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Trial registered on ANZCTR
Registration number
ACTRN12615001132538
Ethics application status
Approved
Date submitted
24/09/2015
Date registered
27/10/2015
Date last updated
5/04/2019
Date data sharing statement initially provided
5/04/2019
Date results information initially provided
5/04/2019
Type of registration
Retrospectively registered
Titles & IDs
Public title
Haemodynamic Effects Of Intravenous Paracetamol In Patients With Chronic Liver Disease Undergoing Liver Transplantation: A Pilot Study
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Scientific title
Haemodynamic Effects Of Intravenous Paracetamol In Patients With Chronic Liver Disease Undergoing Liver Transplantation: A Pilot Study
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Secondary ID [1]
282513
0
NIL
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Chronic Liver Disease
289173
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Liver Transplantation
289174
0
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Condition category
Condition code
Anaesthesiology
289495
289495
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0
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Anaesthetics
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Surgery
289496
289496
0
0
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Surgical techniques
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Oral and Gastrointestinal
296646
296646
0
0
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Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Intravenous paracetamol (Actavis, North Adelaide, SA)
Paracetamol is one of the most commonly used medications in the world. The intravenous format is the preferred method of administration in the intraoperative and immediate postoperative periods.
In 100mL of solution for infusion, intravenous paracetamol contains the following:
Paracetamol = 1g
Mannitol = 3.91g
Cysteine hydrochloride monohydrate
Dibasic dihydrate sodium phosphate
Sodium hydroxide
Hydrochloric acid
Water for injections
For this clinical trial, intravenous paracetamol will be used once intraoperatively only.
The insertion of a pulmonary artery catheter (PAC) is required for routine anaesthesia treatment during liver surgery. Haemodynamic measurements will be monitored via the PAC. After insertion of the PAC, 100mL paracetamol (containing 1g paracetamol and 3.91g mannitol) will be administered intravenously.
Volume of paracetamol to be administered:
Actavis (North Adelaide, SA) recommends 1g of paracetamol per administration with a maximum of 4g of paracetamol per day. The minimum dose interval is 4 hours. The duration of infusion is 15 minutes.
In this trial, one dose of 1g/100mL IV paracetamol will be administered over 15 minutes. This will be administered post arrival to the operating room, prior to induction of anaesthesia, but after the insertion of the pulmonary artery catheter.
The administration of this trial drug will be electronically logged as per hospital protocol. This will be done regardless of whether the trial drug contains paracetamol as the trial is double-blinded and all research staff will be unaware of the contents of the trial drug until the end of the study. This additional safety measure will be in place to ensure there will be no overdose of paracetamol should the trial drug contain paracetamol.
Additional postoperative pain treatment will be administered to patients via patient controlled analgesia as per routine clinical care.
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Intervention code [1]
287169
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Treatment: Drugs
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Comparator / control treatment
Normal saline 0.9% is an intravenous fluid solution that provides maintenance and replacement of deficits of extracellular fluid. It is commonly used throughout the world as an infusion proving water for hydration for patients undergoing major surgery.
In this trial, one dose of 100mL IV Normal Saline 0.9% will be administered over 15 minutes. This will be administered post arrival to the operating room, prior to induction of anaesthesia, but after the insertion of the pulmonary artery catheter.
The administration of this trial drug will be electronically logged as per hospital protocol. This will be done regardless of whether the trial drug contains paracetamol as the trial is double-blinded and all research staff will be unaware of the contents of the trial drug until the end of the study. This additional safety measure will be in place to ensure there will be no overdose of paracetamol should the trial drug contain paracetamol.
Additional postoperative pain treatment will be administered to patients via patient controlled analgesia as per routine clinical care.
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Control group
Placebo
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Outcomes
Primary outcome [1]
289598
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Composite Primary Outcomes will be measured including:
Systolic blood pressure, diastolic blood pressure, mean arterial blood pressure.
These variables will be measured via the PAC device that will be inserted prior to the start of the trial.
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Assessment method [1]
289598
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Timepoint [1]
289598
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Perioperative:
Baseline (BL) just after pulmonary artery catheter insertion
5 minutes post-infusion (T5)
8 minutes post-infusion (T8)
15 minutes post-infusion (T15)
30 minutes post-infusion(T30)
60 minutes post-infusion (T60)
Postoperative
ICU arrival (ICU 1)
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Secondary outcome [1]
302812
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Cardiac Output
This variable will be measured via the PAC device that will be inserted prior to the start of the trial.
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Assessment method [1]
302812
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Timepoint [1]
302812
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Perioperative:
Baseline (BL) just after pulmonary artery catheter insertion
5 minutes post-infusion (T5)
8 minutes post-infusion (T8)
15 minutes post-infusion (T15)
30 minutes post-infusion(T30)
60 minutes post-infusion (T60)
Postoperative
ICU arrival (ICU 1)
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Secondary outcome [2]
302813
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Cardiac Index
This variable will be measured via the PAC device that will be inserted prior to the start of the trial.
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Assessment method [2]
302813
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Timepoint [2]
302813
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Perioperative:
Baseline (BL) just after pulmonary artery catheter insertion
5 minutes post-infusion (T5)
8 minutes post-infusion (T8)
15 minutes post-infusion (T15)
30 minutes post-infusion(T30)
60 minutes post-infusion (T60)
Postoperative
ICU arrival (ICU 1)
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Secondary outcome [3]
302814
0
Plasma paracetamol levels
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Assessment method [3]
302814
0
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Timepoint [3]
302814
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Perioperative:
Baseline (BL) just after pulmonary artery catheter insertion
5 minutes post-infusion (T5)
8 minutes post-infusion (T8)
15 minutes post-infusion (T15)
30 minutes post-infusion(T30)
60 minutes post-infusion (T60)
Postoperative
ICU arrival (ICU 1)
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Secondary outcome [4]
302815
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Composite biochemistry secondary endpoints:
Renal biomarkers including serum and urine NGAL and cystatin C
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Assessment method [4]
302815
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Timepoint [4]
302815
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Perioperative:
Baseline (BL) just after pulmonary artery catheter insertion
5 minutes post-infusion (T5)
8 minutes post-infusion (T8)
15 minutes post-infusion (T15)
30 minutes post-infusion(T30)
60 minutes post-infusion (T60)
Postoperative
ICU arrival (ICU 1)
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Secondary outcome [5]
302816
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Pro-inflammatory effects using TNF-a, IL-6 and IL-10.
These variables will be measured via analysis of perioperative blood samples using relevant serum assays.
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Assessment method [5]
302816
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Timepoint [5]
302816
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Perioperative:
Baseline (BL) just after pulmonary artery catheter insertion
5 minutes post-infusion (T5)
8 minutes post-infusion (T8)
15 minutes post-infusion (T15)
30 minutes post-infusion(T30)
60 minutes post-infusion (T60)
Postoperative
ICU arrival (ICU 1)
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Secondary outcome [6]
302817
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Core body temperature.
This variable will be assessed using the PAC device, specifically the thermistor catheter
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Assessment method [6]
302817
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Timepoint [6]
302817
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Perioperative:
Baseline (BL) just after pulmonary artery catheter insertion
5 minutes post-infusion (T5)
8 minutes post-infusion (T8)
15 minutes post-infusion (T15)
30 minutes post-infusion(T30)
60 minutes post-infusion (T60)
Postoperative
ICU arrival (ICU 1)
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Secondary outcome [7]
302818
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Liver Function Tests.
This variable will be measured via a serum assay for ALT levels as standard hospital protocol for patients undergoing liver transplantation.
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Assessment method [7]
302818
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Timepoint [7]
302818
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During stay in ICU:
Upon arrival and then daily post-operatively until discharge from ICU
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Secondary outcome [8]
302819
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Time to first postoperative request for opioid treatment.
This variable will be collected via assessed by review of patient medical records.
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Assessment method [8]
302819
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Timepoint [8]
302819
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During stay in ICU: this variable will be calculated as hours between the end of surgery to first request for opioid treatment.
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Secondary outcome [9]
302820
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Amount of opioid adminstered during stay in ICU.
This variable will be collected via assessed by review of patient medical records.
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Assessment method [9]
302820
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Timepoint [9]
302820
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This variable will be calculated as amount (mL) of opioid administered during the stay in ICU and the time-frame for which will be defined as between the end of surgery to the end of ICU stay.
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Secondary outcome [10]
302821
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Frequency of inotrope use.
This variable will be collected via assessed by review of patient medical records.
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Assessment method [10]
302821
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Timepoint [10]
302821
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This variable will be calculated as amount (mL) of inotrope administered during the stay in ICU and the time-frame for which will be defined as between the end of surgery to the end of ICU stay.
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Eligibility
Key inclusion criteria
1. Adult surgery patients (age >18 years)
2. Patients with chronic liver disease requiring liver transplantation
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
Paracetamol use 24 hours prior to surgery (in paracetamol only or in combination therapy)
Pregnancy
Chronic renal impairment (creatinine >250 umol/L)
Chronic liver disease (ALT >200IU/L)
Morbid obesity (BMI >35kg/m2)
Known allergic reaction to IV paracetamol
Consumption of caffeine (e.g. coffee or energy drinks) <10 hours prior to surgery
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Study design
Purpose of the study
Prevention
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
All patients undergoing liver transplantation are evaluated preoperatively at the liver surgery and anaesthesia pre-admissions clinic at least 4 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 principle investigators by surveillance of patients in the pre-admissions clinic.
Allocation concealment will be by sealed opaque envelopes.
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomly assigned to one of two groups using a computer generated random number allocation system with permuted blocks prior to the commencement of the study.
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 4
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Type of endpoint/s
Pharmacokinetics
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Statistical methods / analysis
We will recruit 24 patients in total, 12 patients in the paracetamol group and 12 patients in the control group. This is in keeping with realistic power calculations used in other studies evaluating the haemodynamic effects of IV paracetamol in patients undergoing major surgery.
Sample size for the study was calculated based on our pilot data evaluating patients undergoing cardiac surgery at Austin hospital. With an average blood pressure of 110mmHg, and a SD of 10 mmHg, if we were to demonstrate a mean difference between the paracetamol group and control group of 10mmHg, with a power value of 90%, we require a minimum of 11 patients to be recruited into each group. We will therefore recruit 12 patients in each arm, a total of 24 patients.
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Recruitment
Recruitment status
Completed
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Date of first participant enrolment
Anticipated
1/04/2014
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Actual
29/03/2014
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Date of last participant enrolment
Anticipated
31/12/2016
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Actual
15/03/2017
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Date of last data collection
Anticipated
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Actual
31/03/2017
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Sample size
Target
24
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Accrual to date
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Final
24
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Recruitment in Australia
Recruitment state(s)
VIC
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Recruitment hospital [1]
1015
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Austin Health - Austin Hospital - Heidelberg
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Recruitment postcode(s) [1]
6890
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3084 - Heidelberg
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Funding & Sponsors
Funding source category [1]
287294
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Hospital
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Name [1]
287294
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Austin Hospital
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Address [1]
287294
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Department of Intensive Care
145 Studley Road, Heidelbeg, Victoria, 3084
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Country [1]
287294
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Australia
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Primary sponsor type
Hospital
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Name
Austin Hospital
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Address
Department of Intensive Care
145 Studley Road, Heidelbeg, Victoria, 3084
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Country
Australia
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Secondary sponsor category [1]
286048
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None
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Name [1]
286048
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Address [1]
286048
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Country [1]
286048
0
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
289271
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Austin Health Research Ethics Unit
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Ethics committee address [1]
289271
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Austin Health Research Ethics Unit
Austin Health
145 Studley Road
Heidelberg
Victoria, 3084
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Ethics committee country [1]
289271
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Australia
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Date submitted for ethics approval [1]
289271
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26/03/2013
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Approval date [1]
289271
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06/06/2013
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Ethics approval number [1]
289271
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H2013/05007
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Summary
Brief summary
Background: Intravenous paracetamol is ubiquitously used in hospitals as an antipyretic and analgesic worldwide. It is administered to a wide array of patients including those undergoing major surgeries due to its minimal side effect profile. Previous studies have suggested that 4g/day paracetamol is safe in patients undergoing liver resection surgery, however other authorities recommend that administration be kept at a maximum of 2g/day in patients with hepatic impairment.
There is now a growing body of evidence that supports the safety of paracetamol use even in patients with liver disease. However, there are no studies to date that have investigated the haemodynamic effects of paracetamol in patients with chronic liver disease. Recent studies have provided evidence that paracetamol may cause hypotension in critically ill patients, which may have important clinical implications for patients undergoing major surgery.
The mechanism for this hypotension is unknown but may be attributable to one the stabilizing compounds found in the formulation, mannitol. Mannitol is a known diuretic and even in small quantities can cause episodes of transient hypotension. There is insufficient evidence evaluating the use of paracetamol in the setting of liver transplantation, and importantly there are no pharmacokinetic studies that evaluate safety and efficacy in this setting.
Hypothesis: A single dose of paracetamol (1g IV) has adverse effects on blood pressure in patients with chronic liver disease undergoing liver transplantation surgery.
Study aims: To determine whether paracetamol has any adverse haemodynamic effects in patients with chronic liver disease who are undegoing liver transplantation.
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Trial website
Nil
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Trial related presentations / publications
Nil
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Public notes
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Contacts
Principal investigator
Name
40106
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Dr Laurence Weinberg
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Address
40106
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Department of Anaesthesia Austin Hospital 145 Studley Road Heidelberg, 3084, Victoria
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Country
40106
0
Australia
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Phone
40106
0
+61 3 94965000
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Fax
40106
0
+61 3 94596421
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Email
40106
0
[email protected]
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Contact person for public queries
Name
40107
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Dr Laurence Weinberg
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Address
40107
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Department of Anaesthesia Austin Hospital 145 Studley Road Heidelberg, 3084, Victoria
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Country
40107
0
Australia
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Phone
40107
0
+61 3 94965000
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Fax
40107
0
+61 3 94596421
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Email
40107
0
[email protected]
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Contact person for scientific queries
Name
40108
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Dr Laurence Weinberg
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Address
40108
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Department of Anaesthesia Austin Hospital 145 Studley Road Heidelberg, 3084, Victoria
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Country
40108
0
Australia
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Phone
40108
0
+61 3 94965000
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Fax
40108
0
+61 3 94596421
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Email
40108
0
[email protected]
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
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No/undecided IPD sharing reason/comment
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What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
Documents added manually
Type
Is Peer Reviewed?
DOI
Citations or Other Details
Attachment
Plain language summary
No
Twenty Four participants were randomly assigned to...
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Documents added automatically
Source
Title
Year of Publication
DOI
Dimensions AI
The hemodynamic effects of intravenous paracetamol (acetaminophen) in patients with chronic liver disease undergoing liver transplantation: a pilot study
2021
https://doi.org/10.1186/s13104-021-05749-8
N.B. These documents automatically identified may not have been verified by the study sponsor.
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