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Trial registered on ANZCTR


Registration number
ACTRN12615000100594
Ethics application status
Approved
Date submitted
13/01/2015
Date registered
4/02/2015
Date last updated
12/08/2019
Date data sharing statement initially provided
12/08/2019
Date results information initially provided
12/08/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The Effects of Bolus and Slow Fluid Infusions in Healthy Volunteers with Shock
Scientific title
The Effects of a Bolus or Slow Intravenous Crystalloid Fluid Infusion on Oxygen Delivery in Healthy Volunteers with Compensated Shock
Secondary ID [1] 285964 0
None
Universal Trial Number (UTN)
U1111-1166-0487
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Haemorrhagic Shock 293895 0
Condition category
Condition code
Anaesthesiology 294199 294199 0 0
Anaesthetics
Cardiovascular 294200 294200 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
After the venesection of 10 ml/kg Ideal Body Weight of blood over a 15 minute period from healthy fit adult subjects, participants will be randomised to receive a intravenous crystalloid fluid (Plasma-Lyte 148) for resuscitation.

The type of fluid used is Plasma-Lyte 148 solution (Baxter Healthcare).

The amount of Plasma-Lyte 148 solution that will be administered is 13 ml/kg (Ideal Body Weight) .

Plasma-Lyte 148 solution will be infused continuously via the intravenous route through a peripheral intravenous cannula.

The Plasma-Lyte 148 infusion will commence exactly 15 minutes after completion of the venesection.

Plasma-Lyte 148 solution will infused over 2 time periods/arms depending on randomisation.

1. Over a 10 minutes period (Bolus infusion group)

2. Over a 30 minutes period (Slow infusion group)

The ratio of 1:1.3 ratio of the volume of blood to the volume of Plasmalyte is adopted from the landmark clinical trial, The Saline versus Albumin Fluid Evaluation Study (SAFE).

Once the Plasma-Lyte 148 solution has been infused, data collection will be conducted for 60 minutes.

Once data collection is completed, the venesected blood will be re-infused back to the participant over a 30 minute period.

The study will then be concluded.

Participants will then be crossed over to the other infusion period/arm between 7 -14 days later i.e there will be a washout period of between 7-14 days between the 2 interventions.
Intervention code [1] 290938 0
Treatment: Drugs
Comparator / control treatment
The control group will be Bolus infusion group. This group will receive the Plasma-Lyte 148 solution over a 10 minutes period (Bolus infusion group).


Control group
Dose comparison

Outcomes
Primary outcome [1] 293987 0
The primary outcome is: Oxygen delivery (mls/kg/min)

This is easily measured by using non-invasive technology which continuously measure cardiac output, O2 saturation and haemoglobin levels throughout the study.

