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Trial registered on ANZCTR


Registration number
ACTRN12612000022864
Ethics application status
Approved
Date submitted
30/12/2011
Date registered
6/01/2012
Date last updated
8/02/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Plasmalyte and Hartmann’s solution for cardiopulmonary pump prime during cardiopulmonary bypass
Scientific title
Effect of Plasmalyte and Hartmann’s solution as cardiopulmonary pump prime on acidosis, strong-ion-difference and unmeasured ions during cardiopulmonary bypass
Secondary ID [1] 279648 0
Nil
Universal Trial Number (UTN)
U1111-1126-7371
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cardiopulmonary bypass 285452 0
Cardiac surgery 285453 0
Condition category
Condition code
Cardiovascular 285636 285636 0 0
Coronary heart disease
Anaesthesiology 285637 285637 0 0
Anaesthetics
Surgery 285638 285638 0 0
Surgical techniques

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Plasmalyte 148 Intravenous Fluid Solution

Plasma-lyte 148 (pH 7.4) is a replacement electrolyte commonly used as a crystalloid priming solution for cardiopulmonary bypass prime. In addition, the presence of bicarbonate precursors (acetate and gluconate) produces a metabolic alkalinising effect that helps counteract metabolic acidosis of patients undergoing cardiopulomary bypass. It is an isontonic solution and compatible with blood or blood components.

The electrolyte composition of Plasmalyte is as follows:

3 mEq of magnesium = 3 mmol/L.
140 Eq of sodium ion = 140 mmol/L.
98 mEq of chloride ion = 98 mmol/L.
27 mEq of acetate = 27 mmol/L.
23 mEq of gluconate = 23 mmol/L.
5 mEq of potassium ion = 5 mmol/L.


For this clinical trial Plasmalyte will be used an a one off intervention only for the duration of cardiopulmonary bypass.

Cardiopulmonary bypass will be performed using a membrane oxygenator (Sorin Monolyth; Biomedica, Mirandola, Italy). The pump rate will be set at 2.4 l.m-2.min-1 and body temperature will be kept at 32 to 34 Degrees.

Plasmalyte will be infused as the cardiopulmonary bypass prime fluid prime fluid together with a standard cardioplegia solution minimising differentiating effects of exogenous ions given by this route.

Prime volume to be administered:
A crystalloid prime volume of 1500mL Plasmalyte will be used in this study representing 30-35% of the patient’s blood volume. Generally, the volume of prime required is either based on a standard empirically derived volume greater than a minimum safe priming volume, or is guided by the patient’s weight or body surface area. In practice the minimum volume required is that which fills both the venous and arterial limbs of the circuit and maintains adequate reserve volume in the venous reservoir to ensure that air is not entrained into the arterial side of the circuit during initiation of CPB. This volume is determined by both the calibre and length of the tubing connecting the patient to the CPB machine and by the design and therefore capacity of the venous reservoir and oxygenator. The volume of the prime in relation to the patient’s pre-CPB haematocrit determines the initial haematocrit achieved after the initiation of CPB. In adults, priming volumes are commonly in the range of 1400-1800mL, typically representing 30-35% of the patient’s blood volume.

Additional fluid boluses of Plasmalyte solution will be administered to any patient if volume supplementation is required.
Intervention code [1] 283934 0
Other interventions
Comparator / control treatment
Hartmanns Intravenous Fluid Solution

Hartmanns solution is a replacement electrolyte commonly used as a crystalloid priming solution for cardiopulmonary bypass prime. In addition, the presence of bicarbonate precursors (lactate) helps counteract metabolic acidosis of patients undergoing cardiopulomary bypass.

The electrolyte composition of Hartmanns solution is as follows:

One litre of Hartmann's solution contains:

131 mEq of sodium ion = 131 mmol/L.
111 mEq of chloride ion = 111 mmol/L.
29 mEq of lactate = 29 mmol/L.
5 mEq of potassium ion = 5 mmol/L.
4 mEq of calcium ion = 2 mmol/L .

For this clinical trial Hartmanns Solution will be used an a one off intervention only for the duration of cardiopulmonary bypass.

Cardiopulmonary bypass will be performed using a membrane oxygenator (Sorin Monolyth; Biomedica, Mirandola, Italy). The pump rate will be set at 2.4 l.m-2.min-1 and body temperature will be kept at 32 to 34 Degrees.

Hartmanns solution will be infused as the cardiopulmonary bypass prime fluid prime fluid together with a standard cardioplegia solution minimising differentiating effects of exogenous ions given by this route.

Prime volume to be administered:
A crystalloid prime volume of 1500mL Hartmanns solution will be used in this study representing 30-35% of the patient’s blood volume. Generally, the volume of prime required is either based on a standard empirically derived volume greater than a minimum safe priming volume, or is guided by the patient’s weight or body surface area. In practice the minimum volume required is that which fills both the venous and arterial limbs of the circuit and maintains adequate reserve volume in the venous reservoir to ensure that air is not entrained into the arterial side of the circuit during initiation of CPB. This volume is determined by both the calibre and length of the tubing connecting the patient to the CPB machine and by the design and therefore capacity of the venous reservoir and oxygenator. The volume of the prime in relation to the patient’s pre-CPB haematocrit determines the initial haematocrit achieved after the initiation of CPB. In adults, priming volumes are commonly in the range of 1400-1800mL, typically representing 30-35% of the patient’s blood volume.

Additional fluid boluses of Hartmanns solution will be administered to any patient if volume supplementation is required.
Control group
Active

Outcomes
Primary outcome [1] 286195 0
Standard base deficit
Timepoint [1] 286195 0
Blood sampling was performed at 5 time points:
1. T1: baseline immediately prior to CPB
2. T2: Five minutes after achieving full flows on CPB, prior to placement of aortic cross clamp
3. T3: Fifteen minutes after achieving full flows on CPB
4. T4: Thirty minutes after achieving full flows on CPB
5. T5: On rewarming, just prior to separation from CPB
Secondary outcome [1] 295352 0
Strong-ion-difference. This is a quantitative physicochemical analysis using Stewart's quantitative equation: The formula used: measured SID, mEq/l =[Na+]+[K+]+[Mg2+]+Ca2+]-[Cl-]-[lactate]
Timepoint [1] 295352 0
Blood sampling was performed at 5 time points:
1. T1: baseline immediately prior to CPB
2. T2: Five minutes after achieving full flows on CPB, prior to placement of aortic cross clamp
3. T3: Fifteen minutes after achieving full flows on CPB
4. T4: Thirty minutes after achieving full flows on CPB
5. T5: On rewarming, just prior to separation from CPB
Secondary outcome [2] 295353 0
Serum albumin. The anion concentrations for albumin will be calculated using Figge's formulae: albumin anions, mEq/l =[albumin] X (0.123 X pH-0.631)
Timepoint [2] 295353 0
Blood sampling was performed at 5 time points:
1. T1: baseline immediately prior to CPB
2. T2: Five minutes after achieving full flows on CPB, prior to placement of aortic cross clamp
3. T3: Fifteen minutes after achieving full flows on CPB
4. T4: Thirty minutes after achieving full flows on CPB
5. T5: On rewarming, just prior to separation from CPB
Secondary outcome [3] 295354 0
Serum phosphate. The anion concentrations for phosphate will be calculated using Figge's formulae:

phosphate anions, mEq/l =[phosphate] X (0.309 X pH-0.469)
Timepoint [3] 295354 0
Blood sampling was performed at 5 time points:
1. T1: baseline immediately prior to CPB
2. T2: Five minutes after achieving full flows on CPB, prior to placement of aortic cross clamp
3. T3: Fifteen minutes after achieving full flows on CPB
4. T4: Thirty minutes after achieving full flows on CPB
5. T5: On rewarming, just prior to separation from CPB
Secondary outcome [4] 295355 0
Serum creatinine
Timepoint [4] 295355 0
Blood sampling was performed at 2 time points:
1. T1: baseline immediately prior to CPB
2. T2 On rewarming, just prior to separation from CPB
Secondary outcome [5] 295356 0
Peak urine neutrophil gelatinase-associated lipocalin (NGAL)
Timepoint [5] 295356 0
Blood sampling was performed at 5 time points:
1. T1: baseline immediately prior to CPB
2. T2: Five minutes after achieving full flows on CPB, prior to placement of aortic cross clamp
3. T3: Fifteen minutes after achieving full flows on CPB
4. T4: Thirty minutes after achieving full flows on CPB
5. T5: On rewarming, just prior to separation from CPB
Secondary outcome [6] 295357 0
Peak serum neutrophil gelatinase-associated lipocalin (NGAL)
Timepoint [6] 295357 0
Blood sampling was performed at 5 time points:
1. T1: baseline immediately prior to CPB
2. T2: Five minutes after achieving full flows on CPB, prior to placement of aortic cross clamp
3. T3: Fifteen minutes after achieving full flows on CPB
4. T4: Thirty minutes after achieving full flows on CPB
5. T5: On rewarming, just prior to separation from CPB
Secondary outcome [7] 295358 0
Serum Cystatin C
Timepoint [7] 295358 0
Blood sampling was performed at 5 time points:
1. T1: baseline immediately prior to CPB
2. T2: Five minutes after achieving full flows on CPB, prior to placement of aortic cross clamp
3. T3: Fifteen minutes after achieving full flows on CPB
4. T4: Thirty minutes after achieving full flows on CPB
5. T5: On rewarming, just prior to separation from CPB
Secondary outcome [8] 295359 0
Serum acetate
Timepoint [8] 295359 0
Blood sampling was performed at 5 time points:
1. T1: baseline immediately prior to CPB
2. T2: Five minutes after achieving full flows on CPB, prior to placement of aortic cross clamp
3. T3: Fifteen minutes after achieving full flows on CPB
4. T4: Thirty minutes after achieving full flows on CPB
5. T5: On rewarming, just prior to separation from CPB
Secondary outcome [9] 295360 0
Serum gluconate
Timepoint [9] 295360 0
Blood sampling was performed at 5 time points:
1. T1: baseline immediately prior to CPB
2. T2: Five minutes after achieving full flows on CPB, prior to placement of aortic cross clamp
3. T3: Fifteen minutes after achieving full flows on CPB
4. T4: Thirty minutes after achieving full flows on CPB
5. T5: On rewarming, just prior to separation from CPB
Secondary outcome [10] 295361 0
Serum lactate
Timepoint [10] 295361 0
Blood sampling was performed at 5 time points:
1. T1: baseline immediately prior to CPB
2. T2: Five minutes after achieving full flows on CPB, prior to placement of aortic cross clamp
3. T3: Fifteen minutes after achieving full flows on CPB
4. T4: Thirty minutes after achieving full flows on CPB
5. T5: On rewarming, just prior to separation from CPB
Secondary outcome [11] 295362 0
Cardiac troponin
Timepoint [11] 295362 0
Blood sampling was performed at 5 time points:
1. T1: baseline immediately prior to CPB
2. T2: Five minutes after achieving full flows on CPB, prior to placement of aortic cross clamp
3. T3: Fifteen minutes after achieving full flows on CPB
4. T4: Thirty minutes after achieving full flows on CPB
5. T5: On rewarming, just prior to separation from CPB
Secondary outcome [12] 295363 0
Interleukin-6
Timepoint [12] 295363 0
Blood sampling was performed at 5 time points:
1. T1: baseline immediately prior to CPB
2. T2: Five minutes after achieving full flows on CPB, prior to placement of aortic cross clamp
3. T3: Fifteen minutes after achieving full flows on CPB
4. T4: Thirty minutes after achieving full flows on CPB
5. T5: On rewarming, just prior to separation from CPB

Eligibility
Key inclusion criteria
1. Adult patient (age > 18years)
2. Elective CABG or valve surgery
3. Requirements for cardiopulmonary bypass
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Decline to participate
2. Pregnancy
3. Abnormal pre-operative venous plasma bicarbonate concentration (< 22 mmol/L or > 27 mmol/L)
4. Hypercapnoeic respiratory failure
5. Chronic renal impairment (creatinine > 150 micromol/L)
6. Known diabetes mellitus or HbA1c > 10% (elevated blood acetate concentrations have been reported in patients with type 2 diabetes mellitus)
7. Chronic liver disease
8. Anaemia (haemoglobin level <10 g/dL)
9. Morbid obesity (BMI > 35kg/m2)
10. Known allergic reaction to study solutions

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Patients will be informed about the study and consented at the cardiac pre-anaesthesia admission clinic 2-4 weeks prior to surgery. On the day of surgery, an independent anaesthetist or research nurse who is not a study investigator will open a sealed opaque randomisation envelope. Participants will be randomly assigned to one of two groups using a random number allocation system with permuted blocks. One group will receive the balanced crystalloid solution Plasmalyte (Baxter, Sydney, NSW) with anions as acetate, gluconate and chloride, the other group will receive Hartmanns solution (Baxter, Sydney, NSW), with anions as lactate. Study participants, cardiac surgeons, perfusionists, anaesthetists and all medical staff involved with the management of the patient throughout the study period will be blinded to treatment allocation. This is a blinded clinical trial. Blinding of both Hartmanns and Plasmalyte solution will be done by Baxter Healthcare Australia. Fluids will be prepared in 1 litre clear plastic fluid container flasks (the exact same packaging that the fluids are normally prepared in), however there will be no labelling/writing on the container that would allow identification of the crystalloid fluid solution.

Each 1-litre flask containing will have the following labelling printed on the side:
1. cardiac Prime Fluid Trial Solution
2. Plasmalyte Solution Hartmanns solution
3. Expiry Date

Baxter Healthcare will compound the products in a strictly aseptic process. The shelf life of any of these solutions prepared under such aseptic conditions would be set at 360 days, when stored at <25C.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation by using a randomization table created by a computer software (i.e., computerised sequence generation) will be preformed. For each patient, an opaque envelope containing the group assignment will be prepared, sealed and sequentially numbered. On the morning of surgery the anaesthetist will open the envelope and randomised the patients into one of the two groups described above.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Nil
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis

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)

Funding & Sponsors
Funding source category [1] 284434 0
Hospital
Name [1] 284434 0
Austin Hospital
Address [1] 284434 0
Department of Anaesthesia
Studley Road, Heidelbeg, Victoria, 3084
Country [1] 284434 0
Australia
Primary sponsor type
Hospital
Name
Austin Hospital
Address
Department of Anaesthesia
Studley Road, Heidelbeg, Victoria, 3084
Country
Australia
Secondary sponsor category [1] 283358 0
None
Name [1] 283358 0
Address [1] 283358 0
Country [1] 283358 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 286404 0
Austin Health Research Ethics Unit
Ethics committee address [1] 286404 0
Austin Health Research Ethics Unit
Henry Buck Building
Austin Hopsital
Studley Road
Heidelberg, 3084
Ethics committee country [1] 286404 0
Australia
Date submitted for ethics approval [1] 286404 0
28/08/2011
Approval date [1] 286404 0
27/10/2011
Ethics approval number [1] 286404 0
H2011/04377

Summary
Brief summary
Changes in acid-base balance, particularly metabolic acidosis are common in cardiac surgery with cardiopulmonary bypass. The mechanisms for such metabolic acidosis however, remain controversial, but previous research strongly suggests that the metabolic acidosis is iatrogenic in nature and that its extent and duration varies according to the priming solution of the
cardiopulmonary bypass circuit. The priming solution has been implicated as one of the potential causes of the disturbances of pH associated with the development of metabolic acidosis on initiation of cardiac bypass. This acidosis is in part caused by hyperchloraemia and is more likely to occur with normal saline, which has a higher chloride load than the more balanced physiological solutions such as Plasmalyte or Hartmanns solutions.

Attempts to prevent metabolic acidosis have entailed alterations to circuit prime fluids, including partial replacement of chloride by rapidly metabolised anions such as L-lactate, acetate and gluconate or else by bicarbonate.
Study rationale: There are no published studies comparing Hartmann’s solution (contains anions lactate and chloride) and Plasmalyte (contains anions acetate, gluconate & chloride) as prime solutions for cardiopulmonary bypass.

Both these crystalloid fluids are commonly used priming solutions for the cardiopulmonary bypass circuit. It is therefore not known if one solution has more beneficial effects on cardiopulmonary associated acidosis, strong-ion
difference and unmeasured ions.

Study design & hypothesis: We will conduct a single centre randomised controlled blinded study to test the hypothesis that when used as cardiopulmonary pump prime solution during cardiopulmonary bypass Plasmalyte solution will have a more favourable effect on metabolic acidosis than Hartmann’s solution.

Primary endpoint: Standard base deficit on rewarming, just prior to separation from cardiopulmonary bypass

Secondary endpoints: Strong-ion-difference; Total weak
acids; Net-unmeasured-ions including lactate, acetate, gluconate; Serum creatinine; Renal biomarkers including: serum and urine NGAL, cystatin C; Pro-inflammatory effects using Interleukin-6; Cardiotoxic biomarkers using cardiac troponin.

Inclusion criteria: Adult patients (age > 18years) undergoing elective Cardiac Artery Bypass Grafting (CABG) or valve surgery requiring cardiopulmonary bypass.

No of participants: 50

Recruiting Hospital: Austin Hospital

Clinical significance: A finding that Plasmalyte solution has more favourable effects than Hartmanns solution on cardiac bypass associated acidosis, strong-ion difference, and
inflammation may influence the fluid chosen for prime solution in patients undergoing cardiopulmonary bypass.
Trial website
Nil
Trial related presentations / publications
Nil
Public notes

Contacts
Principal investigator
Name 33567 0
A/Prof Laurence Weinberg
Address 33567 0
Department of Anaesthesia, Austin Hospital, Heidelberg, 3084, Victoria
Country 33567 0
Australia
Phone 33567 0
+61394965000
Fax 33567 0
Email 33567 0
laurence.weinberg@austin.org.au
Contact person for public queries
Name 16814 0
A/Prof Dr Laurence Weinberg
Address 16814 0
Department of Anaesthesia
Austin Hospital
Studley Road
Heidelberg, 3084, Victoria
Country 16814 0
Australia
Phone 16814 0
+61 3 94965000
Fax 16814 0
+61 3 94596421
Email 16814 0
Laurence.Weinberg@austin.org.au
Contact person for scientific queries
Name 7742 0
A/Prof Dr Laurence Weinberg
Address 7742 0
Department of Anaesthesia
Austin Hospital
Studley Road
Heidelberg, 3084, Victoria
Country 7742 0
Australia
Phone 7742 0
+61 3 94965000
Fax 7742 0
+61 3 94596421
Email 7742 0
Laurence.Weinberg@austin.org.au

No data has been provided for results reporting
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary