within the first 5 days after T0. An independent biostatistician will perform the analysis. All analysis will be performed using standard statistical software. To avoid dangers of over-fitting model, only those covariates with p <0.25 on univariate analysis will be considered as potential predictor variables in the stepwise regression model. Clinically less relevant covariates that show significant collinearity with other predictor variables will also be excluded. Selecting only the significant predictor variables would reduce the number of covariates that need to be accounted for in multivariate regression analysis. We anticipate that up to eight variables may remain in the final multivariate model. Time-weighted average (TWA) values of MAP and CVP will be derived for the period of vasopressor therapy. The TWA is derived as follows: a. First, the sum-product of mean value between consecutive time-points and the period of time between such points is derived. b. This sum-product is then divided by the total time to obtain the TWA value. Sensitivity analysis will be performed to test if the relationship between outcome endpoints and exposure endpoints still exists when the analysis is limited only to patients who died or to patients who remained in the study for at least five days.

Pre-specified subgroup analysis will be performed for 1) <70 and >70 years old 2) septic and cardiogenic shock and 3) pre-morbid creatinine <150 or >150 micromole/l. The association between study exposure variables, based on shorter periods of data collection (T0-T24 and T0-T48), and outcomes will also be assessed. Based on our pilot study data (Panwar et al, J Crit Care. 2013), we require a sample size of 300 patients in order to demonstrate a relative risk of 0.60 for the occurrence of primary outcome in two equally sized groups (those with less-than-median versus greater-than-median MPP-deficit) with an alpha of 0.05 and statistical power of 90%, allowing for 10% attrition.

The time-to-event analysis will be performed using Cox proportional hazard modeling with results reported as hazard ratios with 95% confidence intervals and presented as Kaplan-Meier curves. The cohort will be dichotomised into two groups based on the median value of exposure variables, and comparison between survival curves for groups (i.e., greater than median vs less than median) will be performed using log-rank test.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
16/12/2013
Actual
27/07/2014
Date of last participant enrolment
Anticipated
Actual
31/01/2018
Date of last data collection
Anticipated
15/04/2018
Actual
16/07/2018
Sample size
Target
300
Accrual to date
Final
302
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,VIC

Funding & Sponsors
Funding source category [1] 288393 0
Hospital
Name [1] 288393 0
John Hunter Hospital Charitable Trust
Country [1] 288393 0
Australia
Funding source category [2] 288394 0
Hospital
Name [2] 288394 0
Royal Brisbane Hospital Research Grant
Country [2] 288394 0
Australia
Primary sponsor type
Hospital
Name
John Hunter Hospital
Address
Locked Bag 1, Hunter Region Mail Centre, New Lambton, NSW 2310
Country
Australia
Secondary sponsor category [1] 287097 0
Charities/Societies/Foundations
Name [1] 287097 0
Clinical Trials Group of the Australia and New Zealand Intensive Care Society (ANZICS-CTG)
Address [1] 287097 0
Level 3,
10 Ievers Terrace,
Carlton, VIC 3053
Country [1] 287097 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290279 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 290279 0
Locked Bag 1
New Lambton, NSW 2305
Ethics committee country [1] 290279 0
Australia
Date submitted for ethics approval [1] 290279 0
Approval date [1] 290279 0
11/11/2013
Ethics approval number [1] 290279 0
13/07/17/3.03

Summary
Brief summary
Shock is a medical emergency in which the organs and tissues of the body are not receiving adequate blood flow. Preventing low blood pressure (or hypotension) in such patients is an integral part of standard treatment, but it is unclear what degree of hypotension in relation to patients’ usual resting/basal blood pressure (basal-BP) should be treated. In our pilot study, we reported that in usual practice, the achieved-BP for shocked patients in intensive care unit (ICU) was generally lower and often unrelated to their basal-BP. It resulted in varying degree of untreated relative hypotension (BP-deficit) that was associated with an increased risk of acute kidney injury (AKI). The main purpose of this study is to test or confirm these findings in a broader clinical practice. Further, the novel data on both degree and duration of relative hypotension accepted in routine care in a broad multicentre setting would be crucial to design a major interventional trial.