Determinants of oxygen delivery will be directly measured using state of non-invasive technology (Edwards Life Science ClearSight Device). These will include:
1. Stroke volume index (independent of heart rate)
2. Haemoglobin concentrations
3. Blood arterial saturation
4. Heart rate
Timepoint [1] 293987 0
1. Baseline (before venesection)
2. Immediately post venesection
3. 30 minute post venesetion; pre-Plasmalyte infusion
4. Immediately post Plasmalyte infusion
5. 60 minutes post Plasmalyte infusion
6. Post reinfusion of the patients venesected blood
Secondary outcome [1] 312293 0
Mean arterial pressure using the Edwards Lifesciences ClearSite Advanced haemodynamic monitor
Timepoint [1] 312293 0
1. Baseline (before venesection)
2. Immediately post venesection
3. 30 minute post venesetion; pre-Plasmalyte infusion
4. Immediately post Plasmalyte infusion
5. 60 minutes post Plasmalyte infusion
6. Post reinfusion of the patients venesected blood
Secondary outcome [2] 312294 0
Systolic blood pressure using the Edwards Lifesciences ClearSite Advanced haemodynamic monitor
Timepoint [2] 312294 0
1. Baseline (before venesection)
2. Immediately post venesection
3. 30 minute post venesetion; pre-Plasmalyte infusion
4. Immediately post Plasmalyte infusion
5. 60 minutes post Plasmalyte infusion
6. Post reinfusion of the patients venesected blood
Secondary outcome [3] 312295 0
Diastolic blood pressure using the Edwards Lifesciences ClearSite Advanced haemodynamic monitor
Timepoint [3] 312295 0
1. Baseline (before venesection)
2. Immediately post venesection
3. 30 minute post venesetion; pre-Plasmalyte infusion
4. Immediately post Plasmalyte infusion
5. 60 minutes post Plasmalyte infusion
6. Post reinfusion of the patients venesected blood
Secondary outcome [4] 312296 0
Cardiac index using the Edwards Lifesciences ClearSite Advanced haemodynamic monitor
Timepoint [4] 312296 0
1. Baseline (before venesection)
2. Immediately post venesection
3. 30 minute post venesetion; pre-Plasmalyte infusion
4. Immediately post Plasmalyte infusion
5. 60 minutes post Plasmalyte infusion
6. Post reinfusion of the patients venesected blood
Secondary outcome [5] 312297 0
Systemic vascular resistance using the Edwards Lifesciences ClearSite Advanced haemodynamic monitor
Timepoint [5] 312297 0
1. Baseline (before venesection)
2. Immediately post venesection
3. 30 minute post venesetion; pre-Plasmalyte infusion
4. Immediately post Plasmalyte infusion
5. 60 minutes post Plasmalyte infusion
6. Post reinfusion of the patients venesected blood
Secondary outcome [6] 312298 0
Stroke volume index using the Edwards Lifesciences ClearSite Advanced haemodynamic monitor
Timepoint [6] 312298 0
1. Baseline (before venesection)
2. Immediately post venesection
3. 30 minute post venesetion; pre-Plasmalyte infusion
4. Immediately post Plasmalyte infusion
5. 60 minutes post Plasmalyte infusion
6. Post reinfusion of the patients venesected blood
Secondary outcome [7] 312299 0
Venous blood gas including (pH,Pa02,PaCO2, base deficit) using an ABL 800 Blood Gas Monitor
Timepoint [7] 312299 0
1. Baseline (before venesection)
2. Immediately post venesection
3. 30 minute post venesetion; pre-Plasmalyte infusion
4. Immediately post Plasmalyte infusion
5. 60 minutes post Plasmalyte infusion
6. Post reinfusion of the patients venesected blood
Secondary outcome [8] 312300 0
Plasma haemoglobin using an ABL 800 Blood Gas Monitor
Timepoint [8] 312300 0
1. Baseline (before venesection)
2. Immediately post venesection
3. 30 minute post venesetion; pre-Plasmalyte infusion
4. Immediately post Plasmalyte infusion
5. 60 minutes post Plasmalyte infusion
6. Post reinfusion of the patients venesected blood
Secondary outcome [9] 312301 0
Plasma Atrial natriuetic peptide
Timepoint [9] 312301 0
Baseline (before venesection of the patients blood), immediately post infusion of the Plasmalyte-148 solution, then 30 minutes and 60 minutes post infusion of the Plasmalyte-148 solution
Secondary outcome [10] 312302 0
Plasma Interleukin 6
Timepoint [10] 312302 0
Baseline (before venesection of the patients blood), immediately post infusion of the Plasmalyte-148 solution, then 30 minutes and 60 minutes post infusion of the Plasmalyte-148 solution
Secondary outcome [11] 312303 0
Plasma Tumour necrosis factor (Alpha)
Timepoint [11] 312303 0
Baseline (before venesection of the patients blood), immediately post infusion of the Plasmalyte-148 solution, then 30 minutes and 60 minutes post infusion of the Plasmalyte-148 solution
Secondary outcome [12] 312304 0
Indocyanine green, which will be measured with PULSION non-invasive LiMON–Technology
Timepoint [12] 312304 0
Baseline (before venesection of the patients blood), immediately post infusion of the Plasmalyte-148 solution, then 30 minutes and 60 minutes post infusion of the Plasmalyte-148 solution
Secondary outcome [13] 312305 0
Vascular reactivity index using a VENDYs non invasive vascular reactivity machine.

