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Trial registered on ANZCTR


Registration number
ACTRN12615001099516
Ethics application status
Approved
Date submitted
24/09/2015
Date registered
19/10/2015
Date last updated
5/02/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
Haemodynamic Effect of Intravenous Paracetamol during and after Cardiac Surgery
Scientific title
Haemodynamic Effect of Intravenous Paracetamol during and after Cardiac Surgery
Secondary ID [1] 282277 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cardiopulmonary bypass 288813 0
Cardiac surgery 288814 0
Condition category
Condition code
Anaesthesiology 289170 289170 0 0
Anaesthetics
Surgery 289173 289173 0 0
Surgical techniques
Cardiovascular 296628 296628 0 0
Coronary heart disease

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

The insertion of a pulmonary artery catheter (PAC) is required for routine anaesthesia treatment during cardiac 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, a 1g of paracetamol will be administered every 6 hours, for 3 consecutive doses, which is in line with the manufacturer's recommendations. The first dose will be administered on arrival to the operating room, prior to induction of anaesthesia. The second dose will be administered 6 hours after the first, which may be near completion of surgery or in the intensive care unit. The final dose will be 6 hours later in the intensive care unit. The duration of each infusion will be set at 15 minutes.

Paracetamol will be administered in addition to standard care analgesia. In accordance with strict hospital protocols, all doses of paracetamol administered will be recorded or logged on the participants analgesic chart.
Intervention code [1] 286907 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.

For this clinical trial 100 ml Normal Saline 0.9% will be administered every 6 hours over a 15 minute period, for 3 consecutive doses. The first dose will be administered on arrival to the operating room, prior to induction of anaesthesia. The second dose will be administered 6 hours after the first, which may be near completion of surgery or in the intensive care unit. The final dose will be 6 hours later in the intensive care unit. The duration of each infusion will be set at 15 minutes.

In accordance with strict hospital protocols, all doses of saline administered will be recorded or logged on the participants fluid balance chart.

All patients will also receive standard postoperative analgesia.
Control group
Placebo

Outcomes
Primary outcome [1] 289284 0
The primary outcome is a composite outcome using pressure based haemodynamic variables, namely systolic blood pressure, diastolic blood pressure, mean arterial blood pressure. These will be recorded from a arterial line inserted as part of standard care that measure continuous systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure.
Timepoint [1] 289284 0
The primary outcome will be measures at the following peri-operative timepoints using the measurements from the arterial line.

1. Baseline (BL) just after pulmonary artery catheter insertion
2. 5 minutes (T5)
3. 10 minutes (T10)
4. 15 minutes (T15)
5. 30 minutes (T30)
6. Pre-cardiopulmonary bypass
7. Rewarming
8. ICU arrival (ICU 1)
9. ICU 6 hours (ICU 6)
10. ICU 12 hours (ICU 12)
Secondary outcome [1] 302151 0
Cardiac output will be measured by a bolus thermodilution technique using a Swan-Ganz pulmonary artery catheter
Timepoint [1] 302151 0
The secondary outcome will be measured at the following peri-operative timepoints using the measurements from the Swan-Ganz pulmonary artery catheter:

1. Baseline (BL) just after pulmonary artery catheter insertion
2. 5 minutes (T5)
3. 10 minutes (T10)
4. 15 minutes (T15)
5. 30 minutes (T30)
6. Pre-cardiopulmonary bypass
7. Rewarming
8. ICU arrival (ICU 1)
9. ICU 6 hours (ICU 6)
10. ICU 12 hours (ICU 12)
Secondary outcome [2] 302170 0
Cardiac index will be measured by a bolus thermodilution technique using a Swan-Ganz pulmonary artery catheter
Timepoint [2] 302170 0
The secondary outcome will be measured at the following peri-operative timepoints using the measurements from the Swan-Ganz pulmonary artery catheter:

1. Baseline (BL) just after pulmonary artery catheter insertion
2. 5 minutes (T5)
3. 10 minutes (T10)
4. 15 minutes (T15)
5. 30 minutes (T30)
6. Pre-cardiopulmonary bypass
7. Rewarming
8. ICU arrival (ICU 1)
9. ICU 6 hours (ICU 6)
10. ICU 12 hours (ICU 12)
Secondary outcome [3] 302171 0
Plasma paracetamol levels
Timepoint [3] 302171 0
Plasma paracetamol levels will be measured at the following peri-operative timepoints:

1. Baseline (BL) just after pulmonary artery catheter insertion
2. 5 minutes (T5)
3. 10 minutes (T10)
4. 15 minutes (T15)
5. 30 minutes (T30)
6. Pre-cardiopulmonary bypass
7. Rewarming
8. ICU arrival (ICU 1)
9. ICU 6 hours (ICU 6)
10. ICU 12 hours (ICU 12)
Secondary outcome [4] 302172 0
Composite secondary end point of renal biomarkers, which will include including serum and urine NGAL and cystatin C. These renal biomarkers are sensitive indicators of renal injury and inflammation.
Timepoint [4] 302172 0
Serum and urine NGAL and cystatin C levels will be measured at the following peri-operative timepoints:

1. Baseline (BL) just after pulmonary artery catheter insertion
2. 5 minutes (T5)
3. 10 minutes (T10)
4. 15 minutes (T15)
5. 30 minutes (T30)
6. Pre-cardiopulmonary bypass
7. Rewarming
8. ICU arrival (ICU 1)
9. ICU 6 hours (ICU 6)
10. ICU 12 hours (ICU 12)
Secondary outcome [5] 302173 0
Plasma (blood) levels of Pro-inflammatory effects using TNF-a, IL-6 and IL-10.
Timepoint [5] 302173 0
Plasma levels of TNF-a, IL-6 and IL-10 will be measured at the following peri-operative timepoints:

1. Baseline (BL) just after pulmonary artery catheter insertion
2. 5 minutes (T5)
3. 10 minutes (T10)
4. 15 minutes (T15)
5. 30 minutes (T30)
6. Pre-cardiopulmonary bypass
7. Rewarming
8. ICU arrival (ICU 1)
9. ICU 6 hours (ICU 6)
10. ICU 12 hours (ICU 12)
Secondary outcome [6] 302174 0
Core body temperature will be measure via an electronic nasal probe temperature transducer that will be inserted 8-10cm into the nasopharyngeal area.
Timepoint [6] 302174 0
Core body temperature will be measured at the following peri-operative timepoints:

1. Baseline (BL) just after pulmonary artery catheter insertion
2. 5 minutes (T5)
3. 10 minutes (T10)
4. 15 minutes (T15)
5. 30 minutes (T30)
6. Pre-cardiopulmonary bypass
7. Rewarming
8. ICU arrival (ICU 1)
9. ICU 6 hours (ICU 6)
10. ICU 12 hours (ICU 12)
Secondary outcome [7] 302175 0
Time to first postoperative request for opioid treatment, which will be assessed by review of the medical records.
Timepoint [7] 302175 0
This timepoint will commence at the completion of surgery until the first request for opioid treatment.
Secondary outcome [8] 302176 0
Amount of opioid adminstered during stay in ICU, which will be assessed by review of the medical records.
Timepoint [8] 302176 0
This timepoint will commence at the completion of surgery until the end of ICU stay.
Secondary outcome [9] 302177 0
Frequency of inotrope use, which will be assessed by review of the medical records.
Timepoint [9] 302177 0
This timepoint will commence at the completion of surgery until the end of ICU stay.
Secondary outcome [10] 317933 0
Amount of fluids used, which will be assessed by review of the medical records.
Timepoint [10] 317933 0
This timepoint will commence at the completion of surgery until the end of ICU stay.
Secondary outcome [11] 317934 0
Type of surgery
Timepoint [11] 317934 0
This will be collected from the medical records.
Secondary outcome [12] 317935 0
Total volume of administered CPB prime fluids will be collected from the perfusion medical records.
Timepoint [12] 317935 0
Duration of cardiopulmonary bypass which will commences when full cardiopulmonary bypass flows are established and concludes once the patient has separated from bypass and spontaneous circulation has been achieved.
Secondary outcome [13] 317936 0
Baseline EuroSCORE
Timepoint [13] 317936 0
This will be collected from the medical records.
Secondary outcome [14] 317937 0
Baseline Parsonnet indices.
Timepoint [14] 317937 0
This will be collected form the medical records.
Secondary outcome [15] 317938 0
Duration of ICU stay.
Timepoint [15] 317938 0
This will be collected form the medical records.
Secondary outcome [16] 317939 0
Duration of hospital stay.
Timepoint [16] 317939 0
This will be collected from the medical records.
Secondary outcome [17] 317940 0
Renal failure assessed using the international RIFLE criteria for Acute Kidney injury
Timepoint [17] 317940 0
Duration of hospital stay
Secondary outcome [18] 318145 0
Pneumonia that will be assessed using the international criteria of raised white cell count in addition to focal changes on an x-ray.
Timepoint [18] 318145 0
Duration of hospital stay

Eligibility
Key inclusion criteria
1. Adult surgery patients (age >18 years)
2. Cardiac surgery requiring cardiopulmonary bypass
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), consumed within 10 hours of 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 cardiac surgery are evaluated preoperatively at the cardiac 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 50 patients in total, 25 patients in the paracetamol group and 25 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 120mmHg, 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 80%, we require a minimum of 18 patients to be recruited into each group. We will therefore recruit 25 patients in each arm, a total of 50 patients.

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)
VIC
Recruitment hospital [1] 857 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 6671 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 287054 0
Hospital
Name [1] 287054 0
Austin Hospital
Address [1] 287054 0
Department of Intensive Care
15, Studley Road, Heidelberg, Victoria, 3084
Country [1] 287054 0
Australia
Primary sponsor type
Hospital
Name
Austin Hospital
Address
Department of Intensive Care
15 Studley Road, Heidelberg, Victoria, 3084

Australia
Country
Australia
Secondary sponsor category [1] 285836 0
None
Name [1] 285836 0
Address [1] 285836 0
Country [1] 285836 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289083 0
Austin Health Research Ethics Unit
Ethics committee address [1] 289083 0
Austin Health Research Ethics Unit
Austin Health
145 Studley Road
Heidelberg
Victoria, 3084
Ethics committee country [1] 289083 0
Australia
Date submitted for ethics approval [1] 289083 0
26/03/2013
Approval date [1] 289083 0
06/06/2013
Ethics approval number [1] 289083 0
H2013/05006

Summary
Brief summary
There are currently no double-blinded, randomised controlled trials that assess the haemodynamic effects of paracetamol in patients undergoing cardiac surgery. The effects of cardiopulmonary bypass (CPB) on paracetamol pharmacokinetic are also poorly understood.

This study will add to a growing body of evidence evaluating the safety and efficacy of paracetamol use in patients undergoing cardiac surgery.

Hypothesis: Paracetamol (1g IV) has adverse effects on blood pressure in patients undergoing cardiac surgery.

No of patients: 50

No of recruiting hospitals: 1

Randomisation: Patients will be randomised in a 1:1 fashion via a computer generated randomisation program to either paracetamol IV formulation (N=25) or control treatment (normal saline 0.9%) (N=25).

Blinding: This is a double-blinded clinical trial. Surgical teams, intraoperative and postoperative nursing staff, and patients will be blinded to assignment of treatment.
Trial website
Nil
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 39118 0
A/Prof Laurence Weinberg
Address 39118 0
Department of Anaesthesia Austin Hospital, 15 Studley Road Heidelberg, 3084, Victoria
Country 39118 0
Australia
Phone 39118 0
+61 3 94965000
Fax 39118 0
+61 3 94596421
Email 39118 0
laurence.weinberg@austin.org.au
Contact person for public queries
Name 39119 0
A/Prof Laurence Weinberg
Address 39119 0
Department of Anaesthesia Austin Hospital, 15 Studley Road Heidelberg, 3084, Victoria
Country 39119 0
Australia
Phone 39119 0
+61 3 94965000
Fax 39119 0
+61 3 94596421
Email 39119 0
laurence.weinberg@austin.org.au
Contact person for scientific queries
Name 39120 0
A/Prof Laurence Weinberg
Address 39120 0
Department of Anaesthesia Austin Hospital, 15 Studley Road Heidelberg, 3084, Victoria
Country 39120 0
Australia
Phone 39120 0
+61 3 94965000
Fax 39120 0
+61 3 94596421
Email 39120 0
laurence.weinberg@austin.org.au

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