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Trial registered on ANZCTR


Trial ID
ACTRN12615001132538
Ethics application status
Approved
Date submitted
24/09/2015
Date registered
27/10/2015
Date last updated
13/01/2016
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
Scientific title
Haemodynamic Effects Of Intravenous Paracetamol In Patients With Chronic Liver Disease Undergoing Liver Transplantation: A Pilot Study
Secondary ID [1] 282513 0
NIL
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Liver Disease 289173 0
Liver Transplantation 289174 0
Condition category
Condition code
Anaesthesiology 289495 289495 0 0
Anaesthetics
Surgery 289496 289496 0 0
Surgical techniques
Oral and Gastrointestinal 296646 296646 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
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.
Intervention code [1] 287169 0
Treatment: Drugs
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.
Control group
Placebo

Outcomes
Primary outcome [1] 289598 0
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.
Timepoint [1] 289598 0
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)
Secondary outcome [1] 302812 0
Cardiac Output

This variable will be measured via the PAC device that will be inserted prior to the start of the trial.
Timepoint [1] 302812 0
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)
Secondary outcome [2] 302813 0
Cardiac Index

This variable will be measured via the PAC device that will be inserted prior to the start of the trial.
Timepoint [2] 302813 0
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)
Secondary outcome [3] 302814 0
Plasma paracetamol levels
Timepoint [3] 302814 0
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)
Secondary outcome [4] 302815 0
Composite biochemistry secondary endpoints:

Renal biomarkers including serum and urine NGAL and cystatin C
Timepoint [4] 302815 0
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)
Secondary outcome [5] 302816 0
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.
Timepoint [5] 302816 0
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)
Secondary outcome [6] 302817 0
Core body temperature.

This variable will be assessed using the PAC device, specifically the thermistor catheter
Timepoint [6] 302817 0
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)
Secondary outcome [7] 302818 0
Liver Function Tests.

This variable will be measured via a serum assay for ALT levels as standard hospital protocol for patients undergoing liver transplantation.
Timepoint [7] 302818 0
During stay in ICU:
Upon arrival and then daily post-operatively until discharge from ICU
Secondary outcome [8] 302819 0
Time to first postoperative request for opioid treatment.

This variable will be collected via assessed by review of patient medical records.
Timepoint [8] 302819 0
During stay in ICU: this variable will be calculated as hours between the end of surgery to first request for opioid treatment.
Secondary outcome [9] 302820 0
Amount of opioid adminstered during stay in ICU.

This variable will be collected via assessed by review of patient medical records.
Timepoint [9] 302820 0
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.
Secondary outcome [10] 302821 0
Frequency of inotrope use.

This variable will be collected via assessed by review of patient medical records.
Timepoint [10] 302821 0
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.

Eligibility
Key inclusion criteria
1. Adult surgery patients (age >18 years)
2. Patients with chronic liver disease requiring liver transplantation
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
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

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
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.
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.
Masking / blinding
Blinded (masking used)
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
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Pharmacokinetics
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.

Recruitment
Recruitment status
Recruiting
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] 1015 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 6890 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 287294 0
Hospital
Name [1] 287294 0
Austin Hospital
Address [1] 287294 0
Department of Intensive Care
145 Studley Road, Heidelbeg, Victoria, 3084
Country [1] 287294 0
Australia
Primary sponsor type
Hospital
Name
Austin Hospital
Address
Department of Intensive Care
145 Studley Road, Heidelbeg, Victoria, 3084
Country
Australia
Secondary sponsor category [1] 286048 0
None
Name [1] 286048 0
Address [1] 286048 0
Country [1] 286048 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289271 0
Austin Health Research Ethics Unit
Ethics committee address [1] 289271 0
Austin Health Research Ethics Unit
Austin Health
145 Studley Road
Heidelberg
Victoria, 3084
Ethics committee country [1] 289271 0
Australia
Date submitted for ethics approval [1] 289271 0
26/03/2013
Approval date [1] 289271 0
06/06/2013
Ethics approval number [1] 289271 0
H2013/05007

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.
Trial website
Nil
Trial related presentations / publications
Nil
Public notes

Contacts
Principal investigator
Name 40106 0
Dr Laurence Weinberg
Address 40106 0
Department of Anaesthesia Austin Hospital 145 Studley Road Heidelberg, 3084, Victoria
Country 40106 0
Australia
Phone 40106 0
+61 3 94965000
Fax 40106 0
+61 3 94596421
Email 40106 0
laurence.weinberg@austin.org.au
Contact person for public queries
Name 40107 0
Dr Laurence Weinberg
Address 40107 0
Department of Anaesthesia Austin Hospital 145 Studley Road Heidelberg, 3084, Victoria
Country 40107 0
Australia
Phone 40107 0
+61 3 94965000
Fax 40107 0
+61 3 94596421
Email 40107 0
laurence.weinberg@austin.org.au
Contact person for scientific queries
Name 40108 0
Dr Laurence Weinberg
Address 40108 0
Department of Anaesthesia Austin Hospital 145 Studley Road Heidelberg, 3084, Victoria
Country 40108 0
Australia
Phone 40108 0
+61 3 94965000
Fax 40108 0
+61 3 94596421
Email 40108 0
laurence.weinberg@austin.org.au