Timepoint [13] 312305 0
Baseline (before venesection of the patients blood), then 60 minutes post infusion of the Plasmalyte-148 solution
Secondary outcome [14] 312306 0
Plasma lactate using an ABL 800 Blood Gas Monitor
Timepoint [14] 312306 0
Baseline (before venesection of the patients blood), immediately post infusion of the Plasmalyte-148 solution, then 30 minutes and 60 minutes post infusion of the Plasmalyte-148 solution
Secondary outcome [15] 312307 0
Heart Rate using the Edwards Lifesciences ClearSite Advanced haemodynamic monitor
Timepoint [15] 312307 0
1. Baseline (before venesection)
2. Immediately post venesection
3. 30 minute post venesetion; pre-Plasmalyte infusion
4. Immediately post Plasmalyte infusion
5. 60 minutes post Plasmalyte infusion
6. Post reinfusion of the patients venesected blood

Eligibility
Key inclusion criteria
1. Healthy adults
2. No regular medication other than contraceptive pill
3. Normal Haemoglobin level
Minimum age
18 Years
Maximum age
45 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. <18 years or > 45 years in age
2. Pregnancy or have given birth within 1 year
3. Hereditary haematological conditions (sickle cell anaemia and thalassemia) that are susceptible to anaemia
4. Recent (within 10 days) history of cold, fever, or upper or lower respiratory tract infection (this may theoretically increase risk of infection with venesected blood when it is being stored prior to re-infusion)
5. Morbid Obesity (BMI> 35 kg/m2)
6. Body Weight > 100 kg

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation will be concealment will be by means of sealed opaque envelopes. The sealed envelopes will be stored in a locked facility in the department of Intensive Care at Austin Hospital, where the trial is being conducted. After informed participant consent has been obtained, an independent research assistant/investigator will open the sealed envelope which will contain one of the two randomisation groups.

1) Bolus Plasmalyte infusion group
2) Slow Plasmalyte infusion group

After a wash-period of >7days and <14 days, participants will be assigned to the alternative group.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a computer software (i.e. computerised sequence generation) will be performed by the Principle Investigator. The computer will be password protected and located in the Research Laboratory in the Department of Intensive Care at Austin Hospital. Participants will be randomly allocated to one of the two infusion groups described above.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Regarding the inference for means: the sample calculations are based on comparing two independent sample populations
1. The expected mean oxygen delivery values (mu1) in the slow volume resuscitation group = 500 ml/min/m2
2. The expected mean oxygen delivery values (mu2) in the bolus volume resuscitation group = 400 ml/min/m2
Using a 2-sided test
3. Sigma value (common standard deviation) of the samples population = 75 ml/min/m2
4. Type 1 error rate = 0.05
5. Desired power = 0.80
Result: A sample size of 9 patients is required

Statistical analysis will be performed using computerized software (SPSS for Windows version 12.0, and Graphed). For data that is non-normally distributed a Mann–Whitney test will be used and normally distributed data will be compared using the Student T test. Ordinal and nominal data will be compared using Chi square analysis. A p-value <0.05 will be considered significant.

Recruitment
Recruitment status
Completed
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)
VIC
Recruitment hospital [1] 3325 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 9104 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 290545 0
Hospital
Name [1] 290545 0
Austin Hospital
Address [1] 290545 0
Studley Road, Heidelberg, 3084, Victoria, Australia
Country [1] 290545 0
Australia
Funding source category [2] 290546 0
University
Name [2] 290546 0
Department of Surgery, and Anaesthesia Perioperative Pain Medicine Unit, University of Melbourne
Address [2] 290546 0
University of Melbourne, Parkville, Victoria, 3010, Australia
Country [2] 290546 0
Australia
Primary sponsor type
Hospital
Name
Department of Anaesthesia, Austin Hospital
Address
Study Road, Heidelberg, 3084, Victoria
Country
Australia
Secondary sponsor category [1] 289237 0
University
Name [1] 289237 0
Department of Surgery, and Anaesthesia Perioperative Pain Medicine Unit, University of Melbourne
Address [1] 289237 0
University of Melbourne, Parkville, Victoria, 3084
Country [1] 289237 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292193 0
Human Research Ethics Unit
Ethics committee address [1] 292193 0
Human Research Ethics Committee
Austin Hospital, Studley Road, Heidelberg, 3084, Victoria
Ethics committee country [1] 292193 0
Australia
Date submitted for ethics approval [1] 292193 0
Approval date [1] 292193 0
09/01/2015
Ethics approval number [1] 292193 0
HREC/14/Austin/458

Summary
Brief summary
Numerous animal studies have shown that bolus or fast fluid infusion increases blood loss and mortality compared to a slow fluid infusion. Consistently, a high quality human randomised controlled trial also demonstrated that rapid crystalloid infusion increased mortality and complications in children with severe infections compared to those who received no bolus infusion. To date, no human studies have explored the effects of bolus fluid infusions and the duration of these effects on haemodynamic changes, biochemical, immunological and hormonal responses compared to those effects induced by slow infusions.