Our hypothesis for this study is that some degree of relative hypotension, quantified as mean perfusion pressure deficit (MPP-deficit), would be common in routine care for vasopressor-treated patients. In critically ill patients, who often have blunted autoregulation, a persisting MPP-deficit may fail to restore adequate renal perfusion that may result in worsening kidney function. We hypothesize that such MPP-deficit, a measure of untreated relative hypotension, in patients with shock during vasopressor therapy is associated with an increased risk of new-onset AKI. The association between study exposure variables and outcome measures will be adjusted for pre-specified covariates in a multivariate model.
Trial website
Trial related presentations / publications
Public notes
Basal-MPP will be determined for all patients according to an a priori specified protocol similar to what we followed in our pilot observational study (J Crit Care. 2013; 28). MPP is the difference between mean arterial pressure (MAP) and central venous pressure (CVP). As ICU patients are usually in a resting state, we deem it more appropriate to compare achieved-MPP among vasopressor-treated patients to their resting/nighttime or basal-MPP.

The preset protocol to estimate basal MPP is as follows:

Step 1: Find preferably up to five or at least two pre-morbid MAP (or BP) measurements, recorded at least 12 hours apart, starting with the most recent reading available within the last 3 years. The selected MAP (or BP) readings should be from a period when the patient met following criteria: was not admitted to ICU, was at least two weeks following any surgery, was not in renal failure, was not pregnant, was not receiving intravenous anti-hypertensive drugs, diuretics, or analgesics on that day, and was not transferred to another health care facility within the next two days.

1.1 Find pre-morbid MAP (or BP) measurements recorded during nighttime ambulatory BP monitoring (preferred), outpatient visits, pre-admission assessment or during a non-invasive cardiac investigation. If unavailable, then

1.2 Find pre-morbid MAP (or BP) recorded on the observation charts from the last 48 hrs of a previous hospitalization. If multiple BP readings are available during the night, record the median BP during the last night of previous hospital stay. Then, record BP measurements that were done closest to the 12-hour interval from the selected median BP reading.


Step 2: Derive pre-morbid basal MAP as follows:

2.1 Convert BP readings that are recorded in SBP/DBP format to MAP as per the equation: MAP = DBP + 1/3(SBP-DBP)

2.2 Subtract 15% from daytime MAP values to estimate nighttime (basal) MAP to account for the nighttime fall in BP in accordance with published data on 24h ambulatory BP in previous studies.

2.3 Consider the mean of available basal MAP values as pre-morbid basal-MAP.


Step 3: Derive pre-morbid basal CVP as follows:

3.1 If a previous elective right heart catheterisation (RHC) report is available, the measured right atrial pressure (RAP) will be considered as basal CVP. If unavailable, then

3.2 Estimate CVP from a previous transthoracic echocardiography (TTE) study done in an outpatient setting, based on collapsibility of inferior vena cava (IVC) and IVC diameter (IVCd):
3.2.1 CVP=3 mmHg if IVCd =2.1 cm with >50% collapsibility on sniff (or stated as normal); or
3.2.2 CVP=15 mmHg if IVCd >2.1 cm with <50% collapsibility on sniff (or stated as dilated with minimal or reduced collapsibility); or
3.2.3 For intermediate findings (i.e. normal IVC with reduced collapsibility, or dilated IVC with normal collapsibility),
3.2.3.A If the report mentions diastolic flow predominance in the hepatic veins, then CVP=15 mmHg
3.2.3.B If the report mentions normal or systolic flow predominance in the hepatic veins, then CVP=3 mmHg
3.2.3.C If the report does not make any comment on hepatic vein flow pattern, then CVP=8 mmHg

3.3 If previous outpatient TTE is not available, then estimate CVP=8 mmHg if there is evidence of at least moderate valvular or cardiac dysfunction, or pulmonary hypertension, or raised filling pressures on any previous TOE or inpatient TTE study. If not, or where no echocardiography report is available, then

3.4 Assume basal CVP of 2 mmHgO in patients with no heart disease, or 6 mmHg if there is any available evidence of pre-existing heart disease.

Finally, basal MPP is the difference between basal MAP and basal CVP.

Contacts
Principal investigator
Name 44814 0
Dr Rakshit Panwar
Address 44814 0
ICU, John Hunter Hospital,
64 Lookout Road,
New Lambton, NSW 2305
Country 44814 0
Australia
Phone 44814 0
+61410218808
Fax 44814 0
Email 44814 0
[email protected]
Contact person for public queries
Name 44815 0
Dr Rakshit Panwar
Address 44815 0
ICU, John Hunter Hospital,
64 Lookout Road,
New Lambton, NSW 2305
Country 44815 0
Australia
Phone 44815 0
+61410218808
Fax 44815 0
Email 44815 0
[email protected]
Contact person for scientific queries
Name 44816 0
Dr Rakshit Panwar
Address 44816 0
ICU, John Hunter Hospital,
64 Lookout Road,
New Lambton, NSW 2305
Country 44816 0
Australia
Phone 44816 0
+61410218808
Fax 44816 0
Email 44816 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.