Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12610000147088
Ethics application status
Approved
Date submitted
7/02/2010
Date registered
12/02/2010
Date last updated
8/02/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Intraoperative fluid therapy for patients undergoing elective liver resection
Scientific title
A Randomized, Blinded, Multicentre Non-inferiority Study Comparing the Acid-base Effects of Plasmalyte and Hartmann’s solution in Patients undergoing Liver Resection
Secondary ID [1] 280545 0
Renal Injury
Universal Trial Number (UTN)
U1111-1113-5753
Trial acronym
N/A
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Liver resection surgery 256767 0
Intravenous fluid therapy 256768 0
Acid-base physiology 256769 0
Condition category
Condition code
Anaesthesiology 256919 256919 0 0
Anaesthetics
Oral and Gastrointestinal 256962 256962 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intravenous fluids most frequently used in perioperative care in Australia are Hartmann’s solution, Normal Saline, and to a lesser extent, Plasmalyte. One mechanism where perioperative fluid therapy can change acid-base status is when a high chloride concentration found in fluids like Normal Saline causes a hyperchloremic metabolic acidosis. For this reason, Normal Saline is no longer considered a suitable intraoperative fluid replacement therapy for many major surgical procedures, and Hartmann’s Solution and Plasmalyte have become the crystalloid solutions of choice. These solutions are now termed “balanced” solutions as they contain less chloride and have more favourable acid-base profiles. The quantitative acid-base effects of fluid therapy during liver resection however is unclear and there are few studies directly comparing Hartmann’s solution and Plasmalyte in this setting.

In this study all participants undergoing hepatic resection will be randomised to receive either Hartmanns's solution or Plasmalyte solution for intraoperative crystalloid fluid replacement therapy.

General anaesthesia will be managed by a group of specialist anaesthetists using a protocol designed to standardise patient care for patients undergoing hepatic resection at our institution. Induction of anaesthesia will consists of a balanced technique, and anaesthesia and analgesia will be provided as part of routine care. Routine monitoring will include continuous electrocardiography, pulse oximetry, capnography, invasive arterial blood pressure, central venous pressure, urine output and core body temperature. Intra-operative normothermia will be maintained with warm fluids and a forced-air warming device.

Intravenous fluid protocol:

Preoperatively.
Patients will be fasted as per Hospital protocols. Clear oral fluids (water, tea/coffee with no milk products, clear apple juice) are allowed up to 4 hours before surgery. Prior to anaesthesia and surgery patients will not receive any additional intravenous fluid boluses.

Intraoperatively:
Patients will receive their allocated fluid, Hartmann’s solution or Plasmalyte as the sole crystalloid during their surgery. The fluids will be provided in deidentified bags, provided by Baxter Healthcare, to will blind the anaesthetist to the allocated fluid. As per standard practice for patients undergoing liver at our institution, the administration of fluids will be reduced and central venous pressure will be maintained at less than 6 mmHg for the duration of hepatic parenchymal resection. After hepatic resection, an infusion of warm crystalloid fluids will be administered to render patients euvolaemic.

The crystalloid fluid solution will be infused at a maintenance rate 1.5-2 ml/kg/hr.

Additional crystalloid boluses to replace surgical blood loss will consist of ~3 mls of crystalloid solution for every 1 ml of blood lost.

Urine output will be maintained at greater than 0.5 ml/kg/h, and systolic blood pressure maintained within 20% of the pre-operative value. The use of water to control plasma sodium, dextrose for the treatment of hypoglycaemia, and blood products to correct anaemia or coagulopathy will be at the discretion of treating clinicians and in accordance with hospital protocols. The anaesthetist managing the patient may choose to use colloid in addition to the crystalloid. To avoid the acid-base effects of different colloids being a confounder in this study, the colloid used in this study will be 20% Albumex (CLS) . We think this is a rational choice as it is supplied free of charge by CSL laboratory to all hospitals in Australia, and has a favorable acid base profile for use in liver surgery.

At the completion of surgery the use of the trial fluid (Hartmanns or Plasmalyte) will discontinue and postoperative intravenous fluid therapy (type/amount and duration) will be continued at the discretion of the attending surgeon and perioperative clinician.
Intervention code [1] 256016 0
Treatment: Drugs
Intervention code [2] 256017 0
Treatment: Drugs
Comparator / control treatment
For intraoperative crystalloid replacement intravenous fluid therapy, patients will be randomised to either Hartmann's solution or Plasmalyte solution. Both these fluids are considered standard fluid therapy for this operation and are used as routine care for every patient undergoing major abdominal surgery, including liver resection.

This fluid therapy will commence on initiation of anaesthesia and be continued throughout the intraoperative period and end when the surgery is complete.
Control group
Active

Outcomes
Primary outcome [1] 257792 0
Acid-base status (measured by base excess)
Timepoint [1] 257792 0
Immediately preoperative (baseline), intraoperatively (post hepatic resection) and postoperatively (in the post anaesthesia care unit)
Primary outcome [2] 257793 0
Strong ion difference (sampled from routine blood tests and calculated from the diffrence between plasma cations (sodium and potassium) and anions (chloride and bicarbonate)
Timepoint [2] 257793 0
Immediately preoperative (baseline), intraoperatively (post hepatic resection) and postoperatively (in the post anaesthesia care unit)
Primary outcome [3] 257794 0
Total weak acids (measured from routine blood tests which include plasma albumin, and phosphates)
Timepoint [3] 257794 0
Immediately preoperative (baseline), intraoperatively (post hepatic resection) and postoperatively (in the post anaesthesia care unit)
Secondary outcome [1] 263201 0
Plasma lactate concentration
Timepoint [1] 263201 0
Immediately preoperative (baseline), intraoperatively (post hepatic resection) and postoperatively (in the post anaesthesia care unit)
Secondary outcome [2] 263202 0
Neutrophil gelatinase associated lipocalin (NGAL). Neutrophil gelatinase-associated lipocalin is a small protein expressed in neutrophils and certain epithelia, including the renal tubules. Renal expression of NGAL is dramatically increased in kidney injury from a variety of causes, and NGAL is released into both urine and plasma. NGAL levels rise within 2 hours of the insult, making NGAL an early and sensitive biomarker of kidney injury. This will be measured from serial urine and blood samples using western blots and Enzyme-linked immunosorbent assay (ELISA) for NGAL expression.
Timepoint [2] 263202 0
Immediately preoperative (baseline), intraoperatively (post hepatic resection) and postoperatively (in the post anaesthesia care unit)
Secondary outcome [3] 263203 0
Serum creatinine
Timepoint [3] 263203 0
Postoperatively (in the post anaesthesia care unit) and at 24 hours postoperatively
Secondary outcome [4] 263204 0
Need for mechanical ventilation and its duration
Timepoint [4] 263204 0
For 7 days postoperatively
Secondary outcome [5] 263205 0
Length of hospital stay
Timepoint [5] 263205 0
Total days during hospital admission
Secondary outcome [6] 263206 0
Survival to hospital discharge
Timepoint [6] 263206 0
Total days during hospital admission

Eligibility
Key inclusion criteria
Adult patients having elective liver resection surgery
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patient declines to take part
2. Age less than 18 years
3. Abnormal pre-operative coagulopathy: INR (international normalised ratio) > 1.4, platelet count < 75 x 109/l
4. Severe hepatic insufficiency (bilirubin > 30umol/L, ALP (alkaline phosphatase) >300iu/L, ALT (alanine transaminase) > 50iu/L, albumin < 25g/dL, INR > 1.5
5. Moderate/severe renal impairment: serum creatinine > 200ummol/l
6. Hyperkalaemia (serum potassium > 5.6)
7. American Society of Anaesthesiologists (ASA) physical status IV or V
7. Patients with a known previous allergic reaction to study solutions

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)
All adult patients undergoing elective hepatic resection will be evaluated preoperatively at the anaesthesia pre-admsissions clinic at least 1-2 weeks prior to surgery. Patients will be identified for study entry by the investigators or an anaesthetist or research co-ordinator acting on behalf of the investigators by surveillance of patients in the pre-admissions clinic.

Patients will be identified from their preoperative medical records and surgical notes.

A thorough assessment of the participant’s competence and capacity to make a valid informed decision will be made by one of the study investigators prior to the patient being recruited. All patients will be deemed competent if they:
1. are able to comprehend and retain information relevant to making the decision
2. understand the information and implications of the decision
3. are able to weigh the information in the balance and arrive at a decision Inform consent will then be obtained.

For each patient, an opaque envelope containing a participant number described above will be prepared, sealed and sequentially numbered. On the morning of surgery the anaesthetist will open the envelope and randomised the participant.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
This is a double-blinded clinical trial. Blinding of both Hartmann’s solution 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 labeling/writing on the container that would allow identification of the crystalloid fluid solution. Each 1 litre flask will be labeled with a unique Participant Number to ensure complete blinding. Only the Chief Investigators will know the key to the code to unlock the blinding. The principle investigators at each site will not have access to the key ensuring proper blinding.

The following labeling will be printed on the side of each 1 litre flask:

1. Liver Resection Fluid Clinical Trial
2. Participant Identification Number
3. Expiratory date of fluid solution
4. Contact telephone number

From previous research conducted in patients undergoing elective hepatic resection at Austin Hospital, the mean amount (SD) of intraoperative crystalloid solution administered per patient was 2138 mls (SD = 869.1, Range 1750-6600mls). We will therefore prepare 10 X 1 litres flasks for each patient recruited.

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 90 days, when stored at <25C.

Simple randomisation will be performed by using a randomization table created by a computer software (i.e., computerised sequence generation).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



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

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/04/2010
Actual
1/04/2010
Date of last participant enrolment
Anticipated
Actual
31/01/2013
Date of last data collection
Anticipated
Actual
Sample size
Target
50
Accrual to date
Final
50
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 5247 0
Austin Health - Austin Hospital - Heidelberg

Funding & Sponsors
Funding source category [1] 256478 0
Hospital
Name [1] 256478 0
Austin Hospital
Country [1] 256478 0
Australia
Primary sponsor type
Hospital
Name
Austin Hospital
Address
Department of Anaesthesia, Studley Road, Heidelberg, 3084, Victoria
Country
Australia
Secondary sponsor category [1] 255785 0
Commercial sector/Industry
Name [1] 255785 0
Baxter Healthcare
Address [1] 255785 0
Baxter Healthcare
One Baxter Drive
Old Toongabbie
NSW, 2146
AUSTRALIA
Country [1] 255785 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 258532 0
Austin Hospital Research Ethics Committee
Ethics committee address [1] 258532 0
Austin Hospital, Studley Road, Heidelberg, Victoria, 3084
Ethics committee country [1] 258532 0
Australia
Date submitted for ethics approval [1] 258532 0
27/01/2010
Approval date [1] 258532 0
17/03/2010
Ethics approval number [1] 258532 0
10/Vic Admin/36

Summary
Brief summary
Acid-base disorders are frequently associated with liver dysfunction and may occur in patients undergoing partial liver resection. Liver resection decreases the working liver mass and causes a variable degree of liver insufficiency that in turn, may cause or aggravate metabolic acidosis. The quantitative acid-base effects of fluid therapy during liver resection are unclear with few reported studies.

For patients undergoing liver resection, the most frequently administered intravenous crystalloid (clear) fluids are Hartmann’s solution, Normal Saline, and to a lesser extent, Plasmalyte. Normal Saline is not considered an acceptable fluid for prolonged perioperative administration due to its high chloride content that results in hyperchloremic metabolic acidosis. Therefore, both Hartmann’s Solution and Plasmalyte, being more “balanced” solutions compared to Normal Saline, remain the fluids of choice for patients undergoing hepatic resection. However there are no studies to determine which of these fluid has a more favourable acid-base profile.

We propose to conduct a prospective, multicentre-centre, blinded, randomized non-inferiority trial to test whether Plasmalyte solution is associated with similar or improved metabolic status (non-inferiority) than Hartmann’s solution.

Adult patients undergoing elective hepatic resection will be randomized to receive either Plasmalyte or Hartmann’s solution for all crystalloid fluid therapy during elective liver resection surgery.

Primary aim: to examine the effect of Plasmalyte or Hartmann’s solution on acid-base status (measured by base excess).
Secondary aims: to compare changes in plasma lactate concentration, effect on NGAL (a novel marker for acute kidney injury), need for blood and blood products, need for mechanical ventilation and its duration, length of hospital stay and survival to hospital discharge.

Another factor that may affect acid-base status after liver resection is perioperative kidney injury. In research conducted in the Intensive Care Unit at Austin Hospital, it was found that a new marker for early postoperative kidney injury called NGAL (neutrophil gelatinase associated lipocalin) can be used to predict acute kidney injury in patients undergoing major cardiac surgery. From the published data, the incidence of acute kidney injury after elective hepatic resection is between 10-15%. The value of NGAL after liver resection has not been examined, therefore we also propose to examine if the acid-base status effects of the study fluids have any influence on the incidence of postoperative acute kidney injury.

Number of recruiting hospitals: 3 (Austin Hospital, Monash Medical Centre, Peter MaCallum Cancer Centre)
Number of patients planned for involvement at each hospital: 15- 20
Trial website
N/A
Trial related presentations / publications
Publication: Weinberg L, Pearce B, Sullican R, Siu L, Scurrah N, Tan C, Story D, Christophi C, Nikfarjam M, McNicol L, Bellomo R. The association of Plasmalyte-148 or Hartmann’s solution with metabolic acidosis and complications after liver resection: a multicenter, randomized, non-inferiority trial: Minerva Anestesiol 2015; 81:1288-97
Public notes

Contacts
Principal investigator
Name 30811 0
A/Prof Laurence Weinberg
Address 30811 0
Department of Anaesthesia, Austin Hospital, Studley Road, Heidelberg, 3084, Victoria, Australia
Country 30811 0
Australia
Phone 30811 0
+61394965000
Fax 30811 0
+61394966421
Email 30811 0
laurence.weinberg@austin.org.au
Contact person for public queries
Name 14058 0
A/Prof Dr Laurence weinberg
Address 14058 0
Department of Anaesthesia
Austin Hospital
Studley Road
Heidelberg, 3084, Victoria
Country 14058 0
Australia
Phone 14058 0
+61 3 94965000
Fax 14058 0
+61 3 94596421
Email 14058 0
laurence.Weinberg@austin.org.au
Contact person for scientific queries
Name 4986 0
A/Prof Dr Laurence Weinberg
Address 4986 0
Department of Anaesthesia
Austin Hospital
Studley Road
Heidelberg, 3084, Victoria
Country 4986 0
Australia
Phone 4986 0
+61 3 94965000
Fax 4986 0
+61 3 94596421
Email 4986 0
laurence.Weinberg@austin.org.au

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
SourceTitleYear of PublicationDOI
EmbaseThe effects of plasmalyte-148 vs. Hartmann's solution during major liver resection: A multicentre, double-blind, randomized controlled trial.2015
N.B. These documents automatically identified may not have been verified by the study sponsor.