This study is the first human randomised controlled trial to investigate the effects of bolus (fast) and slow infusion of crystalloid (clear) fluids in healthy volunteers. Participants will be randomly assigned to either a bolus (fast) infusion or a slow infusion group. The controlled venesection (removal) of 10 ml/kg Ideal Body Weight of blood will be conducted over a 15 minute period. Following that and after 30 minutes, participants will be resuscitated with 13 ml/kg of a either a bolus (fast) infusion (10 minutes), or a slow infusion (30 minutes) with a balanced crystalloid solution. After a 60-minute measurement period, the participants’ blood will be re-infused over a further 30-minute period. After 2 weeks, the participants will be crossed over to the other arm.

Primary end point: Oxygen delivery, which can easily be measured by using a validated non-invasive haemodynamic monitor (Edwards Life Science ClearSight Device), a device that is used routinely as standard of care at Austin Health.

Secondary endpoints: The effects of the rate of fluid resuscitation on mean arterial pressure, systemic vascular resistance, vascular reactivity index, biochemical, immunological and hormonal responses will also be investigated in similar timeline.

Study Hypothesis: A slow crystalloid infusion has a more beneficial effect on oxygen delivery than a bolus (fast) crystalloid infusion in healthy volunteers (age 18 to 45 years) with induced compensated shock.

No of participants: 9

Setting: A single centre University teaching hospital.

Safety: Detailed and stringent safety guidelines will be followed in accordance with advice from the Department of Haematology at Austin Hospital, Austin Hospital Blood Bank, Victorian Red Cross, and the Department’s of Anaesthesia and ICU.
Each experiment will conducted by a senior anaesthetist, in a theatre environment, with the appropriate monitoring and safety equipment to effectively and safely conduct this study.

Clinical significance: These results will used to generate hypotheses and establish outcome benchmarks for future controlled trials that will directly influence how patients with haemorrhagic shock are optimally resuscitated.
Trial website
Nil
Trial related presentations / publications
Nil
Public notes
Nil

Contacts
Principal investigator
Name 54006 0
A/Prof Laurence Weinberg
Address 54006 0
Department of Anaesthesia, Austin Hospital, Studley Road, Heidelberg, 3084, Victoria
Country 54006 0
Australia
Phone 54006 0
+61 3 94965000
Fax 54006 0
+61 3 94596421
Email 54006 0
Laurence.Weinberg@austin.org.au
Contact person for public queries
Name 54007 0
A/Prof Laurence Weinberg
Address 54007 0
Department of Anaesthesia, Austin Hospital, Studley Road, Heidelberg, 3084, Victoria
Country 54007 0
Australia
Phone 54007 0
+61 3 94965000
Fax 54007 0
+61 3 94596421
Email 54007 0
Laurence.Weinberg@austin.org.au
Contact person for scientific queries
Name 54008 0
A/Prof Laurence Weinberg
Address 54008 0
Department of Anaesthesia, Austin Hospital, Studley Road, Heidelberg, 3084, Victoria
Country 54008 0
Australia
Phone 54008 0
+61 3 94965000
Fax 54008 0
+61 3 94596421
Email 54008 0
Laurence.Weinberg@austin.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Participants have not consented for sharing of data
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
Yes
Journal publication details
Publication date and citation/details [1] 3955 0
Ho L, Lau L, Churilov L, Riedel B, McNicol L, Hahn RG, Weinberg L. Comparative Evaluation of Crystalloid Resuscitation Rate in a Human Model of Compensated Haemorrhagic Shock. Shock 2016 Aug;46(2):149-57. doi: 10.1097/SHK.0000000000000610.
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary