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Trial registered on ANZCTR


Registration number
ACTRN12608000028303
Ethics application status
Approved
Date submitted
15/01/2008
Date registered
18/01/2008
Date last updated
17/11/2009
Type of registration
Prospectively registered

Titles & IDs
Public title
Intravenous paracetamol in patients undergoing major abdominal surgery
Scientific title
The pharmacokinetic, metabolic and safety profile of intravenous paracetamol in adult patients undergoing major abdominal surgery
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Major abdominal surgery 2716 0
sepsis 2717 0
pharamacokinetics and metabolism 2718 0
Condition category
Condition code
Anaesthesiology 2836 2836 0 0
Pain management
Surgery 2837 2837 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intravenous paracetamol, 1g, is given 6 hourly for 3 days in adult patients undergoing major abdominal surgery
Intervention code [1] 2454 0
Treatment: Surgery
Intervention code [2] 2455 0
Treatment: Drugs
Comparator / control treatment
None
Control group
Uncontrolled

Outcomes
Primary outcome [1] 3722 0
Urine levels of paracetamol metbolites at 2, 4, 6 hours
Timepoint [1] 3722 0
After 1st dose and after 1st dose on 3rd day
Primary outcome [2] 3734 0
Blood levels of paracetamol at 0, 10, 20, 40, 60, 90, 120, 240 and 360 minutes
Timepoint [2] 3734 0
After the 1st dose and on 3rd day (after 1st dose)
Secondary outcome [1] 6282 0
blood cytokine levels, IL-6, TNF-a, IL-8, IL-1b, IL-10 and IL-12(p70) will be assayed using multiplex biometric enzyme-linked immunosorbant assay (ELISA)-based immunoassay
Timepoint [1] 6282 0
once daily on postoperative days 1-3
Secondary outcome [2] 6305 0
pain scores
Timepoint [2] 6305 0
once daily on postoperative days 1-3
Secondary outcome [3] 6307 0
'sickness score' scale based on vital signs and biochemical parameters
Timepoint [3] 6307 0
once daily on postoperative days 1-3

Eligibility
Key inclusion criteria
Adults undergoing major abdominal surgery
Minimum age
20 Years
Maximum age
85 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria: history of past or present ethanol or substance misuse; nutritional deficiency; hepatic disease, including history of hepatitis B or C; previous adverse reaction to paracetamol; comedication with enzyme inducing or inhibiting drugs, including barbiturates, phenytoin and rifampicin.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Illness severity score will be used to record the severity of illness/ sepsis if any in the post-operative period
Phase
Not Applicable
Type of endpoint(s)
Pharmacokinetics / pharmacodynamics
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 outside Australia
Country [1] 734 0
New Zealand
State/province [1] 734 0
Otago
Country [2] 735 0
New Zealand
State/province [2] 735 0

Funding & Sponsors
Funding source category [1] 2965 0
Charities/Societies/Foundations
Name [1] 2965 0
HealthCare Otago Charitable Trust
Address [1] 2965 0
C/O Dunedin Hospital
Gt King Street
Dunedin
Dunedin
Country [1] 2965 0
New Zealand
Primary sponsor type
University
Name
Dunedin School of Medicine, University of Otago
Address
Gt King Street
Dunedin
Country
New Zealand
Secondary sponsor category [1] 2676 0
Hospital
Name [1] 2676 0
Dunedin hospital
Gt King Street
Dunedin
Address [1] 2676 0
Dept Anaesthesia & Intensive Care
Dunedin hospital
Gt King St
Dunedin
Country [1] 2676 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 4915 0
Lower South Regional Ethics Committee
Ethics committee address [1] 4915 0
229 Moray Place
Dunedin
Ethics committee country [1] 4915 0
New Zealand
Date submitted for ethics approval [1] 4915 0
01/11/2007
Approval date [1] 4915 0
07/01/2008
Ethics approval number [1] 4915 0
LRS/07/11/039

Summary
Brief summary
Recently, in New Zealand, intravenous paracetamol has become available, and is used for postoperative pain control after major operations. However there are a number of concerns regarding the safety of paracetamol: firstly paracetamol is toxic in overdose because of a toxic metabolite, produced by a minor metabolic pathway; secondly this toxic metabolite is detoxified using glutathione, a substance that may be deficient in fasted patients; and thirdly the major metabolic pathways of paracetamol may be inhibited by cytokines (released by tissue inflammation) resulting in an increase in the toxic metabolite produced by the minor pathway. This raises the possibility of an increased risk of hepatotoxicity in this vulnerable group of patients. Interleukin 1b is known to inhibit the expression of a number of Phase I, Phase II and transporter genes, some of which are involved in paracetamol metabolism. In cultured hepatocytes, expression of UGT1A1 and UGT2B3 mRNA is reduced by IL-6, even in the presence of an inducer (dexamethasone). Exposure to IL-6, and to a lesser extent IL-1b, was associated with decreased expression of sulfotransferases in cultured hepatocytes. In animal models interferon-? has been shown to down regulate P-glycoprotein. In critically ill children with sepsis, CYP activity is reduced in association with increased levels of interleukin 6. Phenytoin metabolism (CYP2C9) is decreased in association with elevated IL-6. In patients with heart failure, reduced activity of CYP1A2 was associated with increased IL-6, and reduced CYP2C19 was associated with increased TNF-a, but CYP2D6 and CYP2E1 were not affected by either cytokine. However, in human hepatocyte cultures, CYP2E1 mRNA had decreased expression under the influence of interferon-?, but had increased expression with IL-4. The down-regulation of hepatic metabolism may be influenced by enzyme induction and species, in addition to being cytokine specific.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 28300 0
Address 28300 0
Country 28300 0
Phone 28300 0
Fax 28300 0
Email 28300 0
Contact person for public queries
Name 11457 0
Mathew Zacharias
Address 11457 0
Dept Anaesthesia & Intensive Care
Dunedin Hospital
Dunedin
Country 11457 0
New Zealand
Phone 11457 0
+64 3 4740999
Fax 11457 0
+64 3 4747650
Email 11457 0
mathew.zacharias@stonebow.otago.ac.nz
Contact person for scientific queries
Name 2385 0
Mathew Zacharias
Address 2385 0
Dept Anaesthesia & Intensive Care
Dunedin Hospital
Dunedin
Country 2385 0
New Zealand
Phone 2385 0
+64 3 4740999
Fax 2385 0
+64 3 4747650
Email 2385 0
mathew.zacharias@stonebow.otago.ac.nz

No information has been provided regarding IPD availability
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